Experimental colitis is comorbid with social interaction deficits and anxiety-like behaviors in mice: mechanistic intuitions into neuroinflammation and Claudin 5 expression in the hippocampus.

Inflammatory bowel disease (IBD) is accompanied by psychiatric disorders, including Schizophrenic-like manifestations. Although incompletely illustrated, intestinal mucosal membrane damage and blood-brain barrier (BBB) penetrability may have significant roles in psychiatric symptoms of IBD. This study aimed to investigate role of the Claudin-5 (CLDN5) (a regulator of the permeability of BBB) and neuroinflammatory response in the comorbid behavioral disorders in experimental colitis in mice. Acetic acid was used to induce colitis in mice. 7 days after induction of colitis, behaviors including social interaction and locomotor activity as well as anxiety-like behaviors were evaluated. Then, the colon was extracted for gross and microscopic evaluations. The expression of CLDN5, TNF-α, IL1ß and IL23 was measured by RT-PCR in the colon and hippocampus. Histopathologic evaluations demonstrated mucosal, submucosal, and crypt-related damages in the colon. The negative and positive number of social interactions significantly increased in the colitis group. A considerable increase in locomotor activities (horizontal and vertical components) shown in the colitis group. Mice in colitis group spent less time in the central zone in the open field apparatus. Gene expressions of TNF-α, IL1ß, and IL23 increased and CLDN5 decreased in the colitis group. The barrier function of the intestine and brain would be impaired, partially at least, following colitis (as we observed decrease in CLDN5 gene expression). Furthermore, we found that beside inflammatory response in the colon, a neuro-immune response triggered in the hippocampus following colitis. These alterations probably, mediated comorbid behavioral disorders in acetic acid-induced colitis in mice.

LINC01366 and LINC01433 in Glioblastoma Multiforme: A Potential Role at the Intersection of Inflammation and Angiogenesis.

Glioblastoma multiforme (GBM) is an aggressive cancer with a poor prognosis. Inflammation and angiogenesis are important processes in GBM that are interrelated. In this study, bioinformatic investigations were performed to detect common and key genes in the inflammatory and angiogenesis pathways of GBM. Additionally, relevant long non-coding RNAs (lncRNAs) were recognized as important gene regulators. Consequently, real-time PCR and correlation analyses were used to investigate changes in gene and lncRNA expression levels and explain their relationship. RELA emerged as a common key gene in these biological processes. LINC01366 and LINC01433 were identified as putative RELA regulators in different metabolic pathways using computational assays. According to our findings, the expression levels of RELA, LINC01366 and LINC01433 were found to be significantly upregulated in GBM samples. Correlational studies revealed a significant positive relationship of gene expressions between LINC01366 and LINC01433, indicating that they may have a coordinated effect on GBM biology. Nevertheless, there was no significant correlation between these lncRNAs and RELA. The current study highlights the high expression of LINC01366 and LINC01433 in GBM and emphasizes the importance of studying lncRNAs as putative regulators in the pathophysiology of GBM. Further research is needed to clarify their specific functions, in particular the associated inflammatory and angiogenesis pathways.

Antitumor activity and phenolic profile of Melissa officinalis extract against human gastric adenocarcinoma cells.

Gastric cancer remains a global health concern, driving the exploration of natural products with anticancer potential. This study investigated the antiproliferative activity and chemical composition of a 70% ethanolic extract from Melissa officinalis L. against human gastric cancer cells. The extract was prepared and evaluated for total phenolic content, antioxidant capacity and flavonoid content. The MTT test checked how well it stopped the growth of human gastric adenocarcinoma (AGS) and normal dermal fibroblast (HDF) cells. Data analysis (SPSS Statistics) determined viable cell percentages and performed regression analysis (p<0.05). The extract exhibited significant antiproliferative activity against AGS cells compared to normal cells (p<0.05), with decreasing IC50 values (564.3, 258.0 and 122.5 µg/ml) over 24, 48 and 72 hours. It also displayed antioxidant activity (IC50=16.8±1.41µg/ml) and contained substantial phenolics (225.76±4.1 mg GAE/g) and flavonoids (22.36±2.6 mg RUT/g). This study suggests the 70% ethanolic extract of M. officinalis effectively suppresses AGS cell growth and possesses promising antioxidant properties, highlighting its potential as a natural source of anticancer and antioxidant agents, deserving further investigation.

Enhancing the Antiviral Potential and Anti-inflammatory Properties of Astragalus membranaceus: A Comprehensive Review.

