Nucleoside analogues are widely used as anti-infectious and antitumoral agents. However, their clinical use may face limitations associated with their physico-chemical properties, pharmacokinetic parameters, and/or their peculiar mechanisms of action. Indeed, once inside the cells, nucleoside analogues require to be metabolized into their corresponding (poly-)phosphorylated derivatives, mediated by cellular and/or viral kinases, in order to interfere with nucleic acids biosynthesis. Within this activation process, the first-phosphorylation step is often the limiting one and to overcome this limitation numerous prodrug approaches have been proposed. Herein, we will focus on recent literature data (from 2015 and onwards) related to new prodrug strategies, the development of original synthetic approaches and novel applications of nucleotide prodrugs (namely pronucleotides) leading to the intracellular delivery of 5'-monophosphate nucleoside analogues.

BACKGROUND: Abundant studies have shown that non-coding RNA is connected with the growth, migration and invasion of tumor cells. As a newly discovered non-coding RNA, WDFY3-AS2 has gradually emerged in the molecular mechanism of various tumors and has a potential prospect as a biological indicator of tumor prognosis. In this review, we describe the pathophysiological mechanism and prognostic value of WDFY3-AS2 in different cancers. OBJECTIVE: This review reveals the changes and roles of WDFY3-AS2 in many tumors and cancers. The change of WDFY3-AS2 can be used as a biomarker of cancer and plays an important role in improving tumor growth, migration and invasion. WDFY3-AS2 is unique in that it can be considered as a prognostic marker for many tumors and is of great significance for clinical diagnosis and treatment. WDFY3-AS2 shows potential prognostic value and prospect of therapeutic targets in a variety of tumors. METHODS: The related literatures were reviewed by PubMed to analyze and summarize the regulatory molecular mechanism of WDFY3-AS2 in various tumors and its value as a prognostic indicator. RESULTS: The abnormal expression of LncRNA WDFY3-AS2 in many cancers was connected with the poor prognosis of cancer patients, including diffuse glioma, hepatocellular carcinoma, ovarian cancer, esophageal cancer, triple negative breast cancer, Clear Cell Renal Carcinoma, Esophageal squamous cell carcinoma, Lung adenocarcinoma, which participated in the recovery of orthodontic teeth. WDFY3-AS2 has revealed the cellular process of cancer cell growth, migration, and invasion. CONCLUSION: The molecular mechanism of LncRNA WDFY3-AS2 regulating tumor specifically proves that WDFY3-AS2 has a good prospect in the biological index of prognosis or clinical treatment target of cancer patients.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint damage. Systemic complications and progressive disability are burdens that lead to a significant socio-economic cost in patients with RA. Current RA biomarkers used in predicting, diagnosing, and monitoring the treatment of the disease have not been very successful. Moreover, only 60% of patients show a satisfactory response to current biological and conventional therapies. Studies on immunometabolism have suggested that dysregulated enzymes, transcription factors, metabolites, and metabolic pathways could be considered potential therapeutic targets for the treatment of RA. Factors such as the high concentration of various intermediate molecules arising from metabolism, hypoxia, lack of nutrients, and other metabolic alterations affect local immune responses and preserve a state of chronic inflammation in synovial tissues. Fortunately, in vitro and in vivo studies have shown that targeting specific metabolic pathways is associated with a decreased level of inflammation. Specifically, targeting metabolic intermediates, such as succinate or lactate, has shown promising clinical outcomes in RA treatment. These findings open an avenue for the identification of novel biomarkers for diagnosis, prognosis, and determining the success of various treatments in RA patients, as well as the discovery of new therapeutic targets.

