Long-term diabetes can lead to renal injury known as diabetic nephropathy (DN), which is a major cause of end-stage renal disease (ESRD). However, its pathogenesis has not been well explained. Adipose tissue is recognized as an important energy storage device for the body. Interestingly, many studies have shown that adipose tissue can also act as an endocrine organ by secreting a variety of adipokines to maintain homeostasis. Here, we summarize some of the adipokines that have been identified thus far to, more specifically, to emphasize their role in DN progression and propose that the "adipose-renal axis" may be a potential target for the treatment of DN.

Pharmacological treatment of complex pathologies, such as neurodegenerative diseases still represents a major challenge, due to the networked pathways involved in their onset and progression that may require equally complex therapeutic approaches. Polypharmacology, based on the simultaneous modulation of multiple targets involved in the disease, may offer the potential to increase effectiveness and reduce the drawbacks related to the use of drug combinations. Clearly, this approach requires both the knowledge of the systems responsible for disease development and the discovery of new attractive targets to be exploited to design a multitarget drug. Over the last years, an ever increasing interest has focused on the endocannabinoid system, implicated in the modulation of several physiological functions, among which neuroinflammation, a crucial process for most neurodegenerative diseases. In this respect, the cannabinoid receptor subtype 2 represents a promising therapeutic target, being overexpressed in microglia cells and thus involved in neuroinflammation. The indirect modulation of this system through the inhibition of the main enzymes responsible for endocannabinoids metabolism, namely fatty acid amide hydrolase and monoacylglycerol lipase, may also significantly affect neurodegenerative processes. The aim of this review is to give an overview of the opportunities posed by the endocannabinoid system for neurodegenerative diseases management, mainly focusing on the potential for a multitarget strategy.

Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein-coupled receptors, and, to date, four subtypes have been characterized and named A1, A2A, A2B, and A3. In recent years, adenosine receptors, particularly the A2A subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson's and Alzheimer's diseases, multiple sclerosis, and neuropsychiatric conditions. In fact, it has been demonstrated that inhibition of A2A adenosine receptors exerts neuroprotective effects counteracting neuroinflammatory processes and astroglial and microglial activation. The A2A adenosine receptor antagonist istradefylline, developed by Kyowa Hakko Kirin Inc., was approved in Japan as adjunctive therapy for the treatment of Parkinson's disease, and very recently, it was also approved by the US Food and Drug Administration. These findings pave the way for new therapeutic opportunities, so, in this review, a summary of the most relevant and promising A2A adenosine receptor antagonists will be presented along with their preclinical and clinical studies in neuroinflammation related diseases.

In the nervous system, inflammatory responses physiologically occur as defense mechanisms triggered by damaging events. If improperly regulated, neuroinflammation can contribute to the development of chronically activated states of glial cells, with the perpetuation of inflammation and neuronal damage, thus leading to neurological and neurodegenerative disorders. Interestingly, neuroinflammation is associated with the overexpression of the mitochondrial translocator protein (TSPO) in activated glia. Despite the precise role of TSPO in the immunomodulatory mechanisms during active disease states is still unclear, it has emerged as a promising target to promote neuroprotection. Indeed, TSPO ligands have been shown to exert beneficial effects in counteracting neuroinflammation and neuronal damage in several in vitro and in vivo models of neurodegenerative diseases. In particular, the regulation of neurosteroids' production, cytokine release, metabolism of radical oxidative species, and cellular bioenergetics appear to be the main cellular events that underlie the observed effects. The present review aims to illustrate and summarize recent findings on the potential effect of TSPO ligands against neuroinflammation and related neurodegenerative mechanisms, taking into consideration some pathologies of the nervous system in which inflammatory events are crucial for the onset and progression of the disease and attempting to shed light onto the immunomodulatory effects of TSPO.

The translocator protein 18kDa (TSPO) is expressed in the outer mitochondrial membrane and is implicated in several functions, including cholesterol transport and steroidogenesis. Under normal physiological conditions, TSPO is present in very low concentrations in the human brain but is markedly upregulated in response to brain injury and inflammation. This upregulation is strongly associated with activated microglia. Therefore, TSPO is particularly suited for assessing active gliosis associated with brain lesions following injury or disease. For over three decades, TSPO has been studied as a biomarker. Numerous radioligands for positron emission tomography (PET) that target TSPO have been developed for imaging inflammatory progression in the brain. Although [11C]PK11195, the prototypical first-generation PET radioligand, is still widely used for in vivo studies, mainly now as its single more potent R-enantiomer, it has severe limitations, including low sensitivity and poor amenability to quantification. Second-generation radioligands are characterized by higher TSPO specific signals but suffer from other drawbacks, such as sensitivity to the TSPO single nucleotide polymorphism (SNP) rs6971. Therefore, their applications in human studies have the burden of needing to genotype subjects. Consequently, recent efforts are focused on developing improved radioligands that combine the optimal features of the second generation with the ability to overcome the differences in binding affinities across the population. This review presents essential principles in the design and development of TSPO PET ligands and discusses prominent examples among the main chemotypes.

BACKGROUND: Obese individuals have higher rates of cancer incidence and cancer-related mortality. The worse chemotherapy outcomes observed in this subset of patients are multifactorial, including the altered physiology in obesity and its impact on the pharmacokinetics, the possible increased risk of underdosing, and treatment-related toxicity. AIM: The present review aimed to discuss recent data on physiology, providing just an overall perspective, and pharmacokinetic alterations in obesity concerning chemotherapy. We also reviewed the controversies of dosing adjustment strategies in adult and pediatric patients, mainly addressing the use of actual total body weight and ideal body weight. METHODS: This narrative review tried to provide the best evidence to support antineoplastic drug dosing strategies in children, adolescents, and adults. RESULTS: Cardiovascular, hepatic, and renal alterations of obesity can affect the distribution, metabolism, and clearance of drugs. Anticancer drugs have a narrow therapeutic range, and variations in dosing may result in either toxicity or underdosing. Obese patients are underrepresented in clinical trials that focus on determining recommendations for chemotherapy dosing and administration in clinical practice. After considering associated comorbidities, the guidelines recommend that chemotherapy should be dosed according to body surface area (BSA) calculated with actual total body weight, not an estimate or ideal weight, especially when the intention of therapy is the cure. CONCLUSION: The actual total body weight dosing appears to be a better approach to dosing anticancer drugs in both adults and children when aiming for curative results, showing no difference in toxicity and no limitation in treatment outcomes compared to adjusted doses.

BACKGROUND: It is relevant to study the general patterns and to identify non-specific mechanisms of body protective and adaptive reactions violation, which can lead to the various pathological processes and to develop principles for the correction of these disorders. One of the therapy and prevention directions is the search for new medicines. In recent years, new derivatives of pyrimidine bases have been synthesized and studied. Pyrimidine based medicines have a membrane-stabilizing, immunomodulatory effect, normalize metabolic disorders, and increase the oxidative activity of leukocytes. Disruption of the free radical oxidation processes - the generation of reactive oxygen species and lipid peroxidation, including in whole blood and bone marrow, has gained importance in recent years. METHODS: Each reaction was monitored by thin layer chromatography. 1H, 13C, 15N NMR spectra were recorded (chemical shifts were expressed as δ-values). We studied the effect of 6-methyl-3-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione on the generation of reactive oxygen species (ROS) in the whole blood and bone marrow using study of whole blood spontaneous and stimulated chemiluminescence (CL). CL methods make it possible to quickly and easily assess the studied material (whole blood, bone marrow) effect on free radical oxidation. Using CL methods it is possible to reveal the presence of medicines pro- or antioxidant properties, opening up new possibilities in the search for substances with antioxidant properties and comparison their activity. RESULTS: Alkylation of 6-methylpyrimidine-2,4(1H,3H)-dione by 2-chloromethylthiirane in protic solvents in the presence of alkali leads to the formation of an N-thietane derivative. NMR spectroscopy showed that 6-methylpyrimidine-2,4(1H,3H)-dione is alkylated at position 3 The oxidation reactions of N-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione were studied and it was determined that, depending on the excess of the oxidizing agent and the duration of the process, N-(1-oxothietan-3-yl)- or N-(1,1-dioxothietan-3-yl)pyrimidine-2,4(1H,3H)-diones are formed. The effect of free radical oxidation processes of new biologically active pyrimidine-2,4(1H,3H)-diones were studied. CONCLUSION: New pyrimidine-2,4(1H,3H)-diones increase the general adaptive capabilities of the body and have protective effects in extreme conditions.

Type 2 diabetes mellitus (T2DM) is one of the main causes of mortality and morbidity worldwide. It leads to various long-term complications such as diabetic nephropathy. Diabetes nephropathy is the leading cause of renal failure in patients with chronic kidney diseases undergoing hemodialysis. Hence preventing the development and progression of diabetic nephropathy is one of the main goals in the management of patients with type 2 diabetes. Sodium-glucose cotransporter 2 inhibitor of empagliflozin is a potent anti-hyperglycemic agent. In addition, it has been shown to have some pharmacologic potentials to provide renoprotective effects in patients with T2DM. In current study, we review the available clinical data on the potential renoprotective effects of this drug from a mechanistic and molecular viewpoint.

