Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors are FDA-approved drugs recommended for high-risk patients with LDL-cholesterol (LDL-c) levels ≥ 70 mg/dl. Several studies have also investigated the relationship between PCSK9 and periodontitis. Specifically, studies have investigated the association between periodontitis and periodontal PCSK9 levels in humans, and periodontium status in PCSK9-knockout versus wild-type mice. While a positive association between periodontitis and periodontal PCSK9 levels has been noted, the findings on the comparison of periodontium status between PCSK9-knockout and wild-type mice have been inconsistent. Different methodologies among these studies may explain this discrepancy. Future experimental studies on the impact of pharmacological PCSK9 inhibition on periodontal status as well as observational studies comparing periodontium status between patients receiving PCSK9 inhibitors and those receiving other lipid-lowering drugs will shed light on the role of PCSK9 in periodontal health and disease.

Despite substantial advancements in curative modern medicine in the last few decades, cancer risk and casualty rates have continued to mount globally. The exact reason for cancer's onset and progression is still unknown. However, skeletal and functional abnormalities in the genetic code are assumed to be the primary cause of cancer. Many lines of evidences reported that some medicinal plants can be utilized to curb cancer cell proliferation with a safe, fruitful, and cost-efficient perspective. Curcuminoids, isolated from Curcuma longa, have gotten a lot of focus due to their anticancer potential as they reduce tumor progression, invasion, and dissemination. Further, they modulated signal transduction routes like MAPK, PI3K/Akt/mTOR, JAK/STAT, and Wnt/β-catenin, etc., and triggered apoptosis as well as actuated autophagy in malignant cells without altering the normal cells, thus preventing cancer progression. Besides, Curcuminoids also regulate the function and expression of anti-tumor and carcinogenic miRNAs. Clinical studies also reported the therapeutic effect of Curcuminoids against various cancer through decreasing specific biomarkers like TNF-α, Bcl-2, COX-2, PGE2, VEGF, IκKβ, and various cytokines like IL-12p70, IL-10, IL-2, IFN-γ levels and increasing in p53 and Bax levels. Thus, in the present review, we abridged the modulation of several signal transduction routes by Curcuminoids in various malignancies, and its modulatory role in the initiation of tumor-suppressive miRNAs and suppression of the oncogenic miRNAs are explored. Additionally, various pharmacokinetic approaches have been projected to address the Curcuminoids bioavailability like the use of piperine as an adjuvant; nanotechnology-based Curcuminoids preparations utilizing Curcuminoids analogues are also discussed.

BACKGROUND: Hyperuricemia belongs to metabolic syndromes where increased uric acid levels are identified in the blood serum. Such a syndrome could be responsible for kidney stone formation, gout, hypertension, and chronic kidney diseases. It has been reported that cardiovascular risks have been linked with hyperuricemia. Gout is of the most frequent manifestations due to hyperuricemia; its management involves various pharmacological available options and dietary changes. Throughout the literature, various dosage forms are studied as alternative options to the present drug delivery systems. OBJECTIVE: To update and summarize the current information for gout and hyperuricemia management Methods: Authors have performed a thorough literature research from 2010-2023 using keywords such as hyperuricemia, gout, diagnosis, guidelines, drug delivery and clinical trials. The databases used were PubMed, ScienceDirect. According to our inclusion criteria, all studies which include the previous terms, as well as drugs or other molecules that can be applied for gout and/or hyperuricemia management, were added. RESULTS: In this article, authors have summarized the pathogenesis, diagnosis and updated guidelines for gout and hyperuricemia management. Moreover, the authors have reviewed and discussed current drug delivery systems found in the literature, including drugs targeting the above disorders. Finally, the available clinical trials assessing the efficacy of newer drugs or combinations of the past ones, are being discussed. CONCLUSION: The available drugs and dosage forms are limited, and therefore, scientific society should focus on the development of more efficient drug delivery systems for hyperuricemia and gout management.

Atherosclerosis, the pathological basis of most cardiovascular diseases, is a main risk factor causing about 20 million deaths each year worldwide. Oxidized low-density lipoprotein is recognized as the most important and independent risk factor in initiating and promoting atherosclerosis. Numerous antioxidants are extensively used in clinical practice, but they have no significant effect on reducing the morbidity and mortality of cardiovascular diseases. This finding suggests that researchers should pay more attention to the important role of non-oxidative modified low-density lipoprotein in atherosclerosis with a focus on oxidized low-density lipoprotein. This review briefly summarizes several important non-oxidative modified low-density lipoproteins associated with atherosclerosis, introduces the pathways through which these non-oxidative modified low-density lipoproteins induce the development of atherosclerosis in vivo, and discusses the mechanism of atherogenesis induced by these non-oxidative modified low-density lipoproteins. New therapeutic strategies and potential drug targets are provided for the prevention and treatment of atherosclerotic cardiovascular diseases.