Introduction Opioid free anesthesia (OFA) is a relatively new technique that has been questioned due to the lack of evidence regarding its benefit-risk balance. Methods Four international databases were searched for clinical trials comparing OFA with opioid based anesthesia. The primary outcome was pain control and the secondary included postoperative nausea and vomiting (PONV), gastrointestinal recovery, respiratory depression, urinary retention, length of hospital stay, surgical complications, number of patients with cessation of the intervention and other side effects. Results Pain was better controlled in the OFA group in all the measurements made (VAS 1h: Md= -0.81, CI95%= -0.48- -1.14, VAS 24h: Md= -1.25,CI95%=-2.41- -0.1, VAS >24h: Md= -1.36, CI95%= -1.73- -1). In the opioid group there was an increase in the risk of nausea (RR=2.69, CI95%=2-3.61) and vomiting (RR= 3.99, CI95%=2.06-7.74), whilst in the OFA group there was an increased risk of bradycardia (RR=1.62, CI95%=1.02-2.57). The rest of the variables showed no differences between groups or could not be analyzed. Conclusion There is a clear benefit of OFA in pain control and PONV, but there is also a higher risk of bradycardia. This technique should be considered in patients with special risk of difficult postoperative pain control or PONV. However the best drug combination to perform OFA is still unknown, as well as the type of patient that benefits more with less risk.

Given the importance of COVID-19-induced ARDS, recently, researchers have strived to determine underlying mechanisms involved in the inflammatory responses. In this regard, inflammasomes possess a distinct priority for cytokine storm occurrence and subsequently ARDS progression in ill patients with SARS-CoV-2 infection. In this mini-review, the characteristics of known inflammasome inhibitors and designed research in this field were concretely deciphered.

Thrombosis is one of the most important pathogenic factors that related to cardiovascular diseases. Presently, thrombin inhibitors have gradually gained prominence in clinical practice due to their unique potential, such as dabigatran. Nevertheless, the risk of bleeding is not completely eliminated, and the threats of gastrointestinal bleeding are even increased in some cases. Therefore, it is urgent to develop new oral thrombin inhibitors with low side effects. In this paper, we summarized recent advances on the newly synthesized and isolated thrombin inhibitors from 2000 to 2019 and their structure-activity relationships (SARs) along with structure-dependent pharmacokinetic parameters, providing guidance for next generation of oral thrombin inhibitors.

BACKGROUND: This study presents the synthesis and multi-target behavior of the new 5'-hydroxy-3-(chalcogenyl-triazoyl)-thymidine and the biological evaluation of these compounds as antioxidant and anti-HIV agents. OBJECTIVE: Antiretroviral therapy induces oxidative stress. Based on this, the main objective of this manuscript is the preparation of compounds that combine anti-HIV and antioxidant activities. METHODS: The compounds were prepared from commercially available AZT, through a copper-catalyzed Huisgen 1,3-dipolar cycloadditions exploiting the AZT azide group and chalcogenyl alkynes. RESULTS: The chalcogenium-AZT derivatives were obtained in good yields via click chemistry. The compounds evaluated showed antioxidant and anti-HIV activity. Additionally, in vivo toxicity of this class of compounds was also evaluated and the representative nucleoside did not change the survival, behavior, biochemical hepatic, and renal markers compared to the control mice. CONCLUSION: Data suggest the feasibility of modifying the AZT nucleus with simple organochalcogen fragments, exploring the reactivity of the azide group via 1,3-dipolar Huisgen cycloaddition reaction. The design of these new compounds showed the initially desired biological activities.

