Pro- and anti-inflammatory cytokines are the game-changers in childhood obesity-associated metabolic disorders (diabetes and non-alcoholic fatty liver diseases).

Childhood obesity is a chronic inflammatory epidemic that affects children worldwide. Obesity affects approximately 1 in 5 children worldwide. Obesity in children can worsen weight gain and raise the risk of obesity-related comorbidities like diabetes and non-alcoholic fatty liver disease (NAFLD). It can also negatively impact the quality of life for these children. Obesity disrupts immune system function, influencing cytokine (interleukins) balance and expression levels, adipokines, and innate and adaptive immune cells. The altered expression of immune system mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17 (IL-17), interleukin-18 (IL-18), transforming growth factor (TGF), tumor necrosis factor (TNF), and others, caused inflammation, progression, and the development of pediatric obesity and linked illnesses such as diabetes and NAFLD. Furthermore, anti-inflammatory cytokines, including interleukin-2 (IL-2), have been shown to have anti-diabetes and IL-1 receptor antagonist (IL-1Ra) anti-diabetic and pro-NAFLFD properties, and interleukin-10 (IL-10) has been shown to have a dual role in managing diabetes and anti-NAFLD. In light of the substantial increase in childhood obesity-associated disorders such as diabetes and NAFLD and the absence of an effective pharmaceutical intervention to inhibit immune modulation factors, it is critical to consider the alteration of immune system components as a preventive and therapeutic approach. Thus, the current review focuses on the most recent information regarding the influence of pro- and anti-inflammatory cytokines (interleukins) and their molecular mechanisms on pediatric obesity-associated disorders (diabetes and NAFLD). Furthermore, we discussed the current therapeutic clinical trials in childhood obesity-associated diseases, diabetes, and NAFLD.

Natural products act as game-changer potentially in treatment and management of sepsis-mediated inflammation: A clinical perspective.

BACKGROUND: Sepsis, a life-threatening condition resulting from uncontrolled host responses to infection, poses a global health challenge with limited therapeutic options. Due to high heterogeneity, sepsis lacks specific therapeutic drugs. Additionally, there remains a significant gap in the clinical management of sepsis regarding personalized and precise medicine. PURPOSE: This review critically examines the scientific landscape surrounding natural products in sepsis and sepsis-mediated inflammation, highlighting their clinical potential. METHODS: Following the PRISMA guidelines, we retrieved articles from PubMed to explore potential natural products with therapeutic effects in sepsis-mediated inflammation. RESULTS: 434 relevant in vitro and in vivo studies were identified and screened. Ultimately, 55 studies were obtained as the supporting resources for the present review. We divided the 55 natural products into three categories: those influencing the synthesis of inflammatory factors, those affecting surface receptors and modulatory factors, and those influencing signaling pathways and the inflammatory cascade. CONCLUSION: Natural products' potential as game-changers in sepsis-mediated inflammation management lies in their ability to modulate hallmarks in sepsis, including inflammation, immunity, and coagulopathy, which provides new therapeutic avenues that are readily accessible and capable of undergoing rapid clinical validation and deployment, offering a gift from nature to humanity. Innovative techniques like bioinformatics, metabolomics, and systems biology offer promising solutions to overcome these obstacles and facilitate the development of natural product-based therapeutics, holding promise for personalized and precise sepsis management and improving patient outcomes. However, standardization, bioavailability, and safety challenges arise during experimental validation and clinical trials of natural products.

Pro-inflammatory Cytokines and CXC Chemokines as Game-Changer in Age-Associated Prostate Cancer and Ovarian Cancer: Insights from Preclinical and Clinical Studies' Outcomes.