The role of herbal medicines in the treatment of viruses and the identification of potential antiviral drugs has been the focus of researchers for decades. The control and treatment of viral diseases are very important due to the evolution of viruses and the emergence of new viruses compared to other pathogens such as fungi and bacteria. Astragalus membranaceus (AM) is a significant medicinal plant. The potential use of this plant and its chemical components in the treatment of inflammatory illnesses and viral diseases has been vigorously researched recently. Astragalus polysaccharides (APS) make up the majority of AM's ingredients. The main mechanisms of the antiviral effect of APS have been investigated in some studies. The results of these studies show that APS can exert its antiviral effect by enhancing type I IFN signaling, inhibiting the expression of Bax and Caspase-3 proteins in the apoptosis pathway, and other antiviral mechanisms such as anti-inflammatory activities. The most well-known inflammatory products of APS's antiviral effects are B-cell proliferation, antibody products, nuclear factor-kappa B (NF-κB), and IL(s). Although it has a known effectiveness, there are some limitations to this substance's use as medicine. The use of nanotechnology is removing these limitations and its ability to be used as an anti-virus agent. The purpose of this review is to emphasize the role of AM, especially APS, in controlling inflammatory pathways in the treatment of viral infections. With the emergence of these herbal medications, a new path has been opened in the control and treatment of viral infections.

Immunological processes of enhancers and suppressors of long non-coding RNAs associated with brain tumors and inflammation.

Immunological processes, such as inflammation, can both cause tumor suppression and cancer progression. Moreover, deregulated levels of long non-coding RNA (lncRNA) expression in the brain may cause inflammation and lead to the growth of tumors. Like other biological processes, the immune system's role in cancer is complicated, varies, and can help or hurt the cancer's maintenance. According to research, inflammation and brain cancer are correlated via several signaling pathways. A variety of lncRNAs have recently been revealed to influence cancer by modulating inflammatory pathways. As a result, lncRNAs have the potential to influence carcinogenesis, tumor formation, or tumor suppression via an increase or decrease in inflammation functions. Although the study and targeting of lncRNAs have made great progress in the treatment of cancer, there are definitely limitations and challenges. Using new technologies like nanocarriers and cell-penetrating peptides (CPPs) to target treatments without hurting healthy body tissues has shown to be very effective. In this review article, we have collected significantly related lncRNAs and their inhibitory or stimulating roles in inflammation and brain cancer for the first time. However, there are limitations, such as side effects and damage to normal tissues. With the advancement of new targeting technologies, these lncRNAs may be candidates for the specific targeting therapy of brain cancers by limiting inflammation or stimulating the immune system against them in the future.

Immunological processes, such as inflammation, can both cause tumor suppression and cancer progression. Long non-coding RNA (lncRNA) expression in the brain may cause inflammation and lead to the growth of tumors. LncRNAs have the potential to influence carcinogenesis, tumor formation, or tumor suppression via an increase or decrease in inflammation functions. However, there are limitations and challenges to the study and targeting of lncRNAs. New targeting technologies, such as nanocarriers and cell-penetrating peptides (CPPs), may be used to target brain cancer without hurting healthy body tissues.

The Antidiabetic Mechanisms of Hesperidin: Hesperidin Nanocarriers as Promising Therapeutic Options for Diabetes.

A natural flavonoid with exceptional medicinal capabilities, hesperidin, has shown encouraging results in the treatment of diabetes. Thoughts are still being held on the particular processes through which hesperidin exerts its anti-diabetic effects. This work clarifies the complex antidiabetic mechanisms of hesperidin by investigating the molecular pathways involved in glucose homeostasis, insulin signaling, and oxidative stress control. Additionally, the article explores the newly developing field of nanocarrier-based systems as a prospective means of boosting the therapeutic efficiency of hesperidin in the treatment of diabetes. This is because there are difficulties connected with the efficient delivery of hesperidin. These cutting-edge platforms show enormous potential for changing diabetes therapy by utilizing the benefits of nanocarriers, such as enhanced solubility, stability, and targeted delivery. In conclusion, our comprehensive review emphasizes the antidiabetic potential of hesperidin and underscores the intriguing possibilities provided by hesperidin nanocarriers in the search for more effective and individualized diabetes therapies.

Adipose-derived mesenchymal stem cells -conditioned medium effects on Glioma U87 cell line migration, apoptosis, and gene expression.