BACKGROUND: Alzheimer's disease (AD) is one of the most common diseases in the elderly, with a high incidence of dementia. The pathogenesis of AD is complex, and there is no unified conclusion and effective treatment in clinic. In recent years, with the development of traditional Chinese medicine (TCM), researchers put forward the idea of prevention and treatment of AD based on TCM according to the characteristics of multi-target of TCM. Ferulic acid (FA), also known as 3-methoxy-4-hydroxycinnamic acid, is an active ingredient in TCM that inhibits β-amyloid (Aβ) aggregation and has antioxidant and anti-inflammatory effects. FA derivatives have been reported to have low toxicity, high biological activity, and high blood-brain barrier permeability. However, the multi-target of FA in the treatment of AD have not been systematically elucidated. OBJECTIVES: In this systematic review we aimed to comprehensively assess the neuroprotective effects of FA and its derivatives on in vitro and in vivo AD models. METHODS: We searched PubMed, Chinese National Knowledge Infrastructure (CNKI), Baidu Academic, and Wanfang databases for relevant pre-clinical studies until November 2021. RESULTS: We identified studies that evaluated the efficacy of FA and its derivatives using relevant keywords. 864 studies were included, of which 129 were found in PubMed, 111 in CNKI, 454 in Baidu Academic, and 170 in Wanfang. Due to duplication between databases, and after applying the exclusion and inclusion criteria, 43 articles were selected. Thereafter, the abstracts of the 43 articles were reviewed. Finally, 21 articles were included in this review, including 11 in vivo, 5 in vitro, 5 in vivo and in vitro studies. CONCLUSION: Previous studies have shown that FA or its derivatives have multiple therapeutic effects on AD models, and can improve the symptoms of AD and resistance of AD cell models. FA and its derivatives have anti-Aβ aggregation, antioxidant, anti-inflammatory, and other effects and are potential drugs for the multi-targeted treatment of AD. The result of our study showed that FA and its derivatives have significant therapeutic effects on animal and cell models of AD, suggesting that they may be potential therapeutic drugs for patients with AD.

Targeted protein degradation (TPD) strategies have become a new trend in drug discovery due to the capability of triggering the degradation of protein of interest (POI) selectively and effectively in recent decades. Particularly, the hydrophobic tag tethering degrader (HyTTD) has drawn a lot of attention and may offer a promising strategy for new drug research and development in the future. Herein, we will give an overview of the development of HyTTD, the structure-activity relationship (SAR) between HyTTD and linkers, HyTs, and ligand motifs, as well as the various HyTTDs targeting different targets, thus offering a rational strategy for the design of HyTTDs in further TPD drug discovery.

AIM: To evaluate the immunogenic potential of the carrier-free peptide-based anti-PCSK9 (proprotein convertase subtilisin/kexin 9) vaccine in albino mice. METHODS: The immunogenic pcsk9 peptide and 0.4% alum adjuvant were mixed thoroughly at a 1:1 ratio and used as a vaccine formulation. To assess the humoral immune response, animals' blood was sampled two weeks after the last immunization. The ELISA method was employed to measure serum anti-PCSK9 antibody titers, PCSK9 concentrations, and PCSK9/LDLR interaction. RESULTS: ELISA analysis showed significant induction of IgG antibody titers by PCSK9 peptide vaccine in vaccinated mice sera compared to the control mice (in male and female mice were 12000±586 and 11566±642, respectively, p<0.001). Mechanistic analyses showed a significant reduction in serum PCSK9 concentrations by vaccine-induced antibodies in vaccine groups compared to the control groups (in male mice by 29±5 ng/mL (22.4%), p<0.001 and female mice by 26±5 ng / mL (21.0%), p<0.001). Serum concentrations of PCSK9 in control and vaccine groups were 131±8.6 ng / mL and 102±8.1 ng/ml in male mice and 124±6 ng/ml and 98±10 ng/ml in female mice, respectively. Moreover, vaccine-induced antibodies inhibited the PCSK9-LDLR interaction in male and female groups by 34% and 26%, respectively. No significant difference was detected between the male and female groups in all tests (p>0.05). CONCLUSIONS: According to our results, the PCSK9 peptide vaccine provoked the humoral immune system in albino mice to produce functional antibodies that inhibit plasma PCSK9. These effects were seen in both genders without any significant difference.