Prostate cancer (PC) and Ovarian cancer (OC) are two of the most common types of cancer that affect the reproductive systems of older men and women. These cancers are associated with a poor quality of life among the aged population. Therefore, finding new and innovative ways to detect, treat, and prevent these cancers in older patients is essential. Finding biomarkers for these malignancies will increase the chance of early detection and effective treatment, subsequently improving the survival rate. Studies have shown that the prevalence and health of some illnesses are linked to an impaired immune system. However, the age-associated changes in the immune system during malignancies such as PC and OC are poorly understood. Recent research has suggested that the excessive production of inflammatory immune mediators, such as interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor (TGF), tumor necrosis factor (TNF), CXC motif chemokine ligand 1 (CXCL1), CXC motif chemokine ligand 12 (CXCL12), and CXC motif chemokine ligand 13 (CXCL13), etc., significantly impact the development of PC and OC in elderly patients. Our review focuses on the latest functional studies of pro-inflammatory cytokines (interleukins) and CXC chemokines, which serve as biomarkers in elderly patients with PC and OC. Thus, we aim to shed light on how these biomarkers affect the development of PC and OC in elderly patients. We also examine the current status and future perspective of cytokines (interleukins) and CXC chemokines-based therapeutic targets in OC and PC treatment for elderly patients.

Establishing and Validating an Innovative Focal Adhesion-Linked Gene Signature for Enhanced Prognostic Assessment in Endometrial Cancer.

Studies have highlighted the significant role of focal adhesion signaling in cancer. Nevertheless, its specific involvement in the pathogenesis of endometrial cancer and its clinical significance remains uncertain. We analyzed TCGA-UCEC and GSE119041 datasets with corresponding clinical data to investigate focal adhesion-related gene expression and their clinical significance. A signature, "FA-riskScore," was developed using LASSO regression in the TCGA cohort and validated in the GSE dataset. The FA-riskScore was compared with four existing models in terms of their prediction performance. We employed univariate and multivariate Cox regression analyses towards FA-riskScore to assess its independent prognostic value. A prognostic evaluation nomogram based on our model and clinical indexes was established subsequently. Biological and immune differences between high- and low-risk groups were explored through functional enrichment, PPI network analysis, mutation mining, TME evaluation, and single-cell analysis. Sensitivity tests on commonly targeted drugs were performed on both groups, and Connectivity MAP identified potentially effective molecules for high-risk patients. qRT-PCR validated the expressions of FA-riskScore genes. FA-riskScore, based on FN1, RELN, PARVG, and PTEN, indicated a poorer prognosis for high-risk patients. Compared with published models, FA-riskScore achieved better and more stable performance. High-risk groups exhibited a more challenging TME and suppressive immune status. qRT-PCR showed differential expression in FN1, RELN, and PTEN. Connectivity MAP analysis suggested that BU-239, potassium-canrenoate, and tubocurarine are effective for high-risk patients. This study introduces a novel prognostic model for endometrial cancer and offers insights into focal adhesion's role in cancer pathogenesis.

Revolutionizing pediatric neuroblastoma treatment: unraveling new molecular targets for precision interventions.

Neuroblastoma (NB) is the most frequent solid tumor in pediatric cases, contributing to around 15% of childhood cancer-related deaths. The wide-ranging genetic, morphological, and clinical diversity within NB complicates the success of current treatment methods. Acquiring an in-depth understanding of genetic alterations implicated in the development of NB is essential for creating safer and more efficient therapies for this severe condition. Several molecular signatures are being studied as potential targets for developing new treatments for NB patients. In this article, we have examined the molecular factors and genetic irregularities, including those within insulin gene enhancer binding protein 1 (ISL1), dihydropyrimidinase-like 3 (DPYSL3), receptor tyrosine kinase-like orphan receptor 1 (ROR1) and murine double minute 2-tumor protein 53 (MDM2-P53) that play an essential role in the development of NB. A thorough summary of the molecular targeted treatments currently being studied in pre-clinical and clinical trials has been described. Recent studies of immunotherapeutic agents used in NB are also studied in this article. Moreover, we explore potential future directions to discover new targets and treatments to enhance existing therapies and ultimately improve treatment outcomes and survival rates for NB patients.

Unlocking the potential of oncology biomarkers: advancements in clinical theranostics.