Malaria remains one of the most challenging tropical diseases. Since malaria cases are reportedly alarming in terms of infections and mortality, urgent attention is needed for addressing the issues of drug resistance in falciparum malaria. High throughput screening methods have paved the way for rapid identification of anti-malarial. Furthermore, drug repurposing helps in shortening the time required for drug safety approvals. Hence, the discovery of new antimalarials by drug repurposing is a promising approach for combating the disease. This article summarizes the recent computational approaches used for identifying novel antimalarials by using drug target interaction tools followed by pharmacokinetic studies.

The need for wearable bioelectronics continues to grow, and this technology might significantly alter the medical field. In order to diagnose and treat a patient, conventional medicine takes a "reactive" approach and waits for symptoms to appear first. Therefore, it is preferable to progress toward continuous non-invasive wearable biomonitoring, a preventative strategy that may assist individuals in diagnosing or treating illnesses at the earliest stages, sometimes before any outward symptoms have appeared. Wearable physiological sensors, such as the Apple Watch and FitBit, have arrived on the market as a result of technology advances and have quickly become commonplace. However, few devices currently exist that can report directly on these biomarkers of relevance. This is mostly due to the challenges involved in real-time fluid sampling and generating correct readouts utilising extremely selective and sensitive sensors. Sweat is an excretory fluid that is only allowed to be used in order to reduce invasiveness, but this restriction places additional strain on sensors owing to the diluted concentration of the relevant biomarkers and the changes in pH, salinity, and other biophysical parameters that directly influence the read-out of real-time biosensors. Sweat is favoured amid slightly invasive biofluids due to its low concentration of interfering chemicals and the fact that it may be collected without touching the mucosal layers. This review offers a concise outline of the latest advances in sweat-based wearable sensors, their promise in healthcare monitoring, and the problems faced in analysis based on sweat.

Background Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies. Aims This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM. Method The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs). Result Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features. Conclusion In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

BACKGROUND AND OBJECTIVE: The literature suggests that statins may increase superoxide dismutase (SOD) levels by different mechanisms. These effects may contribute to the antioxidant and anti-inflammatory effects of statins, which are thought to be beneficial in preventing cardiovascular events. However, there are also conflicting results concerning the effect of statins on SOD levels. The goal of this systematic review was to evaluate the effect of statin therapy on SOD activity. METHODS: This systematic review was performed based on the PRISMA statement. The terms ("statin" or "HMG-CoA reductase inhibitor" OR "lipid-lowering agents" OR "Atorvastatin" OR "Simvastatin" OR "Pravastatin" OR "Fluvastatin" OR "Lovastatin") AND ("superoxide dismutase" OR "SOD" OR "anti-oxidative" OR "oxidative stress") were searched in database systems Google Scholar, PubMed/MEDLINE, and Scopus from inception to April 2022. RESULTS: A total of 14 controlled clinical trials - 10 randomized and 4 non-randomized - were found to be eligible. Four studies measured SOD levels in plasma, six in serum, two in red blood cells, one in venous blood, and one on both red blood cells and venous blood matrices. Seven clinical trials used atorvastatin, six used simvastatin, and four used rosuvastatin. Six studies reported an increase in SOD activity, seven found no significant changes, and one showed a reduced SOD activity. CONCLUSION: Our systematic review suggests that treatment with statins has a positive effect on SOD activity. However, evidence from further randomized controlled trials is required to confirm the potential antioxidant effect of statin therapy.

BACKGROUND: Ovarian cancer (OVC) is the most common and costly tumor in the world with unfavorable overall survival and prognosis. This study is aimed to explore the prognostic value of natural killer cells related genes for OVC treatment. METHODS: RNA-seq and clinical information were acquired from the TCGA-OVC dataset (training dataset) and the GSE51800 dataset (validation dataset). Genes linked to NK cells were obtained from the immPort dataset. Moreover, ConsensusClusterPlus facilitated the screening of molecular subtypes. Following this, the risk model was established by LASSO analysis, and immune infiltration and immunotherapy were then detected by CIBERSORT, ssGSEA, ESTIMATE, and TIDE algorithms. RESULTS: Based on 23 NK cell-related genes with prognosis, TCGA-OVC samples were classified into two clusters, namely C1 and C2. Of these, C1 had better survival outcomes as well as enhanced immune infiltration and tumor stem cells. Additionally, it was more suitable for immunotherapy and was also sensitive to traditional chemotherapy drugs. The eight-gene prognosis model was constructed and verified via the GSE51800 dataset. Additionally, a high infiltration level of immune cells was observed in low-risk patients. Low-risk samples also benefited from immunotherapy and chemotherapy drugs. Finally, a nomogram and ROC curves were applied to validate model accuracy. CONCLUSION: The present study identified a RiskScore signature, which could stratify patients with different infiltration levels, immunotherapy, and chemotherapy drugs. Our study provided a basis for precisely evaluating OVC therapy and prognosis.