BACKGROUND: COVID-19 disrupted NTD programs in 60% of countries, impairing public health goals. Thus, boosting NTD&#039;s research knowledge is pressing, and in vivo screening of candidates allows for the prospect of auspicious options based on their overall profile. OBJECTIVE: In this work, we highlighted the relevant research done between 2015-2021 in the fields of synthetic and repurposed drugs that were tested in vivo for Chagas disease, malaria, and schistosomiasis. METHODS: MEDLINE, PUBMED, CAPES PERIODIC, and ELSEVIER databases were used for a comprehensive literature review of the last 5 years of research on each area/disease. RESULTS: Overall, research focused on nitro heterocyclic, aromatic nitro, nucleoside, and metal-based scaffolds for analogue-based drug generation. Repurposing was widely assessed, mainly with heterocyclic drugs, their analogues, and in combinations with current treatments. Several drug targets were aimed for Chagas treatment, specific ones such as iron superoxide dismutase, and more general ones, such as mitochondrial dysfunction. For malaria, hemozoin is still popular, and for schistosomiasis, more general structural damage and/or reproduction impairment were aimed at in vitro analysis of the mechanism of action. CONCLUSION: Latest in vivo results outlined trends for each disease - for Chagas Disease, heterocyclics as thiazoles were successfully explored; for Malaria, quinoline derivatives are still relevant, and for schistosomiasis, repurposed drugs from different classes outstood in comparison to synthetic compounds. This study uprises the continuous development of Chagas disease, malaria, and schistosomiasis drugs, providing researchers with tools and information to address such unmet therapeutic needs.

Poly(ethylene glycol) (PEG) has been widely applied in biomedical field as a gold standard. The conjugation of PEG to proteins, peptides, oligonucleotides (DNA, small interfering RNA (siRNA), microRNA (miRNA)) and nanoparticles, also known as PEGylation, is a common method to improve the efficiency of drug delivery and pharmacokinetics in vivo. The effect of PEGylation on the in vivo fate of various formulations has been and continues to be extensively studied based on the successful PEGylation of proteins to improve in vivo circulation time and reduce immunogenicity. The PEG shell protects the particles from aggregation, immune recognition, and phagocytosis, thereby prolonging the in vivo circulation time. This article mainly describes the development background, advantages and applications of PEGylation in the field of drug delivery, its defects or development bottlenecks, and possible alternatives.

BACKGROUND: Tumor plasticity processes impact the treatment of different types of cancer, as an effect of this, the bioprospecting of therapies from natural and/or synthetic compounds that can regulate or modulate the immune system has increased considerably. Oxadiazole derivatives are structures that exhibit diverse biological activities. Therefore, this review aimed to evaluate the activity of oxadiazole compounds against tumor cell lines and their possible immune-mediated mechanisms. METHODS: A search in PubMed, Web of Science, and Science Direct databases was carried out on studies published from January 1, 2004, to January 31, 2022, using "oxadiazole*" in combination with the other descriptors "cancer" and "macrophage". Only experimental in vitro and in vivo articles were included. Similar search strategy was used in Derwent Innovation Index database for technology mapping. The search was performed on Drugbank using the descriptor oxadiazole for commercial mapping. RESULTS: 23 oxadiazole studies were included in this review and some biological activities linked to antitumoral and immunomodulation were listed. Oxadiazole derivatives inhibited tumor cell growth and proliferation, blocked cell cycle, modulated mitochondrial membrane potential, presented immunoregulatory activity by different mechanisms reducing proinflammatory cytokines levels and acted directly as selective inhibitors of the COX enzyme. There was an increase in oxadiazole patent publications in the last 11 years, with emphasis on chemistry, pharmacy and biotechnology applied to microbiology areas. Compounds with 1,2,4-oxadiazole isomer are predominant in patent publications and approved drugs as observed in the technological and commercial mapping. CONCLUSION: Therefore, oxadiazole derivatives are therapeutic molecules that can be considered promising for the development of cancer therapies.