INTRODUCTION: Cancer biomarkers have revolutionized the field of oncology by providing valuable insights into tumor changes and aiding in screening, diagnosis, prognosis, treatment prediction, and risk assessment. The emergence of "omic" technologies has enabled biomarkers to become reliable and accurate predictors of outcomes during cancer treatment. CONTENT: In this review, we highlight the clinical utility of biomarkers in cancer identification and motivate researchers to establish a personalized/precision approach in oncology. By extending a multidisciplinary technology-based approach, biomarkers offer an alternative to traditional techniques, fulfilling the goal of cancer therapeutics to find a needle in a haystack. SUMMARY AND OUTLOOK: We target different forms of cancer to establish a dynamic role of biomarkers in understanding the spectrum of malignancies and their biochemical and molecular characterization, emphasizing their prospective contribution to cancer screening. Biomarkers offer a promising avenue for the early detection of human cancers and the exploration of novel technologies to predict disease severity, facilitating maximum survival and minimum mortality rates. This review provides a comprehensive overview of the potential of biomarkers in oncology and highlights their prospects in advancing cancer diagnosis and treatment.

Warfarin-A natural anticoagulant: A review of research trends for precision medication.

BACKGROUND: Warfarin is a widely prescribed anticoagulant in the clinic. It has a more considerable individual variability, and many factors affect its variability. Mathematical models can quantify the quantitative impact of these factors on individual variability. PURPOSE: The aim is to comprehensively analyze the advanced warfarin dosing algorithm based on pharmacometrics and machine learning models of personalized warfarin dosage. METHODS: A bibliometric analysis of the literature retrieved from PubMed and Scopus was performed using VOSviewer. The relevant literature that reported the precise dosage of warfarin calculation was retrieved from the database. The multiple linear regression (MLR) algorithm was excluded because a recent systematic review that mainly reviewed this algorithm has been reported. The following terms of quantitative systems pharmacology, mechanistic model, physiologically based pharmacokinetic model, artificial intelligence, machine learning, pharmacokinetic, pharmacodynamic, pharmacokinetics, pharmacodynamics, and warfarin were added as MeSH Terms or appearing in Title/Abstract into query box of PubMed, then humans and English as filter were added to retrieve the literature. RESULTS: Bibliometric analysis revealed important co-occuring MeShH and index keywords. Further, the United States, China, and the United Kingdom were among the top countries contributing in this domain. Some studies have established personalized warfarin dosage models using pharmacometrics and machine learning-based algorithms. There were 54 related studies, including 14 pharmacometric models, 31 artificial intelligence models, and 9 model evaluations. Each model has its advantages and disadvantages. The pharmacometric model contains biological or pharmacological mechanisms in structure. The process of pharmacometric model development is very time- and labor-intensive. Machine learning is a purely data-driven approach; its parameters are more mathematical and have less biological interpretation. However, it is faster, more efficient, and less time-consuming. Most published models of machine learning algorithms were established based on cross-sectional data sourced from the database. CONCLUSION: Future research on personalized warfarin medication should focus on combining the advantages of machine learning and pharmacometrics algorithms to establish a more robust warfarin dosage algorithm. Randomized controlled trials should be performed to evaluate the established algorithm of warfarin dosage. Moreover, a more user-friendly and accessible warfarin precision medicine platform should be developed.

Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. Using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

BACKGROUND: Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. AIM: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. METHODS: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. RESULTS: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. CONCLUSION: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Exploring the pathophysiological influence of heme oxygenase-1 on neuroinflammation and depression: A study of phytotherapeutic-based modulation.

BACKGROUND: The heme oxygenase (HO) system plays a significant role in neuroprotection and reduction of neuroinflammation and neurodegeneration. The system, via isoforms HO-1 and HO-2, regulates cellular redox balance. HO-1, an antioxidant defense enzyme, is highlighted due to its association with depression, characterized by heightened neuroinflammation and impaired oxidative stress responses. METHODOLOGY: We observed the pathophysiology of HO-1 and phytochemicals as its modulator. We explored Science Direct, Scopus, and PubMed for a comprehensive literature review. Bibliometric and temporal trend analysis were done using VOSviewer. RESULTS: Several phytochemicals can potentially alleviate neuroinflammation and oxidative stress-induced depressive symptoms. These effects result from inhibiting the MAPK and NK-κB pathways - both implicated in the overproduction of pro-inflammatory factors - and from the upregulation of HO-1 expression mediated by Nrf2. Bibliometric and temporal trend analysis further validates these associations. CONCLUSION: In summary, our findings suggest that antidepressant agents can mitigate neuroinflammation and depressive disorder pathogenesis via the upregulation of HO-1 expression. These agents suppress pro-inflammatory mediators and depressive-like symptoms, demonstrating that HO-1 plays a significant role in the neuroinflammatory process and the development of depression.