Cardiovascular diseases (CVD) are the primary cause of death globally. Activation of oxidative stress and inflammatory pathways are contributory to the development of CVD. Pharmacological activities of vanillic acid have been investigated suggesting that they may have therapeutic utility clinically. Given its phenolic nature, the anti-inflammatory and antioxidant properties of vanillic acid have been shown to exert potent inhibitory activity against Adenosine Monophosphate-Activated Protein Kinase (AMPK), Nuclear Factor Kappa B (NF-κB), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Nod-like receptor family protein (NLRP), Toll like receptors (TLRs), Mitogen-Activated Signaling Proteins (MAPK) and Mammalian Target of Rapamycin (mTOR) signaling pathways. Vanillic acid has been shown to block pro-inflammatory cytokines and suppress inflammatory cascades. The inhibitory impact of vanillic acid on reactive oxygen species (ROS) and nitric oxygen synthase (iNOS) expression has also been demonstrated. Vanillic acid reduces oxidative-related markers such as superoxide dismutase (SOD), glutathione (GSH), Heme Oxygenase 1 (HO-1), and glutathione peroxidase (GSH-Px). Here, we review the cardioprotective effects and mechanisms of action of vanillic acid in CVD. Current potential applications of vanillic acid in CVD are discussed with respect to preclinical and clinical studies.

BACKGROUND: Due to the importance of amiodarone-induced hyperthyroidism in patients with heart failure, the purpose of the present systematic review and meta-analysis was to determine the prevalence of thyroid dysfunction (hypothyroidism and hyperthyroidism) in patients with heart disease who received amiodarone. METHODS: Electronic databases including Scopus, PubMed, Web of science, and Science Direct were searched by two investigators. To assess the heterogeneity between the included studies, the chi-square χ2 test (α=0.05) and I2 index were used. Additionally, a random-effects model with 95% CI was used to estimate the pooled prevalence of thyroid dysfunction due to heterogeneity of the studies. To identify the cause of heterogeneity, a meta-regression analysis was employed. All analyses were performed using Stata ver13 (Stata Corporation, College Station, TX, USA). RESULTS: The pooled prevalence of hypothyroidism was 23.43% (95% CI: 11.54-35.33) and hyperthyroidism was 11.61% (95% CI: 7.20-16.02). There was no significant association between the prevalence of hypothyroidism and the year of the study (P=0.152), sample size (P=0.805), and mean age of subjects in the sample groups (P=0.623). However, there was a significant association between the prevalence of hyperthyroidism and the year of the study (p=0.037), but no statistically significant association between either the prevalence of hyperthyroidism and sample size (P=0.425), or the prevalence of hyperthyroidism and the mean age of subjects in the sample groups (P=0.447). CONCLUSION: The prevalence of thyroid dysfunction in patients with cardiac arrhythmias receiving amiodarone was considerable. Extreme care should be exercised to improve monitoring of any thyroid abnormalities that may arise in patients receiving amiodarone.

Atherosclerotic cardiovascular diseases remain the leading cause of morbidity and mortality worldwide despite all efforts made towards their management. Other than targeting the traditional risk factors for their development, scientific interest has been shifted towards epigenetic regulation, with microRNAs (miRs) being at the forefront. MiR-126, in particular, has been extensively studied in the context of cardiovascular diseases. Downregulated expression of this miR has been associated with highly prevalent cardiovascular risk factors such as arterial hypertension and diabetes mellitus. At the same time, its diagnostic and prognostic capability concerning coronary artery disease is still under investigation, with up-to-date data pointing towards a dysregulated expression in a stable disease state and acute myocardial infarction. Moreover, a lower expression of miR-126 may indicate a higher disease complexity, as well as an increased risk for future major adverse cardiac and cerebrovascular events. Ultimately, overexpression of miR-126 may emerge as a novel therapeutic target in atherosclerotic cardiovascular diseases due to its potential in promoting therapeutic angiogenesis and anti-inflammatory effects. However, the existing challenges in miR therapeutics need to be resolved before translation to clinical practice.

The posterior urethral valve (PUV) is one of the main causes of congenital obstruction of the lower urinary tract in pediatrics. Its occurrence, although rare, can cause chronic kidney disease (CKD), with frequent progression to end stage kidney disease. Therefore, the development of new diagnostic strategies, such as biomarkers, is crucial to better assess the prognosis of patients with PUV. We aimed to review the literature on traditional and new biomarkers in PUV. For that, searches were performed in PubMed/MEDLINE, Scopus and SciELO databases. To systematize the search, terms such as Posterior Urethral Valve, Prognosis, Biomarkers and variations described in the Medical Subject Headings (MeSH) database were used. The literature showed new biomarkers of disease prognosis, with emphasis on inflammatory cytokines, proteomics and genomics techniques, as well as classic biomarkers, focusing on serum creatinine and urine osmolality. As for biomarkers recently described in the literature, the 12PUV, a set of 12 fetal urinary peptides that accurately predicted postnatal kidney function in fetuses with PUV, stands out. Similarly, oxidative stress markers, inflammatory cytokines and components of the renin-angiotensin system (RAS), when increased, were indicative of severe kidney outcomes. Genetic alterations also correlated to worse prognosis among patients with PUV, with emphasis on RAS polymorphisms and, specifically, those affecting the angiotensin-converting enzyme (ACE) and the angiotensin II receptors types 1 and 2 (AGTR1 and AGTR2) genes. Considering the severity of the PUV condition, the identification of sensitive and cost-effective biomarkers, beyond improving diagnosis, may favor the investigation of new therapeutic strategies.

Chitosan is derived from chitin polysaccharide, the main component of crustacean shells. Chitosan is a biocompatible, nontoxic, and biodegradable polymer soluble in acidic solutions. It is widely used in the medical and pharmaceutical fields. Antimicrobial activities of chitosan against different bacterial, fungal, and viral pathogens have been considered one of its attractive properties, making chitosan valuable for biological applications, including textiles, food, tissue engineering, agriculture, and environmental protection. Additionally, chitosan has beneficial effects on livestock, poultry, fish, and crustaceans, which can enhance immunity, improve feed conversion, and promote growth. However, the water solubility of chitosan influences antimicrobial capabilities, limiting its application. In the present work, we reviewed the preparation, factors affecting antimicrobial activity, morphological structure, antimicrobial mechanism, and application of chitosan derivatives, and the problems and prospects were pointed out. Collectively, this review provided an update on the application of chitosan derivatives and their potential for further advanced applications in the antimicrobial field.

BACKGROUND: PROTACs is an emerging technique that addresses the disease causing proteins by targeting protein degradation. PROTACs molecules are bifunctional small molecules that simultaneously bind to the protein of interest (POIs) and an E3 ligase followed by ubiquitination and degradation of the protein of interest by the proteasome. OBJECTIVE: PROTACs technology offers many advantages over classical inhibition such as PROTACs molecules can target intracellular proteins regardless of their function and have good tissue distribution. They are capable to target mutated and overexpressed proteins, thus potent molecules with high degradation selectivity can be designed. Moreover, PROTACs molecules can target the undruggable proteome which makes almost 85% of human proteins. Several PROTACs based compounds have exhibited high therapeutic potency and some of them are currently under clinical trials. METHODS: Current article gives a comprehensive overview of the current development of PROTACs based anticancer compounds along with the structure-activity relationship of the reported molecules. RESULTS: The development in PROTACs based compounds and related research regarding medicinal chemistry are one of the most active and hot topics for research. CONCLUSION: It is believed that the current review article can be helpful to understand the logical design of more efficacious PROTACs based molecules with less toxicity and more selectivity.

OBJECTIVE: To evaluate the effectiveness of Partnership Care Model (PCM) on health-related quality of life (HRQoL) in adults with chronic diseases. METHOD: Data Sources/Study Setting: Existing literature dealing with the effect of HRQoL on chronic patients according to the HRQoL outcomes based on SF36 questionnaires. STUDY DESIGN: Systematic review and meta-analysis. DATA COLLECTION: Medline, PubMed, Scopus, Web of Science, Embase, Cochran database and Persian databases including SID, Magiran, Iranmedex, Irandoc were searched according to the MeSH terms until May 15, 2022. Data analysis was made by using the random effects model and heterogeneity by I2 index and all analyses were made by STATA vers.16 (Stata Corp, College Station, Texas, USA). PRINCIPAL FINDINGS: Three studies were included in the meta-analysis. Computing the common effect size there was a significant intervention effect in all HRQoL dimensions, physical and mental subscales as well as HRQoL total score. The results showed that there was significantly moderate to high substantial heterogeneity between studies except for vitality (I2=45.9%, P=0.157) and physical functioning (I2=30.9%, P=0.235) dimensions. CONCLUSIONS: According to the results of the study and realizing the efficiency of PCM on the eight dimensions of quality of life of chronic patients, it can be stated that this national model which is in line with the culture and context of Iran is effective, simple, efficient and reliable. It can be used in promotion and improvement of various dimensions of HRQoL in chronic diseases.

Protein lysine methylation is a significant protein post-translational modification (PTMs), and has a key function in epigenetic regulation. Protein lysine methyltransferase (PKMTs) mainly catalyze the lysine methylation of various core histones, but also catalyze a few non-histone proteins. It has been observed that aberrant activity of PKMTs has been found in many cancers and other diseases, and some PKMTs inhibitors have been discovered and progressed to clinical trials. This field developed rapidly and has aroused great interest. In this paper, we reviewed the biochemical and biological activities of PKMTs and their association with various cancers. Selective small-molecule inhibitors including their chemical structure, structure-activity relationship, and in vitro/vivo studies are also be described with the aim of providing ideas for the discovery highly potent, selective PKMTs inhibitors.

COVID-19 is caused by SARS-CoV-2 and leads to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severely affected cases. However, most of the affected cases are mild or asymptomatic. Cannabinoids (CBs) such as tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on G-protein-coupled receptors called CB1 and CB2, have anti-inflammatory effects. Many published studies show that CBs are effective in various inflammatory disorders, viral infections, and attenuation of ALI and ARDS. Therefore, the aim of the present narrative review was to summarize the possible immunological role of CBs in COVID-19. The effects of CBs are controversial, although they have beneficial effects via CB2 receptors and adverse effects via CB1 receptors against ALI, ARDS, and hyperinflammation, which are hallmarks of COVID-19. The present narrative review has shown that CBs effectively manage ALI and ARDS by suppressing pro-inflammatory cytokines, which are common in COVID-19. Therefore, CBs may be used to manage COVID-19 because of their potent anti-inflammatory effects with suppression of pro-inflammatory cytokines and inhibition of inflammatory signaling pathways.