Free fatty acids (FFAs) present in our dietary fats not only act as vital nutrients but also function as signalling molecules and modulate key biological functions through their active involvement in a multitude of energy metabolism pathways. However, it has been reported that excessive intake of dietary fat contributes to the development of different types of Diabetes mellitus. Free fatty acid receptors are the key regulators of the most metabolic disorders. Among them, diabetes mellitus is a severe growing disorder and found in every corner of the world. Various metabolic disorders, particularly for type 2 diabetes mellitus, these different free fatty acid receptors are being explored as drug targets. In the present review, it has been explored various FFAs sensing G-protein coupled receptors (GPR) likes GPR40 (FFAR1), GPR43 (FFAR2), GPR41 (FFAR3), GPR120 (FFAR4), and GPR84 as emerging novel therapeutic targets for antidiabetic drugs. Additionally, this review has covered pre-clinical discovery and development of different selective ligands targeted to these receptors starting from hit identification to lead optimization via chemical modification and the challenges and tactics selected by different medicinal chemists to improve potency, physicochemical properties, safety profiles, and pharmacokinetics of different FFAR agonists for making a potential drug candidate. Several molecules have been withdrawn in the clinical trials without reporting any reasons. We believe that this review will help the researchers to find a new direction in the discovery of new antidiabetic drugs.

COVID-19 is a contagious disease. Paxlovid, a combination of Nirmatrelvir and Ritonavir, was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19 on December 22, 2021. These are peptidomimetic coronavirus main protease inhibitors. Nirmatrelvir is a proline derivative. The present patent describes similar proline- like compounds, their preparation, use, and pharmaceutical composition, and treatment.

Cancer remains a major worldwide health challenge. Current studies emphasize the tumor microenvironment that plays a vital role in tumor proliferation, invasion, metastasis, and drug resistance. The tumor microenvironment supports the cancer cell to evade conventional treatment such as surgery, radiotherapy, and chemotherapy. Moreover, the components of tumor microenvironments have a major contribution to developing therapy resistance in solid tumors. Therefore, targeting the tumor microenvironment can be a novel approach to achieving advancement in cancer nanomedicine. The recent progress in understanding TME and developing TME-responsive nanoparticles offers a great advantage in treating cancer drug resistance. These nanoparticles developed in response to TME stimuli such as low pH, redox, and hypoxia improve nanomedicine's pharmacokinetic and therapeutic efficacy. This review discusses the various components of the tumor microenvironment responsible for drug resistance and nanomedicine's role in overcoming it.

Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and non-histone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus produce adverse issues, causing therapeutic resistance and they have poor pharmacokinetic properties. The designing of HDAC based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDACinhibitor is generally accomplished on the basis of systematic high-throughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target.The objective of this review is to elucidate the designing strategies of the potential targets along with biological activity and recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents.This review elucidate the designing strategies of the potential target along with biological activity and recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is an important approach for overcoming side effects, drug resistance, and effective cancer control.

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus and the main cause of end-stage renal disease (ESRD). Activation of the NLRP3 inflammasome has been proven to play an important role in the development of DN. Thus, specific and direct targets of NLRP3 inflammasome assembly may have therapeutic potential. CY-09 is a new NLRP3 inflammasome specific inhibitor that has been shown to protect against non-alcoholic fatty liver disease (NAFLD) by inhibiting the activation of the NLRP3 inflammasome. However, its role in kidney disease, especially DN, has not been reported. METHODS: In this study, we used HE staining to assess renal pathological damage in each group, and RT-PCR, immunofluorescence and WB were performed to detect the expression changes in inflammatory and fibrosis proteins. The apoptosis level was detected by TUNEL staining. RESULTS: Here, we showed increased inflammation, oxidative stress, apoptosis and fibrosis in db/db mice, while CY-09 exerted renoprotection by inhibiting NLRP3 inflammasome activation. In vitro, CY-09 also inhibited NLRP3 and reduced caspase-1, IL-18, IL-1β and apoptosis in a dose-dependent manner. CONCLUSION: CY-09 effectively protects the kidney from hyperglycemia induced damage by inhibiting the NLRP3 inflammasome and may be a promising therapeutic strategy to prevent the progression of DKD.