Fermented formulation of Silybum marianum seeds: Optimization, heavy metal analysis, and hepatoprotective assessment.

BACKGROUND: Fermented formulations are extensively used in Ayurveda due to several benefits like improved palatability, bioavailability, pharmacological potential, and shelf life. These formulations can also quench the heavy metals from the plant material and thus reduce the toxicity. Seeds of Silybum marianum (L.) Gaertn. are widely used for the management of many liver diseases. STUDY DESIGN AND METHODS: In the present study, we developed a novel fermented formulation of S. marianum seeds and evaluated parameters like safety (heavy metal analysis) and effectiveness (hepatoprotective). As the developed formulation's validation is crucial, the critical process variables (time, pH, and sugar concentration) are optimized for alcohol and silybin content using the Box-Behnken design (BBD). RESULTS: The response surface methodology coupled with BBD predicted the optimized conditions (fermentation time (28 days), pH 5.6, and sugar concentration (22.04%)) for the development of a fermented formulation of the selected herb. Moreover, the alcohol content (6.5 ± 0.9%) and silybin concentration (26.1 ± 2.1%) were confirmed in optimized formulation by GC-MS and HPTLC analysis. The optimized formulation was also analyzed for heavy metals (Pb, As, Hg, and Cd); their concentration is significantly less than the decoction of herbs. Further, the comparative evaluation of the developed formulation with the marketed formulation also confirmed that the fermented formulation's silybin concentration and percentage release were significantly enhanced. In addition, the developed fermented formulation's percentage recovery of HepG2 cell lines after treatment with CCl4 was significantly improved compared with the marketed formulation. CONCLUSION: It can be summarized that the developed fermented formulation improves safety and effectiveness compared to other market formulations. Finally, it can be concluded that the developed fermented formulation could be further explored as a better alternative for developing Silybum marianum preparation.

Involvement of CXC chemokines (CXCL1-CXCL17) in gastric cancer: Prognosis and therapeutic molecules.

Gastric cancer (GC) is the fifth-most prevalent and second-most deadly cancer worldwide. Due to the late onset of symptoms, GC is frequently treated at a mature stage. In order to improve the diagnostic and clinical decision-making processes, it is necessary to establish more specific and sensitive indicators valuable in the early detection of the disease whenever a cancer is asymptomatic. In this work, we gathered information about CXC chemokines and GC by using scientific search engines including Google Scholar, PubMed, SciFinder, and Web of Science. Researchers believe that GC chemokines, small proteins, class CXC chemokines, and chemokine receptors promote GC inflammation, initiation, and progression by facilitating angiogenesis, tumor transformation, invasion, survival, metastatic spread, host response safeguards, and inter-cell interaction. With our absolute best professionalism, the role of CXC chemokines and their respective receptors in GC diagnosis and prognosis has not been fully explained. This review article updates the general characteristics of CXC chemokines, their unique receptors, their function in the pathological process of GC, and their potential application as possible indicators for GC. Although there have only recently been a few studies focusing on the therapeutic efficacy of CXC chemokine inhibitors in GC, growing experimental evidence points to the inhibition of CXC chemokines as a promising targeted therapy. Therefore, further translational studies are warranted to determine whether specific antagonists or antibodies designed to target CXC chemokines alone or in combination with chemotherapy are useful for diagnosing advanced GC.

Pathophysiological impact of CXC and CX3CL1 chemokines in preeclampsia and gestational diabetes mellitus.