BACKGROUND: MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all mutations in advanced lung adenocarcinomas. While until 2020 no specific treatment was available for this subset of patients, as of today, three MET Tyrosine Kinase Inhibitors (TKIs) are currently approved in this setting, namely capmatinib, tepotinib and savolitinib. OBJECTIVE: This article aims to provide an extensive overview of the current therapeutic standard of care for exon 14 skipped advanced Non-Small Cell Lung Cancer (NSCLC) patients, alongside with mentions of the main future challenges and opportunities. CONCLUSION: FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.

Due to the ever-increasing rate of antibacterial resistance, the search for effective antibacterial agents has become imperative. Researchers have investigated the potential antimicrobial properties of various classes of nonantibiotic drugs. Statins are a group of antihyperlipidemic drugs with several cholesterol-independent effects, including anti-inflammatory, immune-modulating, antioxidant, and antibacterial effects. In vitro and in vivo studies have demonstrated the antibacterial properties of statins against various gram-positive and gram-negative bacteria. Simvastatin and atorvastatin are the most potent members of the family. Their antibacterial effect can be attributed to several direct and indirect mechanisms. Bacterial invasion, growth, and virulence are affected by statins. However, since in vitro minimum inhibitory concentrations (MICs) are significantly higher than serum concentrations at the lipid-lowering dosage, indirect mechanisms have been suggested to explain the positive clinical results, including reducing inflammation and improving immune response capacity. Further, statins have shown promising results when combined with antibiotics and other antibacterial agents, such as triazenes and silver nanoparticles. Despite this, the controversial aspects of statins have cast doubt on their efficacy as a possible solution for antibacterial resistance, and further research is required. Consequently, this review will examine in detail the current clinical and in vitro findings and controversies regarding statins' antibacterial properties and their relevance to antibacterial resistance.

BACKGROUND: The hallmark of non-alcoholic fatty liver disease (NAFLD) is aberrant buildup of triglycerides (TGs) in hepatocytes. Many genes promote NAFLD development. Using bioinformatics tools, we investigated the possible effect of statins on genes involved in NAFLD progression. METHODS: Protein interactions of statins and NAFLD were searched in gene-drug and gene-disease databases. A Protein-Protein interaction (PPI) network was constructed to find hub genes and Molecular Complex Detection (MCODE) of NAFLD-related genes. Shared protein targets between protein targets of statins and NAFLD-associated genes were identified. Next, targets of each statin were assayed with all modular clusters in the MCODEs related to NAFLD. Biological process and pathway enrichment analysis for shared proteins was performed. RESULTS: Screening protein targets for conventional statins and curated NAFLD-related genes identified 343 protein targets and 70 genes, respectively. A Venn diagram of NAFLD-related genes and protein targets of statins showed 24 shared proteins. The biological pathways on KEGG enrichment associated with the 24 shared protein sets were evaluated and included cytokine-cytokine receptor interaction, adipocytokine, PPAR, TNF and AMPK signaling pathways. Gene Ontology analysis showed major involvement in lipid metabolic process regulation and inflammatory response. PPI network analysis of 70 protein targets indicated 13 hub genes (PPARA, IL4, CAT, LEP, SREBF1, PRKCA, CYP2E1, NFE2L2, PTEN, NR1H4, ADIPOQ, GSTP1 and TGFB1). Comparing all seven statins with the three MCODE clusterings and 13 hub genes revealed that simvastatin as the most associated statin with NAFLD. CONCLUSIONS: Simvastatin has the most impact on NAFLD-related genes versus other statins.

Cancers are a huge threat to human life and health. Every year, many people suffer and die from various cancers, and numerous resources have been used to combat cancer. Due to several disadvantages of anticancer agents, such as drug-induced side effects, drug resistance, etc., there are still wide gaps in their ability to conquer cancer. Therefore, there is an urgent need to discover and develop many novel chemotypes to suppress cancer. In this review, we mainly focus on the anticancer potency of two representative sorts of carbazole-based compounds: carboline derivatives and diazacarbazole derivatives. Diazacarbazole derivatives, which have not been fully explored yet, might bring us a new vision and a valuable opportunity for overcoming the enormous hurdle we are now facing in the cancer campaign. We also provide several synthetic approaches for constructing the critical skeletons of the carbazole-based tricyclic compounds.