BACKGROUND: The role of WT1-associated protein (WTAP) in mediating the N6-methyladenosine (m6A) modification of pyruvate dehydrogenase kinase 4 (PDK4) in colorectal cancer (CRC) has been previously reported. OBJECTIVE: This research manages to unveil the function and mechanism of WTAP mediating the m6A modification in CRC. METHODS: Expressions of PDK4 and WTAP in CRC were assessed by bioinformatics analysis and verified by Western blot. After the transfection with short hairpin RNAs (shRNAs) for WTAP (shWTAP) and PDK4 (shPDK4) to manipulate the expressions of PDK4 and WTAP, the viability, proliferation, migration, invasion, and levels of m6A, PDK4 and WTAP in CRC cells were determined by cell counting kit-8 (CCK-8), colony formation, transwell, Western blot, or M6A-RNA Immunoprecipitation (MeRIP)-qPCR assays. M6A binding sites in PDK4 were additionally predicted through bioinformatics analysis and the interaction of PDK4 and WTAP was confirmed using RNA pull-down assay. Tumor volume and weight in the constructed xenograft-tumor mouse model were recorded. RESULTS: PDK4 expression was lowyet WTAP and m6A expressions were high in CRC cells. WTAP bound with the m6A binding sites in PDK4. PDK4 silencing facilitated the viability, proliferation, migration and invasion, inhibited the expression of PDK4 in CRC cells, and accelerated the growth of xenografts in vivo. However, the depletion of WTAP4 exerted the opposite effects and further offset the impact of PDK4 silencing. CONCLUSION: WTAP mediates the m6A modification of PDK4 to regulate the malignant behaviors of CRC cells in vitro and in vivo.

Systemic arterial hypertension (SAH) is a major risk factor for several secondary diseases, especially those involving cardiovascular and renal conditions. SAH has a high prevalence worldwide and its precise and early recognition is important to prevent the development of secondary outcomes. In this field, the study of biomarkers represents an important approach to diagnose and predict the disease and its associated conditions. The use of biomarkers in hypertension and hypertension-related disorders, such as ischemic stroke, intracerebral hemorrhage, transient ischemic attack, acute myocardial infarction, angina pectoris and chronic kidney disease, are discussed in this review. Establishing a potential pool of biomarkers may contribute to a non-invasive and improved approach for their diagnosis, prognosis, risk assessment, therapy management and pharmacological responses to a therapeutic intervention, in order to improve quality of life in patients and prevent unfavorable outcomes.

Emodin is a natural anthraquinone extract of Chinese medicinal herbs. Several studies demonstrated the antitumor activity of this extract, particularly for lung cancer. However, the mode of action of emodin remains obscure. In this study we evaluated in vitro and in vivo anti-lung cancer properties of emodin in human lung adenocarcinomas and the underlying molecular mechanism involved. Our results demonstrated emodin caused a significant inhibition of cell viability and induced apoptosis in lung cancer cells to a level that is relative to that of normal epithelial cells. Furthermore, RNA-seq transcriptome analysis revealed 65 common genes(>2-fold change) with a significant expression in A549, and H1650 cells under emodin treatment. In vitro qRT-PCR results confirmed that 4 genes (ATP6V0D2, C11orf96, TIPARP, and CDKN1A) were up-regulated, and 9 genes (TNFSF10, IFIT1, EGLN3, RCOR2, ARRB1, FLVCR2, BAIAP2-DT, FAM111B, and TGFB2) were down-regulated in A549 and H1650 adenocarcinoma cell lines. The in vivo experiment demonstrated emodin could significantly decrease tumor volume and tumor weight of mice compared with the control group. However, emodin treatment has no obvious effect on body weight of mice. Moreover, in vivo qRT-PCR results revealed that 3 genes (ATP6V0D2, C11orf96, and TIPARP) were up-regulated, and 6 genes (TNFSF10, IFIT1, EGLN3, BAIAP2-DT, FAM111B, and TGFB2) were down-regulated in tumor tissues compared with the control group. These findings suggested that emodin could help treat lung cancer and has a potential for further investigations as an anti-lung cancer drug.