Diabetes-related pathophysiological alterations and various female reproductive difficulties were common in pregnant women with gestational diabetes mellitus (GDM), who had 21.1 million live births. Preeclampsia (PE), which increases maternal and fetal morbidity and mortality, affects approximately 3%-5% of pregnancies worldwide. Nevertheless, it is unclear what triggers PE and GDM to develop. Therefore, the development of novel moderator therapy approaches is a crucial advancement. Chemokines regulate physiological defenses and maternal-fetal interaction during healthy and disturbed pregnancies. Chemokines regulate immunity, stem cell trafficking, anti-angiogenesis, and cell attraction. CXC chemokines are usually inflammatory and contribute to numerous reproductive disorders. Fractalkine (CX3CL1) may be membrane-bound or soluble. CX3CL1 aids cell survival during homeostasis and inflammation. Evidence reveals that CXC and CX3CL1 chemokines and their receptors have been the focus of therapeutic discoveries for clinical intervention due to their considerable participation in numerous biological processes. This review aims to give an overview of the functions of CXC and CX3CL1 chemokines and their receptors in the pathophysiology of PE and GDM. Finally, we examined stimulus specificity for CXC and CX3CL1 chemokine expression and synthesis in PE and GDM and preclinical and clinical trials of CXC-based PE and GDM therapies.

Revisiting Licorice as a functional food in the management of neurological disorders: Bench to trend.

Traditional and scientific evidence attribute numerous bioactivities of Licorice (Glycyrrhiza glabra Linn.) in aging-related disorders. In this state-of-art review, an extensive search in several databases was conducted to collect all relevant literature and comprehensively analyze Licorice's pharmacological attributes, neuroprotective properties, safety, and its mechanistic role in treating various neurological conditions. Network pharmacology was employed for the first time exploring the mechanistic role of Licorice in neurological disorders. Its neuroprotective role is attributed to phytoconstituents, including liquiritin, glycyrrhizic acid, liquiritigenin, glabridin, 18ß-glycyrrhetinic acid, quercetin, isoliquiritigenin, paratocarpin B, glycyglabrone, and hispaglabridin B, as evident from in vitro and in vivo studies. Network pharmacology analysis reveals that these compounds protect against long-term depression, aging-associated diseases, Alzheimer's disease, and other addictions through interactions with cholinergic, dopaminergic, and serotonergic proteins, validated in animal studies only. Future clinical trials are warranted as Licorice administration has a limiting factor of mild hypertension and hypokalemia. Hopefully, scientific updates on Licorice will propagate a paradigm shift in medicine, research propagation, and development of the central nervous system phytopharmaceuticals.

Opuntia ficus-indica (L.) Mill. - anticancer properties and phytochemicals: current trends and future perspectives.

Cancer is a leading cause of mortality worldwide, and conventional cancer therapies such as chemotherapy and radiotherapy often result in undesirable and adverse effects. Natural products have emerged as a promising alternative for cancer treatment, with comparatively fewer side effects reported. Opuntia ficus-indica (L.) Mill., a member of the Cactaceae family, contains a diverse array of phytochemicals, including flavonoids, polyphenols, betalains, and tannins, which have been shown to exhibit potent anticancer properties. Various parts of the Opuntia plant, including the fruits, stems/cladodes, and roots, have demonstrated cytotoxic effects against malignant cell lines in numerous studies. This review comprehensively summarizes the anticancer attributes of the phytochemicals found in Opuntia ficus-indica (L.) Mill., highlighting their potential as natural cancer prevention and treatment agents. Bibliometric metric analysis of PubMed and Scopus-retrieved data using VOSviewer as well as QDA analysis provide further insights and niche to be explored. Most anticancer studies on Opuntia ficus-indica and its purified metabolites are related to colorectal/colon cancer, followed by melanoma and breast cancer. Very little attention has been paid to leukemia, thyroid, endometrial, liver, and prostate cancer, and it could be considered an opportunity for researchers to explore O. ficus-indica and its metabolites against these cancers. The most notable mechanisms expressed and validated in those studies are apoptosis, cell cycle arrest (G0/G1 and G2/M), Bcl-2 modulation, antiproliferative, oxidative stress-mediated mechanisms, and cytochrome c. We have also observed that cladodes and fruits of O. ficus-indica have been more studied than other plant parts, which again opens the opportunity for the researchers to explore. Further, cell line-based studies dominated, and very few studies were related to animal-based experiments. The Zebrafish model is another platform to explore. However, it seems like more in-depth studies are required to ascertain clinical utility of this biosustainable resource O. ficus-indica.