Among the aromatic heterocycle rings, pyrazole -a five-membered ring with two adjacent nitrogen atoms in its structure- has been postulated as a potent candidate in the pharmacological context. This moiety is an interesting therapeutic target covering a broad spectrum of biological activities due to its presence in many natural substances. Hence, the potential of the pyrazole derivatives as antitumor agents has been explored in many investigations, showing promising results in some cases. In this sense, breast cancer, which is already the leading cause of cancer mortality in women in some countries, has been the topic selected for this review, which covers a range of different research from the earliest studies published in 2003 to the most recent ones in 2021.

: The sartans are a new class of antihypertensive drugs as angiotensin II receptor blockers which possess plenty of ad-vantages in treating hypertension and related pathologies. This review describes the clinical treatment, side effects, and po-tential therapeutic effects of sartans from 1995 to date. The synthesis, structural-activity and molecular docking with Angi-otensin Type 1 receptor of imidazole derivatives, benzimidazole derivatives and other compounds are also described. With clear Structure-Activity Relationship and abundant pharmacological effects, some types of novel Angiotensin Type 1 re-ceptor antagonists are emerging gradually for further research in the meantime.

Targeting the tumor microenvironment is a promising strategy to prevent metastasis, overcome acquired drug resistance, and improve the therapeutic effect. Hypoxia is one of the characteristics of the tumor microenvironment, which is mainly regulated by hypoxia-inducible factors. Hypoxia-inducible factors (HIFs) including HIF-1α, HIF-2α, and HIF-3α, of which HIF-2α has assumed a more important role in tumor hypoxia environment. It has been demonstrated that HIF-2α plays an important role in tumor diseases, including renal cell carcinoma, breast cancer, non-small cell lung cancer, and gastric cancer, among others. Therefore, targeting HIF-2α has become one of the important strategies for treating cancers. HIF-2α inhibitors can be divided into two categories: specific inhibitors and non-specific inhibitors. The former includes synthetic monomer compounds and traditional Chinese medicine extracts. In this review, we summarized, classified, and discussed current research on the structure, structure-activity relationship (SAR), and pharmacology of HIF-2α inhibitors, which is helpful to the rational design of effective drugs for various types of malignant tumors.

Diabetes is a chronic disease state in which the pancreas fails to secrete sufficient insulin, resulting in elevation of the blood glucose levels. As one of the most prevalent diseases worldwide, diabetes is recognized as a global health concern that, if undiagnosed or untreated, can lead to serious and life-threatening complications, such as kidney failure, cardiovascular disease and diabetic retinopathy. Despite progress in the diagnosis of diabetes, limitations still exist with current analytical techniques and, therefore, the development of precise sensing devices for on-site, real-time detection of diabetes is needed. Biosensors have contributed significantly in the field of the diabetes healthcare, due to their cost-effectiveness, portability, ease of use, and rapid assay time. Recently, there has developed a preference for the utilization of aptamers over antibodies in designing biosensors. Aptasensors, biosensors made with aptamers, offer potential in the diagnosis of diabetes. Aptamers, due to having lower molecular weight, low price, and stability over a wide temperature range and pH range, their in vitro synthesis, and the ability to refold after being removed from denaturing conditions compared to antibodies, have some distinctive characteristics as well as diverse types, such as optical FNA-based biosensors, colorimetric biosensors, fluorescent biosensors and electrochemical FNA-based biosensors. With this in mind, we highlight the recent developments and novel perspectives in the field of aptasensor design to quantitatively monitor diabetes biomarkers. Finally, some results are highlighted to offer a basis for future design of aptasensor kits for diabetes diagnosis.

Inhibition of histone deacetylases (HDACs) has proven to be an effective strategy for cancer therapy. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It is proposed an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in both preventing resistance to treatment and potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDACi. Representative classes of reported hybrid HDACis are reviewed here with the purpose of shedding light on the design of novel hybrid HDACis for cancer therapy.

For several years, blood pressure control and blocking of the renin-angiotensin system (RAS) represented the cornerstones of CKD treatment. Cardiovascular outcome trials with sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (DM) suggested that these agents can effectively delay the progression of CKD in these individuals. A major nephroprotective effect of canagliflozin was also shown in a renal outcome trial in patients with proteinuric diabetic CKD. The Study-to-Evaluate-the-Effect-of-Dapagliflozin-on-Renal-Outcomes-and-Cardiovascular-Mortality-in-Patients-With-Chronic-Kidney-Disease (DAPA-CKD) is a recent milestone in the field, as it included patients with both diabetic and non-diabetic proteinuric CKD and showed impressive reduction in the primary renal outcome of CKD progression, as well as the risk of hospitalization for heart failure and all-cause mortality on top of standard-of-care treatment. These benefits were consistent for patients with diabetic and non-diabetic CKD, including patients with ischemic or hypertensive nephropathy and glomerulonephritis (IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy). Based on the above, relevant guidelines should accommodate their recommendations to implement treatment with SGLT-2 inhibitors for CKD patients.

In the last decade, selective modulators of type-2 cannabinoid receptor (CB2) have become a major focus to target endocannabinoid signaling in humans. Indeed, heterogeneously expressed within our body, CB2 actively regulates several physio-pathological processes, thus representing a promising target for developing specific and safe therapeutic drugs. If CB2 modulation has been extensively studied since the very beginning for the treatment of pain and inflammation, the more recent involvement of this receptor in other pathological conditions has further strengthened the pursuit of novel CB2 agonists in the last five years. Against this background, here we discuss the most recent evidence of the protective effects of CB2 against pathological conditions, emphasizing central nervous system disorders, bone and synovial diseases, and cancer. We also summarize the most recent advances in the development of CB2 agonists, focusing on the correlation between different chemical classes and diverse therapeutic applications. Data mining includes a review of the CB2 ligands disclosed in patents also released in the last five years. Finally, we discuss how the recent elucidation of CB2 tertiary structure has provided new details for the rational design of novel and more selective CB2 agonists, thus supporting innovative strategies to develop effective therapeutics. Our overview of the current knowledge on CB2 agonists provides pivotal information on the structure and function of different classes of molecules and opens possible avenues for future research.

BACKGROUND: Inflammatory bowel diseases (IBD), mainly Ulcerative colitis (UC) and Crohn's disease (CD), are recurrent idiopathic non-infectious chronic diseases widely diffused worldwide and characterized by moderate to severe mucosal damage. OBJECTIVE: This study aims to review the literature of the last 10 years to photograph preclinical and clinical data on the use of nutraceuticals in the prevention and treatment, combined with the conventional drugs, of IBD. METHOD: PubMed, MEDLINE, Embase, Web of Science, and ClinicalTrials.gov were used to search for the most recent publications on in vitro, in vivo, and clinical evidence on IBD and nutraceuticals, which were then assessed based on the originality and scientific rigor of the studies. RESULTS: In the last decade, the interest in new healthy or therapeutic complementary or alternative approaches to conventional drugs in IBD has grown inexorably, as well as the incidence of these pathologies and the knowledge of their etiopathogenesis. In this context, a growing development of new nutraceutical products with a consequent increase in pre-clinical studies has been observed. However, this panorama does not yet translate into adequate clinical studies that can effectively endorse what was observed in pre-clinical studies; many of them are mostly aimed at resolving diseases related to IBD rather than IBD itself. CONCLUSION: Despite the promising pre-clinical data about nutraceuticals and IBD, we are still very far from being able to postulate an adequate nutraceutical treatment of these pathologies and further studies are necessary to support this hypothesis.

2-oxazolidinone is well known as a pharmacophore for antibacterial agents represented by two marketed medicines, Linezolid and Tedizolid. On the other hand, there are growing reports on the various biological activities of 2-oxazolidinones beyond antibacterial activities. Therefore, in this review, we provide an overview of the progress of this untraditional area of 2-oxazolidinones in the past 10 years (2011-2021).

Tri and Tetra-substituted Methanes (TRSMs) are a significant structural motif in many approved drugs and prodrugs. There is increasing use of TRSM units in medicinal chemistry, and many derivatives are specifically designed to make drug-target interactions through new chemical space around TRSM moiety. In this perspective, we describe synthetic challenges for accessing a range of functionalized selective TRSMs and their molecular mechanism of action, especially as anti-infectives. Natural anti-infectives like (+)-Bionectin A, B, (+)-Gliocladine C, Balanocarpol having TRSMs selectively and effectively bind to target proteins in comparison to planar motif having more sp2 carbons perhaps due to conformation which reduces the penalty for conformational entropy with the enhancement of three-dimensionality. Properties of repurposed TRSMs like Almitrine, Ifenprodil, Baricitinib and Remdesivir with their recent progress in Covid-19 therapeutics with their mode of action are also delineated. This perspective is expected to deliver a user guide and reference source for scientists, researchers and academicians in pursuing newly designed TRSMs as therapeutics.

BACKGROUND: Matrix metalloproteinases (MMPs), also known as metalloproteinases, are enzymes that degrade proteins and require the presence of active metal atoms. There are more than 20 types of MMPs, and they promote cell migration through the proteolytic degradation of extracellular basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM). In other words, they decompose most of the components related to the ECM, in their roles as key enzymes in cellular and pathophysiological events in the body. INTRODUCTION: Zn2+-containing endo-type peptidases directly degrade and remodel the ECM region in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins in the ECM and the basement membranous region, which are the supporting structures of cells. METHODS: This review describes the developments in the research examining the general and selective inhibitors for MMP associated with various human diseases over the past 20 years in terms of structure remodeling, substrate-recognizing specificities, and pharmacological applicability. RESULTS: Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa, while MMP-9 is termed as gelatinase-B with a 92 kDa. Both of these play a key role in this action. Therefore, both enzymatic expression levels coincide during the onset and progression of diseases. Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP-9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance that inhibits MMPs would be very important for preventing and treating various MMP-dependent diseases. CONCLUSION: Considerable research has examined MMP inhibitors, but most of these have been synthetic compounds. Research using natural products as MMP inhibitors has only recently become a subject of interest. This review intends to discuss recent research trends regarding the physiological properties, functions, and therapeutic agents related to MMPs.