BACKGROUND: The highly heterogeneous, complex pathological histology, and clinical phenotype in bladder cancer (BC) plague the prognostic management of BC to the present day. METHODS: This study was conducted using single-cell sequencing data from the gene expression omnibus (GEO) database (GSE135337). A descending, annotated analysis was performed to identify the cell types contributing to BC aggressiveness. BC cell sequencing data from The Cancer Genome Atlas (TCGA) database were then combined with univariate, least absolute shrinkage and selection operator (LASSO), multivariate COX regression analysis to identify biomarkers of BC prognosis to construct a BC. We identified biomarkers of BC prognosis to construct a prognostic risk guidance system for BC. The feedback of patients in different risk strata to immunotherapy was analyzed. Finally, the regulation of prognostic genes on cancer cell activity was verified in vitro by Western blot and cell counting kit-8 (CCK8) assays. RESULTS: Macrophages specifically expressing CD68 in BC were the cell type with the highest AUCell score, and CD68 was the biomarker of Tumor-associated macrophages (TAMs). CD68 macrophages were potentially the critical cell type in the aggressive BC subtype. Through univariate, LASSO, multivariate COX-based regression analysis. CTSS, GMFG, ANXA5, GSN, SLC2A3, and FTL were authenticated as prognostic biomarkers (p<0.05) and composed the Risk Score. Patients in the low-risk group showed an excellent survival advantage (p<0.01) and immunotherapy feedback. Additionally, inhibition of GSN expression decreased EMT activity to inhibit bladder cancer cell viability. CONCLUSION: In conclusion, this study provided feedback on the immune cell types associated with aggressiveness in BC. Importantly, a prognostic management system for BC was created based on the genes involved, providing more insight into the aggressive pathological phenotype as well as the prognosis of BC.

Although leishmaniasis is one of the most common parasitic diseases, its traditional treatments suffer from some serious problems. To solve such issues, we can take advantage of the effective nanoparticle-based approaches to deliver anti-leishmanial agents into leishmania-infected macrophages either using passive targeting or using macrophage-related receptors. Despite the high potential of nanotechnology, Liposomal Amphotericin B (AmBisome®) is the only FDA-approved nanoparticle-based anti-leishmanial therapy. In an effort to find more anti-leishmanial nano-drugs, this 2011-2021 review study aimed to investigate the in-vivo and in-vitro effectiveness of poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) in the delivery of some traditional anti-leishmanial drugs. Based on the results, PLGA-NPs could improve solubility, controlled release, trapping efficacy, bioavailability, selectivity, and mucosal penetration of the drugs, while they decreased resistance, dose/duration of administration and organotoxicity of the agents. However, none of these nano-formulations have been able to enter clinical trials so far. We summarized the data about the common problems of anti-leishmanial agents and the positive effects of various PLGA nano-formulations on reducing these drawbacks under both in-vitro and in-vitro conditions in three separate tables. Overall, this study proposes two AmB-loaded PLGA with a 99% reduction in parasite load as promising nanoparticles for further studies.

Mitochondria are the energy factories of cells, and their functions are closely related to cell homeostasis. The mitochondrial unfolded protein response (mtUPR) is a newly discovered mechanism for regulating mitochondrial homeostasis. When unfolded/misfolded proteins accumulate in mitochondria, the mitochondria release signals that regulate the transcription of certain proteins in the nucleus, thereby inducing the correct folding or degradation of proteins in mitochondria. Many studies have also shown that an abnormality of mtUPR is closely related to the occurrence and development of diseases. Here, we summarized the pathways regulating mtUPR signaling and reviewed the research progress on mtUPR in diseases. Finally, we summarized the currently identified agonists and inhibitors of the mtUPR and discussed the potential of the mtUPR as a therapeutic target for diseases.

BACKGROUND AND OBJECTIVE: Endothelial cell activation, characterized by increased levels of vascular cell adhesion molecule 1 (VCAM-1), plays a crucial role in the development of atherosclerosis (AS). Therefore, inhibition of VCAM-1-mediated inflammatory response is of great significance in the prevention and treatment of AS. The tripartite motif (TRIM) protein-TRIM65 is involved in the regulation of cancer development, antivirals and inflammation. We aimed to study the functions of TRIM65 in regulating endothelial inflammation by interacting with VCAM-1 in atherogenesis. METHODS AND RESULTS: In vitro, we report that human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (oxLDL) significantly upregulate the expression of TRIM65 in a time- and dose-dependent manner. Overexpression of TRIM65 reduces oxLDL-triggered VCAM-1 protein expression, decreases monocyte adhesion to HUVECs and inhibits the production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α as well as endothelial oxLDL transcytosis. In contrast, siRNA-mediated knockdown of TRIM65 promotes the expression of VCAM-1, resulting in increased adhesion of monocytes and the release of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α and enhances endothelial oxLDL transcytosis. In vivo, we measured the high expression of TRIM65 in ApoE-/- mouse aortic plaques compared to C57BL/6J mouse aortic plaques. Then, we examined whether the blood levels of VCAM-1 were higher in TRIM65 knockout ApoE-/- mice than in control mice induced by a Western diet. Furthermore, Western blot results showed that the protein expression of VCAM-1 was markedly enhanced in TRIM65 knockout ApoE-/- mouse aortic tissues compared to that of the controls. Immunofluorescence staining revealed that the expression of VCAM-1 was significantly increased in atherosclerotic plaques of TRIM65-/-/ApoE-/- aortic vessels compared to ApoE-/- controls. Mechanistically, TRIM65 specifically interacts with VCAM-1 and targets it for K48-linked ubiquitination. CONCLUSION: Our studies indicate that TRIM65 attenuates the endothelial inflammatory response by targeting VCAM-1 for ubiquitination and provides a potential therapeutic target for the inhibition of endothelial inflammation in AS.