Nanomedicine: Innovative Strategies and Recent Advances in Targeted Cancer Therapy.

Nanomedicine's application of nanotechnology in medicine holds tremendous potential for diagnosing and treating life-threatening diseases such as cancer. Unlike conventional therapies, nanomedicine offers a promising strategy to enhance clinical outcomes while minimizing severe side effects. The principle of drug targeting enables specific delivery of therapeutic agents to their intended sites, making it a more precise and effective therapy. Combination strategies, such as the co-delivery of chemotherapeutic drugs with nucleic acids or receptor-specific molecules, are being employed to enhance therapeutic outcomes. Nanocarriers and drug delivery systems designed using these approaches offer resourceful co-delivery of therapeutic agents for anticancer therapy. Targeted drug delivery via nanotechnology-based techniques has become an urgent need and has shown significant improvements in therapeutic implications, pharmacokinetics, specificity, reduced toxicity, and biocompatibility. This review discusses the extrapolation of nanomaterials for developing innovative and novel drug delivery systems for effective anticancer therapy. Additionally, we explore the role of nanotechnology-based concepts in drug delivery research.

Phytochemical profiling and biological activities of Diplazium esculentum (Retz.) Sw.: an edible vegetable fern.

OBJECTIVES: Diplazium esculentum (Retz.) Sw. is an edible vegetable fern of the Himalayan region with high nutritional and therapeutic value owing to its richness in various secondary metabolites and both macro and micronutrients. CONTENT: This updated review discusses the general traditional use, ethnopharmacology, phytochemistry, nutritional value, pharmacology, and toxicity concerns of D. esculentum. SUMMARY: The plant parts, viz. rhizomes, shoots, fronds and leaves, have immense ethnomedicinal importance, being traditionally used to cure several health disorders. Among other pharmacological effects, this botanical reveals excellent anti-inflammatory, analgesic, antifungal, antibacterial, antioxidant, anti-leishmanial, antioxidant, anaphylactic, antipyretic, anthelmintic and hepatoprotective activities, directly attributed to the presence of many secondary metabolites. From a pharmacological point of view, the excellent antioxidant potential of D. esculentum suggests its promising use for nutraceutical or functional food formulation purposes. OUTLOOK: Considering the evidences on popular ethnomedicinal uses of D. esculentum as an edible vegetable, its immense bio-potential, and multiple pharmacological roles, there is a huge need to evaluate its therapeutic applications in light of standard clinical trials.

Exploring the complex relationship between vitamin K, gut microbiota, and warfarin variability in cardiac surgery patients.

BACKGROUND AND OBJECTIVES: Due to the high individual variability of anticoagulant warfarin, this study aimed to investigate the effects of vitamin K concentration and gut microbiota on individual variability of warfarin in 246 cardiac surgery patients. METHODS: The pharmacokinetics and pharmacodynamics (PKPD) model predicted international normalized ratio (INR) and warfarin concentration. Serum and fecal samples were collected to detect warfarin and vitamin K [VK1 and menaquinone-4 (MK4)] concentrations and gut microbiota diversity, respectively. In addition, the patient's medical records were reviewed for demographic characteristics, drug history, and CYP2C9, VKORC1, and CYP4F2 genotypes. RESULTS: The PKPD model predicted ideal values of 62.7% for S-warfarin, 70.4% for R-warfarin, and 76.4% for INR. The normal VK1 level was 1.34±1.12 nmol/ml (95% CI: 0.33-4.08 nmol/ml), and the normal MK4 level was 0.22±0.18 nmol/ml (95% CI: 0.07-0.63 nmol/ml). The MK4 to total vitamin K ratio was 16.5±9.8% (95% CI: 4.3-41.5%). The S-warfarin concentration of producing 50% of maximum anticoagulation and the half-life of prothrombin complex activity tended to increase with vitamin K. Further, Prevotella and Eubacterium of gut microbiota identified as the main bacteria associated with individual variability of warfarin. The results suggest that an increase in vitamin K concentration can decrease anticoagulation, and gut microbiota may influence warfarin anticoagulation through vitamin K2 synthesis. CONCLUSION: This study highlights the importance of considering vitamin K concentration and gut microbiota when prescribing warfarin. The findings may have significant implications for the personalized use of warfarin. Further research is needed to understand better the role of vitamin K and gut microbiota in warfarin anticoagulation.