BACKGROUND: Protein kinase inhibitors have become one of the most successful classes of small-molecule drugs during the last decades. In modern drug discovery, considering 'drug-like' physicochemical and pharmacokinetic properties as early as possible in drug design is widely acknowledged as an important strategy to reduce drug attrition rates. METHODS: In this review, clinically approved 25 protein kinase inhibitors and their key analogues reported in medicinal chemistry literature were compared for their biological, physicochemical, and pharmacokinetic properties. Although there is no common trajectory to follow through complex drug discovery campaigns, knowledge of the structure-activity relationship obtained from the successful lead optimization studies might be extended to other drug design efforts. RESULTS: Among more than 70 protein kinase inhibitors clinically approved around the world, the structure-activity relationships of 25 inhibitors and their key analogues are compiled from medicinal chemistry literature, in which detailed results from the 'lead-to-candidate' stage are available with associated property data. For the other inhibitors, such information has not been disclosed in the literature, or the available data is limited and not sufficient to provide clear structural analysis. CONCLUSION: The structure-property relationships summarized for 25 inhibitors and their analogues illustrate general guidelines for lead optimization and candidate selection, and this information could be extended for better property-based drug design in the future.

Treatment of various diseases, especially cancer treatment, includes the potential use of different types of nanoparticles and nanostructures as drug carriers. However, searching for the less toxic and more efficient therapy requires further progress wherein recent developments in medicine increasingly include the use of various advanced nanostructures. Their more successful application might be achieved by leveling imbalances between the potentiality of different nanostructures and demands required for their safe use. Biocompatibility, biodegradability, prolonged circulation time and enhanced accumulation and uptake by cells are some of the key preconditions for their usage in efficient drug delivery. Thanks to their greatly tunable functions, they are major building blocks for manufacturing novel materials. Nevertheless, given that their toxicity is questionable their practical application is challenging. Hereof, before entering in the sphere of human consumption it is of critical importance to perform more studies regarding their toxicity and drug distribution. This review emphasizes some recent advances in the field of nanomedicine employing different kinds of conventionally used nanoparticles as well as novel nanoparticles and nanostructures. Special emphasis is placed on micro/nanomotors (MNMs) discussing their opportunities, limitations, challenges and possible applications in drug delivery and outlining some perspectives in nanomedicine area.

The in-depth intersection between nanoscience and oncology comes from the fact that nanomaterials are in a similar dimension to basic biomolecules. Drug delivery systems (DDSs), which are either targeted to a particular site and are intended for the controlled release in a particular position, have been studied extensively at the nanoscale and are by far, the most advanced technology in the area of nanoparticle applications. This, consequently lead to the improvement and development of convenient administration routes, lower toxicity, fewer side effects, and extended drug life cycle. Carbon nanomaterials (CNMs) with favorable size and unique fluorescence properties, which was considered an ideal candidate to transport or deliver therapeutic drugs to specific targets in a controlled manner. The development of DDSs based on them constitutes an interesting topic in highly effective and universal therapies to achieve better therapeutic outcomes and reduce the side effects of malignancies. In this review, the cutting-edge progress of CNMs in DDSs was comprehensively summarized. Additionally, the emphasis was placed on the applications of CNMs including fullerene, graphene, carbon nanotubes (CNTs), carbon dots (CDs), and nano-diamonds (NDs) in drug delivering. Further, we gave some insights into the future direction and foreseeable challenges of DDSs based on CNMs used in cancer therapy, which we hope these inspirations in DDSs associated with anti-cancer therapy will provide perspectives in designing new drugs for further tumor treatment.

BACKGROUND: Eph receptors tyrosine kinase (RTK) were identified in 1987 from hepatocellular carcinoma cell lines and were the largest known subfamily of RTK. Eph receptors can be divided into two categories, EphA and EphB, based on their structure and receptor-ligand specificity. EphA can be divided into 10 species (EphA 1-10), and EphB into 6 species (EphB1-6). Similarly, the ligands of Eph receptors are Ephrins. Ephrins also can be divided into Ephrin A and Ephrin B, of which there are five species(Ephrin-A1-5) and three species(Ephrin-B1-3). Among the Eph receptors, EphA1 has been the least studied so far. As far as we know, Eph receptors are involved with multiple pathologies, including cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, neurological disease, and inhibition of nerve regeneration after injury. There is a link between EphA1, integrin and ECM- related signal pathways. Ephrin-A1 is a ligand of the EphA1 receptor. EphA1 and ephrin-A1 functions are related to tumor angiogenesis. EphA1 and ephrin-A1 also play roles in gynecological diseases. Ephrin-A1 and EphA1 receptor regulate follicular formation, ovulation, embryo transport, implantation and placental formation, which are of great significance for the occurrence of gynecological tumor diseases. EphA1 has been identified as an oncoprotein in various tumors, and is associated with the prognosis of a variety of tumors in recent years. EphA1 is considered a driver gene in tumor genomics. There are significant differences in EphA1 expression levels in different types of normal tissues and tumors, and even in different stages of tumor development, suggesting its functional diversity. Changes at the gene level in cell biology are often used as biological indicators of cancer, known as biomarkers, which can be used to provide diagnostic or prognostic information and are valuable for improving the detection, monitoring and treatment of tumors. However, few prognostic markers can selectively predict clinically significant tumors with poor prognosis. These malignancies are more likely to progress and lead to death, requiring more aggressive treatment. Currently available treatments for advanced cancer are often ineffective, and treatment options are mainly palliative. Therefore, early identification and treatment of those at risk of developing malignant tumors are crucial. Although pieces of evidence have shown the role of EphA1 in tumorigenesis and development, its specific mechanism is still unknown to a great extent. OBJECTIVE: This review reveals the changes and roles of EphA1 in many tumors and cancers. The change of EphA1 expression can be used as a biological marker of cancer, which is valuable for improving tumor detection, monitoring and treatment, and can be applied to imaging. Studies have shown that structural modification of EphA1 could make it an effective new drug. EphA1 is unique in that it can be considered a prognostic marker in many tumors and is of important meaning for clinical diagnosis and operative treatment. At the same time, the study of the specific mechanism of EphA1 in tumors can provide a new way for targeted therapy. METHODS: Relevant studies were retrieved and collected through the PubMed system. After determining EphA1 as the research object, by analyzing research articles on EphA1 in the PubMed system in recent 10 years, we found that EphA1 was closely connected with the occurrence and development of tumors, and further determined the references according to the influencing factors for review and analysis. RESULTS: EphA1 has been identified as a cancer protein in various tumors, such as hepatocellular carcinoma, nasopharyngeal carcinoma, ovarian cancer, gastric cancer, colorectal cancer, clear cell renal cell carcinoma, esophageal squamous cell carcinoma, breast cancer, prostate cancer and uveal melanoma. EphA1 is abnormally expressed in these tumor cells, which mainly plays a role in cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, nervous system diseases and gynecological diseases. In a narrow sense, EphA1 is especially effective in breast cancer in terms of gynecological diseases. However, the specific mechanism of EphA1 leading to the change of cancer cells in some tumors is not clear, which needs further research and exploration. CONCLUSION: RTK EphA1 can be used as a biomarker for tumor diagnosis (especially a prognostic marker), an indispensable therapeutic target for new anti-tumor therapies, and a novel anti-tumor drug.

The development of clinically viable metformin analogs is a challenge largely to be overcome. Despite being an extremely efficient drug for the treatment of type 2 diabetes mellitus, multiple studies were conducted seeking to improve its hypoglycemic activity or to ameliorate aspects such as the low oral absorption and the incidence of gastrointestinal side effects. Furthermore, efforts have been made to attribute new activities, or even to expand the pre-existing ones, that could enhance its effects in the diabetes, such as pancreas-protective, antioxidant, and anti-inflammatory activities. In this manuscript, we describe the analogs of metformin developed in the last three decades, highlighting the lack of computationally based rational approaches to guide their development. We also discuss this is probably a consequence of how unclear the mechanism of action of the parent drug is and highlight the recent advances towards establishment of the main molecular target(s) for metformin. We also explored the binding of metformin, buformin and phenformin to the mitochondrial respiratory chain complex I through molecular docking analyses and reviewed the prospects of applying computational tools to improve the success in the development of such analogs. Therefore, it becomes evident the wide range of molecular targets, as well as the multiple activities displayed by metformin, make this drug a promising prototype for the development of novel entities, particularly for the treatment of type 2 diabetes mellitus.