BACKGROUND: Cardiometabolic syndrome (CMS) is a set of metabolic abnormalities that are risk factors for cardiovascular disease (CVD). Apple cider vinegar (ACV) has been used in several studies as a natural agent to improve CMS risk factors. The present study aimed to perform a systematic review and meta-analysis of the effects of ACV consumption on lipid and glycemic parameters. METHODS: PubMed, Scopus, and ISI Web of Science databases were systematically searched to find clinical trials evaluating the effects of ACV consumption on CMS risk factors. RESULTS: Overall, 25 clinical trials (33 arms) comprising 1320 adults were entered in this study. ACV consumption could significantly improve the levels of FBG (-21.20 mg/dl; 95% CI: -32.31 to -2.21; I2: 95.8%), HbA1c (-0.91mg/dl; 95% CI: -1.62 to -0.21; I2: 98.9%), and TC (-6.72 mg/dl; 95% CI: -12.91 to -0.53; I2:50.8%). No significant results were observed for BMI, HOMA-IR, serum insulin, TG, LDL-C, and HDL-C. Subgroup analysis showed a significant decrease in FBG, HbA1c, TC, and TG in diabetic patients. In this type of analysis, ACV consumption significantly reduced FBG levels when administered for both duration subgroups (≥12 and <12 weeks). Moreover, in the subgroup analysis based on duration, TG concentration was significantly decreased following ACV consumption for ≥ 12 weeks. CONCLUSION: This meta-analysis showed that consumption of ACV has a favorable effect in decreasing some CMS risk factors including FBG, HbA1c, and TC.

PURPOSE: It is critical to assess primary liver cancer patients likely to benefit from radiotherapy (RT) or RT plus chemo-immunotherapy. Many potential peripheral biomarkers from blood samples have been proposed for clinical application. Therefore, the aim of this study was to evaluate treatments with radiotherapy alone and radiotherapy plus chemo-immunotherapy in patients with unresectable primary liver cancer based on blood biomarkers. METHODS: From January, 2017, to February, 2022, 63 unresectable primary liver cancer patients receiving radiotherapy alone (RT, n = 21) or radiotherapy plus chemo-immunotherapy (RT plus C/IT, n = 42) were included in this study. We compared the clinical outcomes and adverse effects of these two groups. Also, distant metastasis-free survival (DMFS), overall survival (OS), and progress-free survival (PFS) were retrospectively analyzed. Finally, univariable and multivariable Cox analyses were used to explore the prognostic role of blood biochemical biomarkers. RESULTS: In this study, 1, 2, and 3 years of OS after RT treatment were 63.9%, 27.0%, and 13.5%, and after RT plus C/IT were 68.2%, 37.0%, and 24.7%, respectively (p = 0.617). Compared with baseline, white blood cells (WBC) and lymphocytes were significantly decreased after RT (p=0.002 and p=0.001, respectively) or RT plus C/IT therapy (p=0.135 and p<0.001, respectively). In multivariable Cox regression analyses, higher lymphocyte counts before RT (pre-Lymphocyte) were associated with better OS and PFS (HR=0.439, p=0.023; HR=0.539, p=0.053; respectively), and higher lymphocyte counts before RT (pre- Platelets) were a poor prognostic factor associated with DMFS (HR=1.013, p=0.040). Importantly, OS and PFS were significantly better for patients (pre-Lymphocyte ≥1.10 x 109/L) (p=0.006; p=0.066, respectively). The DMFS was significantly better for patients (pre-platelets < 233.5 ×109/L) (p<0.001). CONCLUSION: Our evaluation of blood biomarkers before and after radiotherapy or plus chem-immunotherapy for primary liver cancer revealed a potential marker for clinics to decide on precise treatment strategies.

This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).

Marine natural products have great pharmacological potential due to their unique and diverse chemical structures. The marine bacterial biodiversity and the unique marine environment lead to a high level of complexity and ecological interaction among marine species. This results in the production of metabolic pathways and adaptation mechanisms that are different from those of terrestrial organisms, which has drawn significant attention from researchers in the field of natural medicine. This review provides an analysis of the distribution and frequency of keywords in the literature on marine bacterial natural products as well as an overview of the new natural products isolated from the secondary metabolites of marine bacteria in recent years. Finally, it discusses the current research hotspots in this field and speculates on future directions and limitations.

Several chronic liver injuries can result in liver fibrosis, a wound-healing response defined by an excessive buildup of diffuse extracellular matrix (ECM). Liver fibrosis may progress to liver cirrhosis, liver failure, or hepatocellular carcinoma. Many cellular routes are implicated in the fibrosis process; however, hepatic stellate cells appear to be the main cell type involved. Curcumin, a polyphenolic substance extracted from the Curcuma longa plant, has a diversity of pharmacologic impacts, including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic actions. The anti-fibrotic property of curcumin is less clear, but curcumin's ability to influence inflammatory cytokines, inflammatory pathways, the expression of pro-apoptotic (up-regulated) and anti-apoptotic (down-regulated) proteins, and its ability to lower oxidative stress likely underlie its anti-fibrotic properties. In this review, we investigate and analyze the impact of curcumin on several disorders that lead to liver fibrosis, and discuss the therapeutic applications of curcumin for these disorders.