Lead optimization as a bottleneck in the process of drug discovery is conducted to tackle problems associated with poor pharmacokinetics, continuous emergence of drug-resistance, adverse side effects and drug-drug interactions of known pharmaceuticals. Due to the intensive application of multi-targeted tyrosine kinase inhibitors (MTKI) in various pathological conditions, optimization of their structures has always been the focus of intensive medicinal chemistry research efforts. Current review portrays the application of scaffold hopping, bioisosterism, structure-based, and hybrid-based drug design methods in optimization of lead compounds aiming to enhance their usefulness as novel drugs. Then, the review proceeds with examples of structural modifications carried out, particularly, on multi-targeted drugs already available on the market. The demonstrated examples cover structural modifications on 7 well known drugs during last twenty years where the application of above mentioned strategies has led to generation of 52 new multi-targeted tyrosine kinase inhibitors. Most of the optimized compounds showed improved properties compared to their parent lead compound. The rationales behind the applied modifications and the achieved outcomes were discussed with the hope of presenting practical examples to the researchers engaged in the area.

BACKGROUND: The change of lncRNA expression is known to affect the progression of tumors. This has fueled numerous investigations aiming at the mystery of lncRNA. Clear lncRNA has been the hotspot of antisense RNAs research. More and more lncRNAs have been proven to take effect as oncogenes of multitudinous cancers and accelerate tumor progression. This review elucidates the pathophysiological functions of lncRNA DLGAP1-AS1 and lncRNA DLGAP1-AS2 in a variety of tumors. METHODS: Via systematic analysis and in-depth study about relevant articles in PubMed, this article analyzes and summarizes the mechanism of antisense transcripts DLGAP1-AS1 and DLGAP1-AS2 in tumor development. RESULTS: DLGAP1-AS1 and DLGAP1-AS2 can exert their effect as oncogenes on various cancers. The expression of DLGAP1-AS1 is aberrantly high in various tumors, including GC, BC, HCC, glioblastoma and CRC. Concurrently, in LC, RC, HCC, GC, glioma and CCA, DLGAP1-AS2 is also discovered to be highly expressed. And they have a strong pertinence with a poor prognosis. The disorder of DLGAP1-AS1 and DLGAP1-AS2 in different tumors has different malignant impacts on tumors, not only to invasion, apoptosis, multiplication and EMT of tumor cells but also to drug resistance and radioresistance. In addition, DLGAP1-AS2 was revealed to have the ability to predict the prognosis of WT and RCC (Tables 1 and 3). CONCLUSION: The regulatory effects of DLGAP1-AS1 and DLGAP1-AS2 on tumors make them possible to be clinical markers for the early diagnosis of tumors and effective therapeutic targets.

Tyrosinase is a bifunctional polyphenol oxidase (PPO), catalyzing two oxidative reactions: monophenols to o-quinones (monophenolase activity) and o-diphenols to o-quinones (diphenolase activity). As tyrosinase is the rate-limiting enzyme for the melanogenesis process, it is an attractive target for melanogenesis inhibition. Aiming at skin whitening, anticancer, Parkinson's disease (PD) treatment, antibacterial, fruit and vegetable preservation and other anti-pigmentation effect, medicinal chemists have exploited diverse tyrosinase inhibitors through various approaches. In addition to discovering inhibitors with novel scaffold, good activity and high safety, researchers also focused on developing strategies for synergistic effects of multiple inhibitors and simultaneously regulating multiple targets to treat cancer or neurodegenerative diseases. This review focused on multiple natural and synthetic tyrosinase inhibitors which could contribute to preventing fruit and vegetable browning, skin whitening, antibacterial, anticancer, Parkinson's Disease etc.