Several epigenome studies reported the ability of genes to modulate the lipogenic, and glucogenic pathways during insulin signaling as well as the other pathways involved in the cardiometabolic diseases. Epigenetic plasticity and oxidative stress are interrelated in the pathophysiology of the insulin resistance (IR) and cardiometabolic disease conditions. The aim of this review is to ascertain the previous research evidences pertinent to the role of epigenome and the variations of histone and non-histone proteins during cardiometabolic disease conditions, and insulin signaling finally to develop effective disease-based epigenetic biomarkers and epigenetics-based chromatic therapy. Several public databases including 'PubMed, National Library of Medicine, and Medline, and google scholar' were searched for the peer-reviewed & published reports. This study delineated the consistent body of evidences regarding the epigenetic alterations of DNA/histone complexes pertinent to oxidative stress, insulin signaling, metabolic cardiomyopathy, and endothelial dysfunction in the patients with cardiometabolic diseases, T2DM. It has been described that both DNA methylation as well as the post-translational histone alterations across visceral and subcutaneous adipose tissue could facilitate gene transcription to modulate the inflammation, lipogenesis and adipogenesis as complex network of chromatinmodifying enzymatic proteins involved in the defensive insulin signaling across vasculature in the patients with cardiometabolic diseases. Resveratrol, vornistat, trichostatin, and apabetalone are reported to have significant implications as epigenetic modulators. Based on the epigenetic alterations, a wide-range of protein/gene markers such as interleukin-4 (IL-4), interferon-γ (IFNγ) genes may be considered as biomarkers in these patients due to their ability for polarization of immune cells involved in tissue inflammation and atherosclerosis. Hence, it is crucial to unravel the cell specific epigenetic information in advance in order to develop individual risk assessment strategies for chromatin modifying therapies in the patients with cardiometabolic diseases.

BACKGROUND: STAT3 (signal transducer and activator of transcription 3) is a member of the STAT family of proteins that function as signal transducers and transcription factors. Previous research has demonstrated its importance in cell proliferation, differentiation, apoptosis, and immunological and inflammatory responses. Targeting the STAT3 protein has recently been hailed as a viable cancer therapeutic method. Even though none of these inhibitors have yet been exploited in clinical cancer therapy, a small number have made them into clinical trials, leading researchers to explore more promising inhibitors. METHODS: Based on the mechanism of STAT3 activation, several types of STAT3 inhibitors were described and summarized according to their origins, structures, bioactivity and mechanism of action. Direct inhibition of STAT3 mainly targeted one of the three distinct structural regions of the protein, namely the SH2 domain, the DNA binding domain, and the coiled-coil domain. RESULTS: The progress in STAT3 inhibitor discovery from 2010 to 2021 is comprehensively summarized in this review. STAT3 inhibitors are mainly classified into small molecule inhibitors, natural product inhibitors, and peptides/peptidomimetics. Moreover, it also covers relevant analogues, as well as their core framework. CONCLUSION: Small-molecule inhibitors of STAT3 like BP-1-102 and BTP analogues displayed great potential against various cancers, while natural products, as well as peptide and peptidomimetics, also showed promising application. Therefore, STAT3 has become a promising target with great research value, and the development of STAT3 inhibitors may provide more therapeutic strategies for STAT3-related diseases.

Immune checkpoints are vital molecules and pathways of the immune system with defined roles of controlling immune responses from being destructive to the healthy cells in the body. They include inhibitory receptors and ligands which keep in check the recognition of most of the cancers by the immune system. This happens when proteins on the surface of T cells called immune checkpoint proteins identify partner proteins on the cancer cells and bind to them sending brake signals to the T cells to evade immune attack. However, drugs called immune checkpoint inhibitors block checkpoint proteins from binding to their partner proteins thereby inhibiting the brake signals from being sent to T cells. This eventually allows the T cells to destroy cancer cells and arbitrate robust tumor regression. Many such inhibitors have already been approved and many are in various developmental stages. The well-illustrated inhibitory checkpoints include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Though many molecules blocking these checkpoints have shown promise in the treatment of many malignancies, there is yet limited success of such treatment options in terms of the immune response in majority of the patients. In this backdrop, exploration of new pathways and next-generation inhibitors becomes imperative for development of more responsive and effective immune checkpoint therapy. Owing to the complex biology and unexplored ambiguities in the mechanistic aspects of immune checkpoint pathways, analysis of the activity profile of new drugs is the subject of strenuous investigation. We herein report the recent progress in the development of new inhibitory pathways, potential therapeutics and delineate the developments based on their merit. Further, the ensuing challenges towards the development of efficacious checkpoint therapies and the impending opportunities are also discussed.

Bronchial asthma is the most common chronic respiratory illness, the incidence of which continues to increase annually. Currently, effective treatments for CS-resistant asthma and severe asthma are still lacking, and new therapeutic regimens are urgently required. PI3Kδ is a key enzyme in hematopoietic cells and represents a major target for oncology and inflammatory disease (particularly respiratory disease, asthma and COPD). In the case of respiratory disease, the ability to inhibit PI3Kδ in the lungs shows a higher safety and therapeutic index relative to systemic inhibition. In recent years, paradigm shifts have occurred in inhalation therapeutics for systemic and topical drug delivery, due to the favorable properties of lungs including their large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including a non-invasive route of administration, low metabolic activity, a controlled environment for systemic absorption and the ability to avoid first bypass metabolism. In this review, we focus on the discovery and development of inhaled drugs targeting PI3Kδ for asthma, by focusing on their activity and selectivity, in addition to their potential in drug design strategies using inhaled administration.

BACKGROUND: As an important determinant in drug discovery, the accurate analysis and acquisition of pharmacokinetic parameters is very important for the clinical application of drugs. At present, the research and development of new drugs mainly obtain their pharmacokinetic parameters through data analysis, physiological model construction and other methods, but the results are often quite different from the actual situation, needing more manpower and material resources. OBJECTIVE: We mainly discuss the application of machine learning technology in the prediction of pharmacokinetic parameters, which are mainly related to the quantitative study of drug absorption, distribution, metabolism and excretion in the human body, such as bioavailability, clearance, apparent volume of distribution and so on. METHOD: This paper first introduces the pharmacokinetic parameters, the relationship between the quantitative structure-activity relationship model and machine learning, then discusses the application of machine learning technology in different prediction models, and finally discusses the limitations, prospects and future development of the machine learning model in predicting pharmacokinetic parameters. RESULTS: Unlike traditional pharmacokinetic analysis, machine learning technology can use computers and algorithms to speed up the acquisition of pharmacokinetic parameters to varying degrees. It provides a new idea to speed up and shorten the cycle of drug development, and has been successfully applied in drug design and development. CONCLUSION: The use of machine learning technology has great potential in predicting pharmacokinetic parameters. It also provides more choices and opportunities for the design and development of clinical drugs in the future.

Cysteine (Cys) is a semi-essential nutrient amino acid, which plays an important role in cells through endogenous production and various transport systems. Intracellular Cys can be used as a precursor of protein synthesis to maintain cell homeostasis and is used to generate sulfur-containing substances, including glutathione (GSH), hydrogen sulfide (H2S), and taurine. There have been quite a few reports that Cys is related to tumor occurrence and development, and its level is closely related to tumor proliferation, invasion, and metastasis. Moreover, it helps in maintaining the tumor redox balance and increasing drug resistance. This review aims to summarize the production and metabolism of Cys and its role in tumors, with special emphasis on the potential therapeutic value of Cys in tumors to improve the quality of life of cancer patients.

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia and associated with multiple organ systems complications. The incidence and prevalence of diabetes are increasing in an epidemic proportion worldwide. In addition to environmental factors, some epigenetic and post-translational modifications have critical roles in the pathogenesis of diabetes and its complications. Reversible covalent modification such as SUMOylation by SUMO (Small Ubiquitin-like Modifier) has emerged as a new mechanism that affects the dynamic regulation of proteins. In this review, we initially focus on the function of SUMO and SUMOylation. Subsequently, we assess the potential effects of this process in the pathogenesis of type 1 and 2 diabetes mellitus.

Organophosphate compounds are regarded as a class of pesticides that are used in farming. Their extensive use, especially in developing countries, is a serious public health problem. Numerous studies have shown the effects of these toxins on various parts of the human and other vertebrates' bodies, including the cardiovascular, hepatobiliary, renal, and reproductive systems. Curcumin is a polyphenol compound obtained from the rhizome of the Curcuma longa. Curcumin has been known as a dietary spice, food additive, and traditional medicine since many years ago. In recent decades, the medicinal characteristics, clinical aspects, and biological activity of Curcumin have been extensively examined. The most examined positive characteristics of Curcumin are its anti-inflammatory and anti-oxidant qualities. This review will deal with the pharmacological properties of Curcumin as well as an update of currently available studies in terms of Curcumin's uses and function against organophosphate pesticides-induced toxicity on different human organs.

It is a common practice to take into consideration: age, diabetes, smoking, treated and untreated systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol for the prediction of atherosclerosis and stroke. There are, however, ultrasound markers in use for the assessment of atherosclerosis and the evaluation of stroke risk. Two areas of investigation are of interest: the carotid artery and the intracranial arterial circulation. Again, within the domain of the carotid artery, two ultrasonic markers have attracted our attention: intima media thickness of the carotid artery and the presence of carotid plaque with its various focal characteristics. In the domain of intracranial circulation, the presence of arterial stenosis and the recruitment of collaterals are considered significant ultrasonic markers for the above-mentioned purpose. On the other hand, a series of serum, urine and tissue biomarkers are found to be related to atherosclerotic disease. Future studies might address the issue of whether the addition of proven ultrasonic carotid indices to the aforementioned serum, urine, and tissue biomarkers could provide the vascular specialist with a better assessment of the atherosclerotic load and solidify their position as surrogate markers for the evaluation of atherosclerosis and stroke risk.

Phenolic acids are now receiving a great deal of interest as pervasive human dietary constituents that have various therapeutic applications against chronic and age-related diseases. One such phenolic acid that is being utilized in traditional medicine is chlorogenic acid (CGA). It is one of the most readily available phytochemicals that can be isolated from the leaves and fruits of plants such as coffee beans (CoffeaarabicaL.), apples (Malus spp.), artichoke (Cynara cardunculus L.), carrots (Daucus carota L.), betel (Piper betle L.), burdock (Arctium spp.) and so on. Despite its low oral bioavailability (about 33%), CGA has drawn considerable attention due to its wide range of biological activities and numerous molecular targets.Several studies have reported that the antioxidant and antiinflammatory potential of CGA mainly account for its broad-spectrum pharmacological attributes. CGA has been implicated in exerting beneficial role against dysbiosis by encouraging the growth of beneficial GUT microbes. At biochemical level its therapeutic action is mediated by free radical scavenging efficacy, modulation of glucose and lipid metabolism, down-regulation of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α),interleukin-6 (IL-6), IL-1β, and interferon gamma (IFN-γ), upregulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and inhibition ofthe activity of nuclear factor- κβ (NF-κβ) and thus help inmanagement of diabetes, cardiovascular diseases, neurodegenerative disorder, cancer, hypertension etc. This review highlights the natural sources of CGA, its bioavailability, metabolism, pharmacotherapeutic potential and underlying mechanisms of action for clinical usefulness of CGA in the management of health disorders.