Quorum-sensing is a communication mechanism between bacteria with the ability to activate signaling pathways in the bacterium and in the host cells. Pseudomonas aeruginosa is a pathogen with high clinical relevance due to its vast virulence factors repertory and wide antibiotic resistance mechanisms. Due to this, it has become a pathogen of interest for developing new antimicrobial agents in recent years. P. aeruginosa has three major QS systems that regulate a wide gene range linked with virulence factors, metabolic regulation, and environment adaption. Consequently, inhibiting this communication mechanism would be a strategy to prevent the pathologic progression of the infections caused by this bacterium. In this review, we aim to overview the current studies about the signaling mechanisms of the QS system of P. aeruginosa and its effects on this bacterium and the host.

Several investigations have revealed that nasopharyngeal carcinoma (NPC), earlier known as lymphoepithelioma, originates from the nasopharynx epithelium (NPE). The global NPC incidence and mortality distribution reports have reported very high rates (more than 20-30 men per 100,000 men and 10 women per 100,000). Genetic background susceptibilities, Epstein-Barr virus (EBV), and their complex interaction are expressed as the pathophysiology. Also, radiotherapy of locoregional lesions is the main treatment for NPC because of the extremely radiosensitive feature of the non-keratinizing variety. On the other hand, surgical intervention might be used for recurrent situations, while simultaneous radiation and chemotherapy for advanced stages are preferable. Since specific disease symptoms do not appear early, biomarkers should be identified to facilitate diagnosis. As overexpression of heat shock proteins (HSPs) has been observed in various cancers, they can be a promising candidate biomarker for many malignancies. The purpose of this study was to peruse different pathogenic roles of a panel of HSPs, including their diagnostic, preventive, and remedial role in NPC, which may provide the basis for future discoveries of novel HSP-based biomarkers of NPC.

Stress is a critical factor in the etiology of inflammation and neurodegeneration. The risk factor for the majority of psychiatric disorders is oxidative stress-induced depression. Mitochondrial damage and oxidative stress are associated with the development of neurodegenerative disorders. During aging, the brain and associated regions become more susceptible due to oxidative stress. The leading cause of oxidative stress is the continuous generation of ROS (reactive oxygen species) and RNS (Reactive nitrogen species) endogenously or exogenously. In this review, discussion on a potent antioxidant natural constituent "curcumin" has been made to alleviate many pathological and neurological disorders. A focused compilation of vast and informative research on the potential of curcumin as a magical moiety used therapeutically has been done in search of its role in controlling the neurological and similar disorders induced by oxidative stress.

BACKGROUND: Single-cell technology enables a deep study on the mechanism of cancers. This work delineated the function of ligand-receptor [1] interaction in colon adenocarcinoma (COAD), and developed a LR pairs-based prognostic model. METHODS: For identifying important LR pairs, Single-cell RNA sequencing data of COAD was included. Unsupervised consensus clustering constructed molecular subtypes. LASSO established a prognostic model. Infiltration of 22 immune cells was evaluated by Cibersort. Enrichment score of oxidative stress related pathways was determined by SsGSEA in each patient. RESULTS: Forty-seven LR pairs were closely associated with the prognosis of COAD. Three molecular subtypes were differentiated according to 47 LR pairs, which displayed differential clinical features and molecular features. There were significant differences in immune T cell lytic activity among different subtypes. In clust1 with poor prognosis, significantly enriched oncogenic pathways were found, especially epithelial-mesenchymal transition (EMT). Additionally, it has been found that clust3 had significantly higher immune infiltration. A prognostic model containing eight LR pairs (PDGFB-PDGFRA, FLT4-VEGFC, CSF1R-CSF1, DLL1-NOTCH4, PDGFB-LRP1, DLL1-NOTCH3, FLT4-PDGFC, and NRP2-PGF) was established, which could effectively divide samples into low-risk and high-risk groups. Significantly higher oxidative stress was found among high-risk patients. CONCLUSIONS: This study integrated expression data and single-cell data for demonstrating the effectiveness of LR pairs in establishing the prognostic model and constructing molecular subtypes. Prognostic LR pairs may contribute to tumorigenesis and progression in COAD. The prognostic model was the potential for predicting prognosis and guiding immunotherapy for COAD patients.