Identification of a novel 5-methylcytosine-related signature for prognostic prediction of kidney renal papillary cell carcinoma and a Putative target for drug repurposing.

BACKGROUND: Many studies have demonstrated the crucial roles of 5-methylcytosine (m5C) RNA methylation in cancer pathogenesis. METHODS: Two datasets, including TCGA-KIRP and ICGC, and related clinical information were downloaded, where the expression of 13 m5C regulators was examined. We applied LASSO regression to construct a multi-m5C-regulator-based signature in the TCGA cohort, which was further validated using the ICGC cohort. Univariate and multivariate Cox regressions were applied to evaluate the independent prognostic value of our model. The differences in biological functions and immune characterizations between high and low-risk groups divided based on the risk scores were also investigated via multiple approaches, such as enrichment analyses, mutation mining, and immune scoring. Finally, the sensitivities of commonly used targeted drugs were tested, and the connectivity MAP (cMAP) was utilized to screen potentially effective molecules for patients in the high-risk group. Experimental validation was done following qPCR tests in Caki-2 and HK-2 cell lines. RESULTS: 3 m5C regulators, including ALYREF, DNMT3B and YBX1, were involved in our model. Survival analysis revealed a worse prognosis for patients in the high-risk group. Cox regression results indicated our model's superior predictive performance compared to single-factor prognostic evaluation. Functional enrichment analyses indicated a higher mutation frequency and poorer tumor microenvironment of patients in the high-risk group. qPCR-based results revealed that ALYREF, DNMT3B, and YBX1 were significantly up-regulated in Caki-2 cell lines compared with HK-2 cell lines. Molecules like BRD-K72451865, Levosimendan, and BRD-K03515135 were advised by cMAP for patients in the high-risk group. CONCLUSION: Our study presented a novel predictive model for KIRP prognosis. Furthermore, the results of our analysis provide new insights for investigating m5C events in KIRP pathogenesis.

Microbiota dysbiosis and myasthenia gravis: Do all roads lead to Rome?

Dysregulated immune system with a failure to recognize self from non-self-antigens is one of the common pathogeneses seen in autoimmune diseases. The complex interplay of genetic and environmental factors is important for the occurrence and development of the disease. Among the environmental factors, disturbed gut microbiota (gut dysbiosis) has recently attracted particular attention, especially with advancement in human microbiome research. Although the alterations in microbiota have been seen in various autoimmune diseases, including those of nervous system, there is paucity of information on neuromuscular system diseases. Myasthenia gravis (MG) is one such rare autoimmune disease of neuromuscular junction, and is caused by generation of pathogenic autoantibodies to components of the postsynaptic muscle endplate. In the recent years, accumulating evidences have endorsed the key role of host microbiota, particularly those of gut, in the pathogenesis of MG. Differential microbiota composition, characterized by increased abundance of Fusobacteria, Bacteroidetes, and Proteobacteria, and decreased abundance of Actinobacteria and Firmicutes, has been seen in MG patients in comparison to healthy subjects. Disturbance of microbiota composition, particularly reduced ratio of Firmicutes/Bacteroidetes, alter the gut permeability, subsequently triggering the immunological response. Resultant reduction in levels of short chain fatty acids (SCFAs) is another factor contributing to the immunological response in MG patients. Modulation of gut microbiota via intervention of probiotics, prebiotics, synbiotics, postbiotics (metabiotics), and fecal microbiota transplantation (FMT) is considered to be the futuristic approach for the management of MG. This review summarizes the role of gut microbiota and their metabolites (postbiotics) in the progression of MG. Also, various bacteriotherapeutic approaches involving gut microbiota are discussed for the prevention of MG progression.