Dihydrochalcones are a class of secondary metabolites, possessing several biological properties such as antitumor, antioxidant, antibacterial, antidiabetic, estrogenic, anti-inflammatory, antithrombotic, antiviral, neuroprotective, and immunomodulatory properties; therefore, they are currently considered promising candidates in the drug discovery process. This review intends to debate their pharmacological actions with particular attention to their antitumor activity against a panel of cancer cell lines and to the description of the inhibition mechanisms of cell proliferation such as the regulation of angiogenesis, apoptosis, etc.

Human parasitic infections cause a combined global mortality rate of over one million people per annum and represent some of the most challenging diseases for medical intervention. Current chemotherapeutic strategies often require prolonged treatment, coupled with subsequent drug-induced cytotoxic morbidity to the host, while resistance generation is also a major concern. Metals have been used extensively throughout the history of medicine, with more recent applications as anticancer and antimicrobial agents. Ruthenium metallotherapeutic antiparasitic agents are highly effective at targeting a range of key parasites, including the causative agents of malaria, trypanosomiasis, leishmaniasis, amoebiasis, toxoplasmosis and other orphan diseases, while demonstrating lower cytotoxicity profiles than current treatment strategies. Generally, such compounds also demonstrate activity against multiple cellular target sites within parasites, including inhibition of enzyme function, cell membrane perturbation, and alterations to metabolic pathways, therefore reducing the opportunity for resistance generation. This review provides a comprehensive and subjective analysis of the rapidly developing area of ruthenium metal- based antiparasitic chemotherapeutics, in the context of rational drug design and potential clinical approaches to combatting human parasitic infections.

BACKGROUND: Kidney transplant patients frequently suffer from Chronic Kidney Disease associated with Mineral Bone Disease (CKD-MBD), a complex condition that affects mainly kidney transplant patients. Post-transplantation bone disease is complex, especially in patients with pre-existing metabolic bone disorders that are further affected by immunosuppressive medications and changes in renal allograft function. Main biochemical abnormalities of mineral metabolism in kidney transplantation (KTx) include hypophosphatemia, hyperparathyroidism (HPTH), insufficiency or deficiency of vitamin D, and hypercalcemia. OBJECTIVE: This review aims to summarize the pathophysiology and main biomarkers of CKD-MBD in KTx. METHODS: A comprehensive and non-systematic search in PubMed was independently made, emphasizing biomarkers in mineral bone disease in KTx. RESULTS: CKD-MBD can be associated with numerous factors, including secondary HPTH, metabolic dysregulations before KTx, and glucocorticoid therapy in post-transplant subjects. Fibroblast growth factor 23 (FGF23) reaches normal levels after KTx with good allograft function, while calcium, vitamin D, and phosphorus, ultimately result in hypercalcemia, persistent vitamin D insufficiency, and hypophosphatemia, respectively. As for PTH levels, there is an initial tendency of a significant decrease, followed by a rise due to secondary or tertiary HPTH. In regard to sclerostin levels, there is no consensus in the literature. CONCLUSION: KTx patients should be continuously evaluated for mineral homeostasis and bone status, both in cases with successful kidney transplantation and those with reduced functionality. Additional research on CKD-MBD pathophysiology, diagnosis, and management is essential to guarantee long-term graft function, better prognosis, good quality of life, and reduced mortality for KTx patients.

Cephalosporins are β-lactam antibiotics, classified into five generations and extensively used in clinical practice against infections caused by Gram-negative pathogens, including Enterobacteriaceae and P. aeruginosa. Commercially, conventional pharmaceutical forms require high doses to ensure clinical efficacy. Additionally, β-lactam resistance mechanisms, such as the production of enzymes (called extended-spectrum β-lactamases) and the low plasma half-life of these antibiotics, have been challenging in clinical therapy based on the use of cephalosporins. In this context, its incorporation into nanoparticles, whether organic or inorganic, is an alternative to temporally and spatially control the drug release and improve its pharmacokinetic and pharmacodynamic limitations. Considering this, the present review unites the cephalosporins encapsulated into organic and inorganic nanoparticles against resistant and nonresistant enterobacteria. We divide cephalosporin generation into subtopics in which we discuss all molecules approved by regulatory agencies. In addition, changes in the side chains at positions R1 and R2 of the central structure of cephalosporins for all semisynthetic derivatives developed were discussed and presented, as the changes in these groups are related to modifications in pharmacological and pharmacokinetic properties, respectively. Ultimately, we exhibit the advances and differences in the release profile and in vitro activity of cephalosporins incorporated in different nanoparticles.

Seven-membered heterocyclic compounds are important drug scaffolds because of their unique chemical structures. They widely exist in natural products and show a variety of biological activities. They have been used commonly in central nervous system drugs in the past 30 years. In the past decade, many studies have been conducted on their activities, including antitumor, antibacterial, etc. Herein, we summarize the research advances in different kinds of seven-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur heteroatoms with antitumor, antisepsis, and anti-inflammation activities in the past ten years, which are expected to be beneficial to the development and design of novel drugs for the corresponding indications.

BACKGROUND: MicroRNAs modify protein expression at the post-transcriptional level, and their circulating levels may help identify the underlying molecular pathways. OBJECTIVE: The purpose of this study was to assess the differential expression of microRNAs related to myocardial cell energy substrate, autophagy, and ischaemia in chronic and acute heart failure (HF). METHODS: In this case-control study, we studied 19 patients with acute HF (AHF) and 19 patients with chronic HF (CHF). Basic demographic and clinical characteristics were collected from the patients upon arrival, at 48 hours, and at 120 hours. Blood samples for microRNAs measurements (miR-22, -92a, and -499), B-type natriuretic peptide (BNP), C reactive protein, and high sensitivity cardiac troponin I, were collected at all study points. In this study, we included subjects with a left ventricular ejection fraction of <40%. RESULTS: At baseline, circulating miR-22 levels were 1.9-fold higher (p<0.001), miR-92a levels were 1.25-fold higher (p=0.003), and miR-499 were 5-times lower (p<0.001) in AHF compared to CHF. Interestingly, circulating miR-499 was found to be associated with BNP levels (r=0.47, p=0.01). At follow-up, there was a stepwise increase in the levels of all three examined microRNAs (miR-22, p=0.001, miR-92a, p=0.001, and miR-499, p<0.001) for AHF but not for CHF subjects. CONCLUSION: MicroRNAs -22, -92a, and -499 are differentially expressed in chronic and acute HF subjects. MicroRNA signatures are also differentially expressed up to the discharge of the patients. These findings may have important implications for diagnosis, progression, and treatment of patients with chronic and acute heart failure.

The author requested to revise the acknowledgements section of the following article [1]. In this correction, the acknowledgements have been revised in the article entitled "Diversity and Functionality of Mycobacterial Mycolic Acids in Relation to Host-pathogen Interactions" in the journal Current Medicinal Chemistry, 2017, 24(38), 4267-4278. Details of corrections are provided here. The original article can be found online at http://dx.doi.org/10.2174/0929867324666170823130445 We regret any errors and apologize to the readers. Original ACKNOWLEDGEMENTS This work was supported by National Science Centre (Poland) under grant no. 2016/21/B/NZ7/01771 and 2013/11/B/NZ6/01304. Corrected ACKNOWLEDGEMENTS This work was supported by National Science Centre (Poland) under grant no. 2013/11/B/NZ6/01304.

The incidence of malignant tumors is rising rapidly and tends to be in the younger, which has been one of the most important factors endangering the safety of human life. Ultrasound micro/nanobubbles, as a noninvasive and highly specific antitumor strategy, can reach and destroy tumor tissue through their effects of cavitation and acoustic perforation under the guidance of ultrasound. Meanwhile, micro/nanobubbles are now used as a novel drug carrier, releasing drugs at a target region, especially on the prospects of biomaterial-modified micro/nanobubbles as a dual modality for drug delivery and therapeutic monitoring. Successful evaluation of the sonoporation mechanism(s), ultrasound parameters, drug type, and dose will need to be addressed before translating this technology for clinical use. Therefore, this paper collects the literature on the experimental and clinical studies of ultrasound biomaterial-modified micro/nanobubbles therapy in vitro and in vivo in recent years.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine properties released by various immune and non-immune cells. It contributes to the pathogenesis of many inflammatory, autoimmune diseases and malignant tumors. OBJECTIVE: Our study aimed to investigate the role of betaine in the modulation of MIF-mediated oxidative stress, inflammation, and fibrogenesis during toxic kidney damage induced by thioacetamide (TAA). METHODS: The experiment is performed on wild-type and knockout MIF-/- C57BL/6 mice. They are randomly divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/- + Bet; TAA-group, treated with TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/- + TAA+Bet group. After eight weeks of treatment, animals are sacrificed and kidney samples are taken to determine oxidative stress parameters, proinflammatory cytokines, profibrogenic factors, and histopathology of renal tissue. RESULTS: In MIF-/-mice, TAA decreases malondialdehyde (MDA) concentration, IL-6, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB) and increases superoxide dismutases (SOD) and catalase (CAT) activities, as well as glutathione (GSH) content in kidneys, compared to TAA group. Betaine alleviates the mechanism of MIF-mediated effects in TAA-induced nephrotoxicity, reducing MDA, IL-6, TNF-α, TGF-β1, and PDGF-BB, and increasing SOD and CAT activity, as well as GSH levels. CONCLUSION: MIF mediates TAA-induced nephrotoxicity by increasing oxidative stress, inflammation, and profibrogenic mediators. MIF-targeted therapy could potentially alleviate oxidative stress and inflammation in the kidney, as well as pathohistological changes in renal tissue, but the exact mechanism of its action is not completely clear. Betaine alleviates MIF nephrotoxic effects by increasing the antioxidative capacity of kidney cells, and decreasing lipid peroxidation and cytokine production in the renal tissue. It suggests that betaine can be used for the prevention of kidney damage.