Radiopharmaceuticals are increasingly playing a leading role in diagnosing, monitoring, and treating disease. In comparison with conventional pharmaceuticals, the development of radiopharmaceuticals does follow the principles of medicinal chemistry in the context of imaging-altered physiological processes. The design of a novel radiopharmaceutical has several steps similar to conventional drug discovery and some particularity. In the present work, we revisited the insights of medicinal chemistry in the current radiopharmaceutical development giving examples in oncology, neurology, and cardiology. In this regard, we overviewed the literature on radiopharmaceutical development to study overexpressed targets such as prostate-specific membrane antigen and fibroblast activation protein in cancer; β-amyloid plaques and tau protein in brain disorders; and angiotensin II type 1 receptor in cardiac disease. The work addresses concepts in the field of radiopharmacy with a special focus on the potential use of radiopharmaceuticals for nuclear imaging and theranostics.

INTRODUCTION: The role of lipid metabolism in lung adenocarcinoma (LUAD) is not completely researched. Lipid metabolism reprogramming is a characteristic of malignancies and contributes to carcinogenesis and progression. The transcriptome and scRNA-seq data and clinical information were downloaded from the public databases. METHOD: Lipid metabolism pathways were collected from the MSigDB database, and molecular subtypes were classified based on lipid metabolism features via consensus clustering. The bidirectional crosstalk between immune cells and malignant cells was analyzed. Differences in lipid metabolism at the single-cell level and their correlation with the tumor microenvironment (TME) were also studied. LUAD patients were classified into two subtypes, showing distinct mutation and lipid metabolism features based on lipid metabolism characteristics. Meanwhile, significant differences in the overall survival, clinical characteristics, and immune landscape were observed between the two subtypes. We also found that clust1 had higher oxidative stress status. There were 116 differentially expressed genes between the two subtypes, which were significantly associated with cell cycle progression. We identified 4001 immune cells, including 483 malignant cells and 3518 normal cells, and found active intercellular communication and significant differences in lipid metabolism characteristics between the malignant cells and normal cells. Furthermore, several lipid metabolism pathways were found to be associated with TME factors, including hypoxia and angiogenesis. RESULT: The current findings indicated that lipid metabolism was involved in the development and cellular heterogeneity of LUAD and revealed widespread reprogramming across multiple cellular elements in the TME of LUAD. CONCLUSION: This characterization improved the current understanding of tumor biology and enabled the identification of novel targets for immunotherapy.

BACKGROUND: Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. METHOD: This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. CONCLUSION: NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the accumulation of α-synuclein and the degeneration of dopaminergic neurons in the substantia nigra. Although the molecular bases for PD development are not fully recognized, extensive evidence has suggested that the development of PD is strongly associated with neuroinflammation. It is noteworthy that while neuroinflammation might not be a primary factor in all patients with PD, it seems to be a driving force for disease progression, and therefore, exploring the role of pathways involved in neuroinflammation is of great importance. Besides, the importance of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and competing endogenous RNAs (ceRNAs), has been widely studied with a focus on the pathogenesis of PD. However, there is no comprehensive review regarding the role of neuroinflammation-related ncRNAs as prospective biomarkers and therapeutic targets involved in the pathogenesis of PD, even though the number of studies connecting ncRNAs to neuroinflammatory pathways and oxidative stress has markedly increased in the last few years. Hence, the present narrative review intended to describe the crosstalk between regulatory ncRNAs and neuroinflammatory targets with respect to PD to find and propose novel combining biomarkers or therapeutic targets in clinical settings.

BACKGROUND: Acne is a highly prevalent disease that mainly affects the pilosebaceous units associated with sebaceous glands, causing inflammatory skin lesions and affecting the self-esteem, mental health, and quality of life of those who suffer from this disease. Different treatments exist today to prevent, reduce, and improve symptoms; however, over the years, there have been problems with bacterial resistance and slight effectiveness with prolonged use. OBJECTIVE: The purpose of this article is based on the review of patents of new products of principal topical administration for the treatment of acne in recent years 2016-2020, to evaluate and analyze novel synthetic molecules and semi-synthetics with potential therapeutic and preventive in the acne treatment. METHODS: A systematic review of patents was conducted through the official database of the European Patent Office - Espacenet, where the search focused on the keywords: "acne and bacteria" in the title or abstract. Only patents granted between the years 2016-2020 were included, with products having molecules with a synthetic and semi-synthetic origin, without considering natural, biological products or those used as diagnostic means. RESULTS: A total of 19 patents were selected, most with principally antimicrobial and anti-inflammatory action, where the reduction in the appearance of resistance by C. acnes is verified, and its action is complemented by inhibiting the different pathophysiological mechanisms that lead to the worsening of the disease. CONCLUSION: Novel approaches in the treatment and prevention of acne, mainly topically, are focused on the reduction of bacterial resistance and irritation compared to current treatments. The use of combined formulations provides better results with additional benefits, improving treatment times and patient adherence.