In the context of a balanced diet, wheat, mainly when used as whole grains, is a good source of nutrients, including fibers and bioactive compounds. Cereals belong to the Poaceae family and are crucial for maintaining a healthy status, granted by their nutritional and chemical properties. Recent studies have demonstrated that the intake of whole grains and grain-based products may reduce the risk of oxidative stress, thus lowering chronic and age-related disorders, such as obesity, cardiovascular diseases, type II diabetes and cancer. Indeed, several studies report that the regular whole grain consumption is associated with lower levels of total and LDL-cholesterol, triglycerides, fasting glucose, blood pressure and body mass index. Moreover, ancient wheat species have acquired increasing interest for human health, as they contain several nutraceutical compounds, such as vitamins, minerals and others. The numerous phytochemicals present in ancient wheat (polyphenols, carotenoids, phytosterols and phenolic compounds) provide, in fact, antioxidant properties, which are essential in the prevention of various chronic and degenerative diseases. The aim of this review is to report the existing information on ancient wheat species, discussing their composition and nutraceuticals properties compared with modern varieties and highlight the beneficial impact on human health.

Metal binding ability and coordination modes of the copper(II) and zinc(II) complexes of various peptide fragments of prion, amyloid-β and tau proteins are summarized in this review. Imidazole-N donors are the primary metal binding sites of all three proteins but the difference in the location of these residues and the presence or absence of other coordinating side chains results in significant differences in the complex formation processes. The presence of macrochelates and the possibility of the formation of multi-copper complexes is the most characteristic for prion fragments. Amyloid-β can form high stability complexes with both copper(II) and zinc(II) ions but the preferred binding sites are different for the two metal ions. Similar observations are obtained for the tau fragments but the metal ion selectivity of the various fragments is even more pronounced. In addition to the complex formation, copper(II) ions can play an important role in the various oxidative reactions of peptides. Results of the metal ion catalyzed oxidation of peptide fragments of prion, amyloid-β and tau proteins are also summarized. Amino acid side chain oxidation (mostly methionine, histidine and aspartic acid) and protein fragmentations are the most common consequences of this process.

BACKGROUND: Cancer continues to be the second leading cause of death worldwide with colorectal cancer (CRC) being the third most common type. Despite significant advances in cancer therapies, current treatment of CRC remains suboptimal. In addition, the effectiveness of available chemotherapeutic drugs such as 5-Fluorouracil (5-FU) is limited by CRC-acquired resistance. METHODS: In this study, we provide innovative approaches employed in synthesizing four novel nucleobase analogs. Equally, we describe the effects of these compounds on proliferation, migration, aggregation, adhesion of 5-FU-sensitive (HCT116) and -resistant (5-FU-R-HCT116) human CRC cells. In either cell type, our synthesized novel analogs significantly inhibited cell viability in a concentration- and time-dependent manner. This highlights the higher potency of these novel analogs. In addition, these compounds attenuated migration and adhesion of both cell types, while they promoted homotypic cell-cell interaction. RESULTS: These changes were reflected by the downregulation matrix metalloproteases (MMP-2 and MMP-9). Furthermore, our analogs exhibited a potent anti-angiogenic activity in vivo. CONCLUSION: In addition, these compounds reduced the level of secreted vascular endothelial growth factor (VEGF) and nitric oxide (NO) production in both 5-FU-sensitive and -resistant cells. Taken together, our data highlight the potential chemotherapeutic properties of our novel analogs against CRC, including the 5-FU-resistant form.

High-density lipoprotein (HDL) is the smallest and densest of the lipoproteins. Beyond its well-known cardiovascular protective function, it has other actions including structural function, anti-inflammatory, antioxidant, anti-thrombotic effects, transport of bioactive molecules, and induction of signal transduction pathways. Further, there is a mutual connection between oral health and general health. Hence HDL could be a potentially crucial factor relating oral health to general health. As far as we know, no comprehensive study has been carried out to date, which has explored the association between HDL concentration and oral diseases including lichen plan, recurrent aphthous ulcers, candidiasis, implant osseointegration, oral cancer and precancerous conditions. Here in this review, we summarized the relationship between HDL and oral health, suggesting a significant association between HDL concentration and oral health.