BACKGROUND: Neuropathic pain (NP) is a complex symptom related to nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed because of the unsatisfactory efficacy and the side effects of the currently available drugs. Among all the approved drugs for chronic NP, voltage- gated calcium channel (VGCC) α2δ subunit ligands, also known as gabapentinoids, are among the first-line treatment and represent a class of efficacious and relatively safe therapeutic agents. However, new strategies are still needed to be explored due to the unsatisfied response rate. OBJECTIVE: The aim of the study is to review the latest status of the discovery and development of gabapentinoids for the treatment of chronic NP by covering both the marketed and the preclinical/clinical ones. Moreover, it aims to analyze the structure-activity relationship (SAR) of gabapentinoids to facilitate the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit. METHODS: We searched PubMed Central, Embase, Cochrane Library, Web of Science, Scopus, and Espacenet for the literature and patents on diabetic peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia, voltage-gated calcium channel α2δ subunit and related therapeutic agents from incipient to June 10, 2021. The SAR of gabapentinoids was analyzed by pharmacophore modeling using the Phase module in the Schrödinger suite. RESULTS: A variety of gabapentinoids were identified as VGCC α2δ ligands that have ever been under development to treat chronic NP. Among them, four gabapentinoids are marketed, one is in the active late clinical trials, and eight have been discontinued. Pharmacophore models were generated using the phase module in the Schrödinger suite, and common pharmacophores were predicted based on pharmacophoric features and analyzed. CONCLUSION: The latest progress in the discovery and development of gabapentinoids for the treatment of chronic NP was reviewed. Moreover, the structure-activity relationship (SAR) of gabapentinoids has been analyzed by pharmacophore modeling, which will be valuable for the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.

BACKGROUND: Recent studies have indicated that epigallocatechin gallate (EGCG) benefits a variety of neurological insults. This study was performed to investigate the neuroprotective effect of EGCG after brachial plexus root avulsion in SD rats. METHODS: One hundred twenty SD rats were randomized into the following three groups: an EGCG group, an Avulsion group, and a Sham group. There were 40 rats in each group. EGCG (100 mg/kg, i.p.) or normal saline was administered to rats immediately following the injuries. The treatment was continued from day 1 to day 7, and the animals were sacrificed on days 3, 7, 14, and 28 post-surgery for the harvesting of spinal cord samples for Nissl staining, immunohistochemistry (caspase-3, p-JNK, p-c-Jun), and western blot analysis (p-JNK, JNK, p-c-Jun, c-Jun). RESULTS: EGCG treatment caused significant increases in the percentage of surviving motoneurons on days 14 and 28 (p<0.05) compared to the control animals. On days 3 and 7 after avulsion, the numbers of caspase-3-positive motoneurons in the EGCG-treated animals were significantly fewer than in the control animals (p<0.05). The numbers of p- JNK-positive motoneurons and the ratio of p-JNK/JNK were no significant differences between the Avulsion group and the EGCG-treated group after injury at any time point. The numbers of p-c-Jun-positive motoneurons and the ratio of p-c-Jun/c-Jun were significantly lower in the EGCG-treated group compared with the Avulsion group at 3d and 7d after injury (p<0.05). CONCLUSION: Our results indicated that motoneurons were protected by EGCG against the cell death induced by brachial plexus root avulsion, and this effect was correlated with inhibiting c-Jun phosphorylation.

The efficacy and tolerability of tubulin binding agents are hampered by their low specificity for cancer cells like most clinically used anticancer agents. To improve specificity, tubulin binding agents have been covalently conjugated to agents that target cancer cells to give actively targeted drug conjugates. These conjugates are designed to increase uptake of the drug by cancer cells while having limited uptake by normal cells, thereby improving efficacy and tolerability. Approaches used include an attachment to small molecules, polysaccharides, peptides, proteins, and antibodies that exploit the overexpression of receptors for these substances. Antibody targeted strategies have been the most successful to date, with six such examples having gained clinical approval. Many other conjugate types, especially those targeting the folate receptor, have shown promising efficacy and toxicity profiles in pre-clinical models and in early-stage clinical studies. Presented herein is a discussion of the success or otherwise of the recent strategies used to form these actively targeted conjugates.

BACKGROUND: Carvacrol, a plant phenolic monoterpene, is largely employed as food additive and phytochemical. OBJECTIVE: We aimed to assess the lipid lowering and protective effects of carvacrol in vitro using cellular models of hepatic steatosis and endothelial dysfunction. We also investigated if and how the binding of carvacrol to albumin, the physiological transporter for small compounds in the blood, might be altered by the presence of high levels of fatty acids (FAs). METHODS: Hepatic FaO cells treated with exogenous FAs mimic hepatosteatosis; endothelial HECV cells exposed to hydrogen peroxide are a model of endothelial dysfunction. In these models, we measured spectrophotometrically lipid accumulation and release, lipoperoxidation, free radical production, and nitric oxide release before and after treatment with carvacrol. The carvacrol binding to albumin in the presence or absence of high levels of FAs was assessed by absorption and emission spectroscopies. RESULTS: Carvacrol counteracted lipid accumulation and oxidative stress in hepatocytes and protected endothelial cells from oxidative stress and dysfunction. Moreover, high levels of FAs reduced the binding of carvacrol to albumin. CONCLUSION: The results suggest the good potential of carvacrol in ameliorating dysfunction of hepatic and endothelial cells in vitro. High levels of circulating FAs might compete with carvacrol for binding to albumin thus influencing its transport and bio-distribution.

Major Depressive Disorder is a chronic, recurring, and potentially fatal disease, affecting up to 20% of the global population. Since the monoamine hypothesis was proposed more than 60 years ago, only a few relevant advances have been made, with very little disease course changing from a pharmacological perspective. Moreover, since the negative efficacy of novel molecules is frequently reported in studies, many pharmaceutical companies have put new studies on hold. Fortunately, relevant clinical studies are currently being performed extensively, developing immense interest among universities, research centers, and other public and private institutions. Depression is no longer considered a simple disease but a multifactorial one. New research fields are emerging, occurring a paradigm shift, such as the multi-target approach beyond monoamines. In this review, we summarize antidepressant drug discovery aiming to shed some light on the current state-of-the-art clinical and preclinical advances to face this increasingly devastating disease.

Janus Kinase (JAK), a nonreceptor protein tyrosine kinase, has emerged as an excellent target through research and development since its discovery in the 1990s. As novel small-molecule targeted drugs, JAK inhibitor drugs have been successfully used in the treatment of rheumatoid arthritis (RA), myelofibrosis (MF), and ulcerative colitis (UC). With the gradual development of JAK targets in the market, JAK inhibitors have also received considerable feedback in the treatment of autoimmune diseases, such as atopic dermatitis (AD), Crohn's disease (CD), and graft-versus-host disease (GVHD). This article reviews the research progress of JAK inhibitor drugs, focusing on the existing JAK inhibitors in the market and some JAK inhibitors in clinical trials currently. In addition, the synthesis of various types of JAK inhibitors and the effects of different drug structures on drug inhibition and selectivity are summarized.

The process by which cells selectively remove damaged organelles or proteins is called autophagy. Chaperone-mediated autophagy (CMA) is a type of autophagy that degrades proteins containing the KFERQ pentapeptide in cells. CMA can degrade damaged or excess proteins and therefore plays an important role in maintaining protein balance in cells. CMA can also play a regulatory role by degrading key proteins in life activities, such as lipid and glucose metabolism. In this review, we introduce the CMA process and described the current commonly used CMA detection methods. In addition, we describe the role of CMA in glucose and lipid metabolism. Finally, we summarize the current role of CMA in metabolic diseases such as diabetic nephropathy (DN), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) and discuss the role of CMA as a potential therapeutic target for metabolic diseases.

A homomultimeric radioligand is composed of multiple identical ligands connected to the linker and radionuclide to detect a variety of overexpressed receptors on cancer cells. Multimer strategy holds great potential for introducing new radiotracers based on peptide and monoclonal antibody (mAb) derivatives in molecular imaging and therapy. It offers a reliable procedure for the preparation of biological-based targeting with diverse affinities and pharmacokinetics. In this context, we provide a useful summary and interpretation of the main results by a comprehensive look at multimeric radiopharmaceuticals in nuclear oncology. Therefore, explanations for the strategy mechanisms and the main variables affecting the biodistribution results will be explained. The discussion is followed by highlights of recent work in the targeting of various types of receptors. The consequences are expressed based on comparing some parameters between monomer and multimer counterparts in each relevant section.