The unique characteristics of nanoparticles (NPs) have captivated scientists in various fields of research. However, their safety profile has not been fully scrutinized. In this regard, the effects of NPs on the reproductive system of animals and humankind have been a matter of concern. In this article, we will review the potential reproductive toxicity of various types of NPs, including carbon nanomaterials, dendrimers, quantum dots, silica, gold, and magnetic nanoparticles, reported in the literature. We also mention some notable cases where NPs have elicited beneficial effects on the reproductive system. This review provides extensive insight into the effects of various NPs on sperm and ovum and the outcomes of their passage through blood-testis and placental barriers and accumulation in the reproductive organs.

Morbidity, disability, and healthcare expenses associated with rheumatoid arthritis (RA) impose a considerable health and economical burden on both patients and healthcare systems. This review aimed to examine the pathophysiological aspects of RA that may help design different types of drugs and drug delivery systems. These include monoclonal antibodies, immunoglobulins, tiny chemicals, and transgenes for gene therapy. These novel nanocarrier-based therapies target the underlying biological processes involved in RA while minimizing the systemic adverse effects of drugs.

Alcoholism is a global health concern. Due to its role as the principal site of ethanol metabolism, the liver endures the most significant amount of tissue damage from heavy drinking. Numerous liver lesions can result from chronic and heavy alcohol use, including steatosis, hepatitis, and fibrosis/cirrhosis. Fatty liver is caused by a redox shift from the oxidized to the reduced form of nicotinamide adenine dinucleotide (NAD+) caused by the ethanol oxidation reaction. The other molecular mechanisms related to the progression of alcohol-induced liver injury are increasing sterol regulatory element-binding protein-1 (SREBP-1) and decreasing PPAR-α activity, cell signaling pathway impairment, reactive oxygen species (ROS) accumulation, and lipid peroxidation. Curcuma longa L. rhizomes contain a substance called curcumin, which is naturally yellow in color and is also known as turmeric yellow. Curcumin has powerful biological and pharmacological properties, including antioxidant, anti-inflammatory, antifungal, antibacterial, antitumor, and anticancer effects. It's been employed as a hepatoprotective substance. Current studies have demonstrated the ability of curcumin to prevent the activation of NF-κB in Kupffer cells via endotoxins, to suppress the expression of various cytokines, chemokines, cyclooxygenase-2 (COX-2), and iNOS, as well as to modulate immune responses. The present study has shown the vital role of curcumin in a variety of hepatotoxic procedures, and summarizes those effects, focusing on the molecular insights they provide.

Tyrosine kinases are implicated in a wide array of cellular physiological processes, including cell signaling. The discovery of the BCR-ABL tyrosine kinase inhibitor imatinib and its FDA approval in 2001 paved the way for the development of small molecule chemical entities of diverse structural backgrounds as tyrosine kinase inhibitors for the treatment of various ailments. Two of the most prominent tyrosine kinases as drug targets are the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), as evidenced by the clinical success of their many inhibitors in the drug market. Among several other physiological roles, EGFR regulates epithelial tissue development and homeostasis, while VEGFR regulates tumor-induced angiogenesis. The pyrrolo[2,3-d]pyrimidine nucleus represents a deaza-isostere of adenine, the nitrogenous base of ATP. The recent introduction of many pyrrolo[2,3-d]pyrimidines to the drug market as tyrosine kinase inhibitors makes them a hot topic in the medicinal chemistry research area at the present time. This review article comprehensively sheds light on the structure-activity relationship (SAR) of pyrrolo[2,3-d]pyrimidines as EGFR and VEGFR tyrosine kinase inhibitors, aiming to provide help medicinal chemists in the design of future pyrrolopyrimidine kinase inhibitors.

BACKGROUND: It has been widely reported that the use of probiotics has beneficial effects on the prevention and treatment of a wide range of human diseases. Previous clinical trials have investigated the effect of probiotics on oxLDL, but the results are controversial. OBJECTIVE: This study aimed to conduct a systematic review and meta-analysis of clinical trials to assess the effect of probiotic consumption on oxLDL levels. METHOD: A comprehensive search was conducted in PubMed, ISI Web of Science, and Scopus using the appropriate search strategy. After the screening, seven studies comparing the effects of probiotic consumption with the control were included in the analysis. A random-effects analysis was used to estimate the overall effect size. RESULTS: Probiotic supplementation significantly reduced oxLDL (Hedge's: -1.18; 95% CI:-1.85, -0.52) compared to the control group. Subgroup analysis showed that reduction was greater in the unhealthy group compared to healthy subjects (-2.05 vs. -0.84). The results also showed that probiotic supplementation reduced TC by -14.77 mg/dl (95% CI: -24.46, -5.08), LDL-C by -10.03 mg/dl (95% CI: -16.05, -4.001), LDL-C/HDL-C ratio by -0.37 (95% CI: -0.66, 0.07), and TG by -14.86 mg/dl (95% CI: -23.45, -6.28) but the effects on HDL-C and glucose were not significant. CONCLUSION: In this study, probiotic supplementation was found to improve oxLDL concentrations and have favorable effects on lipid profiles, but no significant positive effect on HDL-C and glucose was reported. However, the findings should be interpreted with caution due to the low number of included studies.