BACKGROUND: Cancer is the second leading cause of death worldwide. Many anticancer drugs are commercially available, but lack of selectivity, target specificity, cytotoxicity, and development of resistance lead to serious side effects. Several experiments have been going on to develop compounds with minor or no side effects. OBJECTIVE: This review mainly emphasizes synthetic strategies, SAR studies, and mechanism of action if thiazole, benzothiazole, and imidazothiazole-containing compounds as anticancer agents. METHODS: Recent literature related to thiazole and thiazole-related derivatives endowed with encouraging anticancer potential is reviewed. This review emphasizes contemporary strategies used for the synthesis of thiazole and related derivatives, mechanistic targets, and comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency thiazole-based anticancer drug candidates. RESULTS: Exhaustive literature survey indicated that thiazole derivatives are associated with properties of inducing apoptosis and disturbing tubulin assembly. Thiazoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogenmediated activity. Furthermore, thiazole derivatives have been found to modulate critical targets, such as topoisomerase and HDAC. CONCLUSION: Thiazole derivatives seem to be quite competent and act through various mechanisms. Some of the thiazole derivatives, such as compounds 29, 40, 62, and 74a with IC50 values of 0.05 μM, 0.00042 μM, 0.18 μM, and 0.67 μM, respectively, not only exhibit anticancer activity, but they also have lower toxicity and better absorption. Therefore, some other similar compounds could be investigated to aid in the development of anticancer pharmacophores.

BACKGROUND: Although chemotherapy is predominantly used for cancer treatment, it can be ineffective, and can induce serious side effects and lead to chemoresistance. It is essential to discover novel drugs that can enhance the antitumor activity and at the same time counteract the severe side effects, of chemotherapy. The substance P (SP)/neurokinin-1 receptor (NK-1R) interaction system is known to play a key role in the pathogenesis of cancer. Studies with NK-1R antagonists (such as aprepitant) denote that the NK-1R is a potential target for the treatment of cancer. Aprepitant drug combined with major chemotherapeutic drugs has shown the potential to increase antitumor activity and decrease side effects. OBJECTIVE: Since malignant tumor cancer cells overexpress the NK-1R, this combination therapy is a promising approach for the treatment of all kinds of cancer. Since aprepitant shows potential of being a broad-antitumor drug, the repurposing of this NK-1R antagonist as an antitumor agent is warranted. Studies pertaining to combination therapy of aprepitant/radiotherapy will also be outlined in this review. The aim of this review is to provide an update on combinational studies pertaining to chemotherapy/radiotherapy and NK-1R antagonist in cancer. CONCLUSION: This combination strategy once confirmed might open the door to a new era in chemotherapy and radiotherapy with greater antitumor activity and fewer side effects. This treatment strategy could possibly translate into higher cure rates, better quality of life and fewer sequelae in cancer patients.

Even though the promising therapies against cancer are rapidly improved, the oncology patients population has seen exponential growth, placing cancer in 5th place among the ten deadliest diseases. Efficient drug delivery systems must overcome multiple barriers and maximize drug delivery to the target tumors, limiting the side effects simultaneously. Since the first observation of the quantum tunneling phenomenon, many multidisciplinary studies have offered quantum-inspired solutions to optimized tumor mapping and efficient nanodrug design. The property of a wave function to propagate through a potential barrier offer the capability of obtaining 3D surface profiles using imaging of individual atoms on the surface of a material. The application of quantum tunneling on a scanning tunneling microscope offers an exact surface roughness mapping of tumors and pharmaceutical particles. Critical elements to cancer nanotherapeutics apply the fractal theory and calculate the fractal dimension for efficient tumor surface imaging at the atomic level. This review study presents the latest biological approaches to cancer management based on fractal geometry.

Metabolic diseases such as obesity, diabetes, dyslipidemia, and insulin resistance are characterized by glucose and lipid metabolism alterations and represent a global health problem. Many studies have established the crucial role of micro-ribonucleic acids (miRNAs) in controlling metabolic processes in various tissues. miRNAs are single-stranded, highly conserved non-coding RNAs containing 20-24 oligonucleotides that are expressed in a tissue-specific manner. miRNAs mainly interact through base pairing with 3' untranslated regions of target gene mRNAs to promote inhibition of their translation. miRNAs regulate the expression of as many as 30% of the human genes and have a role in crucial physiological processes such as human growth and development, cell proliferation, apoptosis, and metabolism. The number of miRNA molecules with a confirmed role in the pathogenesis of metabolic diseases is quickly expanding due to the availability of high-throughput methodologies for their identification. In this review, we present recent findings regarding the role of miRNAs as endocrine signaling molecules involved in the regulation of insulin production and fat metabolism. We discuss the potential of extracellular miRNAs present in biological fluids miRNAs as biomarkers for the prediction of diabetes and MetS. We also give an updated overview of therapeutic interventions based on antisense oligonucleotides and the CRISPR/Cas9 editing platform for manipulations of levels of miRNAs involved in metabolic disorders.

BACKGROUND: The chemistry of organoselenium reagents provides an asset for organic synthesis. The versatility of these reagents as electrophiles and nucleophiles makes them one of the key components of organic synthesis. Various synthetic transformations such as oxyselenenylations, selenocyclization and selenoxide elimination have been successfully achieved using organoselenium reagents under mild reaction conditions. The presence of selenocysteine in a few mammalian enzymes was the key information for selenium chemists to explore the biochemistry of selenium compounds. Glutathione peroxidase (GPx), a mammalian selenoenzyme, is well known for maintaining redox equilibrium by detoxifying reactive oxygen species. OBJECTIVE: The aim is to critically analyze the recent development and prospects of synthesis and antioxidant properties of organoselenium compounds Method: In this review, we summarised research and review papers from the PubMed and Scopus databases. The primary themes were linked to the synthesis of organoselenium compounds and their capacity to maintain cellular redox equilibrium when exposed to oxidative stress. RESULT: The study reveals that diselenide compounds synthesised by various methods showed a better antioxidant activity profile compared to selenides. In a few cases, the activity was found better than the standard compound ebselen. Moreover, the synthesis and antioxidant activity of Selenium-based nanoparticles have been also included. CONCLUSION: In the past two decades, various biological properties of organoselenium compounds have been extensively studied including the antioxidant properties. This review article would give insight into the synthesis of different types of recently synthesised organoselenium compounds. The review would be helpful to the researchers working in the field of medicinal chemistry in directing the synthesis of new organoselenium compounds as antioxidants.

BACKGROUND: Trk gene fusions are an important driver in the development of cancers including secretory breast cancer and infantile congenital sarcoma. Since the first generation of small molecule Trk inhibitors (Larotrectinib and Entrectinib) came to market, research on small molecule TRK inhibitors, especially second-generation inhibitors that break through the resistance problem, has developed rapidly. Therefore, this article focuses on the research progress of first-generation drugs and second-generation drugs that breakthrough drug resistance. METHODS: We use the database to search for relevant and cutting-edge documents, and then filter and select it based on the content. The articles are analyzed and classified, and finally, write articles according to themes. RESULT: The phenomenon of Trk protein fusion and its relation to tumors is first described, followed by an explanation of the composition and signaling pathways of Trk kinases. The representative Trk inhibitors and the development of novel Trk inhibitors are classified according to whether they overcome drug resistance problems. CONCLUSION: This paper provides a theoretical reference for the development of novel inhibitors by introducing and summarizing the representative and novel Trk inhibitors that break through the drug resistance problem.

BACKGROUND: 2,5-Diketopiperazines (DKPs), also called cyclic dipeptides, are the simplest peptide derivatives in nature that are formed by condensation of two amino acids. They are an important category of bioactive substances with various structures. OBJECTIVE: This review focuses on the natural sources, synthetic processes, biological properties and MS fragmentation regularity of simple DKPs, in order to provide a reference for exploring future scientific and therapeutic potentials of these compounds. METHOD: Pertinent information was collected and organized from several electronic scientific databases (e.g., Web of Science, China Knowledge Resource Integrated, ScienceDirect, PubMed, Wanfang Data and Google Scholar), PhD and MS dissertations. There are 105 articles published from the early 20th century to 2021 were reviewed in this work. RESULTS: DKPs have been obtained from a broad range of natural resources, including fungi, bacteria, plants, and animals, and been synthesized by chemical and biological methods. DKPs have various pharmacological activities, including anticancer, antibacterial, antithrombotic, neuron protective, analgesic, and other activities. Mass spectrometry is the most common method for the structural analysis of DKPs. DKPs can be quickly screened and identified by MS according to the mass spectrum fragmentation pattern of them. CONCLUSION: As a category of relatively unexplored compounds, DKPs have been demonstrated to have various bioactivities, especially with antitumor and antibacterial activities. However, the existing research of DKPs is still in the early stage, and their application in drug development needs to be further studied.

BACKGROUND: Insulin-like growth factor (IGF-1) is associated with breast cancer in menopausal women. Naturally occurring biomolecules found in common dietary protocols such as flavonoids, play a key role in the inhibition and treatment of cancer. In-vitro/in-vivo studies showed that treatment involving flavonoids led to a reduced risk of breast cancer due to the decrease of IGF-1 level in addition to an increased insulin-like growth factor binding protein (IGFBP)-3. However, clinical studies did not show conclusive results in this regard because they are contradictory. OBJECTIVE: The aim of the present study was finding the effect of flavonoids on IGF-1 and IGFBP-3 and the incidence of breast cancer. METHODS: This systematic review was performed using PubMed, Scopus, ISI Web of Science, and EMBASE databases for collecting results about the clinical use of flavonoids and their effects on breast cancer. After eliminating duplicate articles, the title and abstract of the remaining articles were examined in thematic communication and related clinical articles were selected and studied based on inclusion criteria. The data were extracted from each article, then statistical analysis subsequently carried out by Comprehensive Meta-Analysis. RESULTS: The results showed that the effect of flavonoids on changes of IGF1 and IGFBP-3 were not statistically significant. No significant heterogeneity was detected across the studies. Pooled effect size also indicated that the mean change was not statistically significant. No significant heterogeneity was detected across the studies. There was no evidence of publication bias for IGF1 and IGFBP-3. CONCLUSION: This meta-analysis study suggests that flavonoids supplementations have no significant effect on IGF-1 and IGFBP-3 and high soy diet has beneficial effects on IGF system components, which might be useful in breast cancer.