The conditioned medium of mesenchymal stem cells (MSCs) has controversial roles in cancer, either promoting or suppressing tumor growth. Our research on the results of adipose tissue-derived MSC (AD-MSC)-conditioned media on U87 glioma cells was motivated by the disputed role of mesenchymal stem cells (MSCs) in cancer, which may either promote or inhibit tumor growth. Using flow cytometry, AD-MSCs were identified, verified, and their conditioned media was used to treat U87 cells. Through RT-qPCR, scratch assay, and apoptosis analysis, we evaluated gene expression (SOX4, H19, and CCAT1), cell migration, and apoptosis in U87 cells.The conditioned media greatly increased the expression of SOX4 and H19, but not CCAT1. Although there were few differences in migration and apoptosis, both were slightly increased in the treated group.These outcomes have drawn attention to the complexity of the interactions between MSCs and glioma cells. This complexity requires further research to identify the specific mechanisms governing MSC-mediated impacts on the development of glioblastoma multiforme (GBM).

Estimating the Survival Rate in Glioblastoma Multiforme Patients who Received a Peptide Vaccine: A Systematic Review and Meta-analysis.

INTRODUCTION: Glioblastoma Multiforme (GBM) has a poor prognosis, with current treatments providing no advantage in terms of survival. Certain new immunotherapy methods, such as peptide vaccines, have been used in clinical trials. In this meta-analysis, the effectiveness of peptide vaccinations on the survival rate of GBM patients was studied. METHODS: A comprehensive search was carried out using three electronic databases: PubMed, Scopus, and ISI. The purpose of this research was to assess Overall Survival (OS). The pooled overall one-year and two-year survival rates in GBM with peptide vaccination were calculated using the general inverse variance technique as random effects hazard ratios (HRs). In the study, subgroups of countries were compared with each other. Japan had the highest one-year survival rate, and the US had the highest two-year survival rate. RESULTS: With 95% Confidence Intervals (CIs), the one-year OS rate in GBM patients treated with peptide vaccination increased significantly, but the two-year survival rate did not increase. As a result, while additional research is needed, it cannot be concluded that it is an effective therapy for GBM. CONCLUSION: Our study found that while peptide vaccination treatment did not increase second-year survival, it improved first-year survival. More research needs to be done to find effective vaccinebased treatments for GBM that can help patients survive longer.

Resveratrol: Targeting cancer stem cells and ncRNAs to overcome cancer drug resistance.

A major challenge in treating cancer is the development of drug resistance, which can result in treatment failure and tumor recurrence. Targeting cancer stem cells (CSCs) and non-coding RNAs (ncRNAs) with a polyphenolic substance called resveratrol has the ability to combat this problem by lowering cancer resistance to drugs and opening up new therapeutic options. Resveratrol alters the expression of genes related to self-renewal, modulating important signaling pathways involved in cancer initiation and CSC control. Additionally, resveratrol affects non-coding RNAs (ncRNAs), including Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs which are essential for stemness, drug resistance, and other cancer-related activities. Numerous studies have shown that resveratrol has the potential to be an effective anticancer drug when used in combination therapy, but issues with absorption and pharmacokinetics still need to be resolved before it can be used in clinical applications. Reducing chemotherapy resistance by better understanding the intricate mechanisms by which resveratrol affects cancer cells and CSCs, as well as its impact on ncRNA expression, could eventually contribute to more effective cancer treatments. To completely understand these pathways and optimize the utilization of resveratrol in combination treatments, additional study is necessary.

Glutathione Therapy in Diseases: Challenges and Potential Solutions for Therapeutic Advancement.

An endogenous antioxidant, reduced glutathione (GSH), is found at high concentrations in nearly all typical cells. GSH synthesis is a controlled process, and any disruption in the process of GSH synthesis could result in GSH depletion. Cellular oxidative damage results from GSH depletion. Various pathological conditions such as aging, cardiovascular disease (CVD), psychiatric disorders, neurological disorders, liver disorders, and diabetes mellitus are more affected by this stress. There are various reasons for GSH reduction, but replenishing it can help to improve this condition. However, there are challenges in this field. Low bioavailability and poor stability of GSH limit its delivery to tissues, mainly brain tissue. Today, new approaches are used for the optimal amount and efficiency of drugs and alternative substances such as GSH. The use of nano-materials and liposomes are effective methods for improving the treatment effects of GSH. The difficulties of GSH decrease and its connection to the most important associated disorders are reviewed for the first time in this essay. The other major concerns are the molecular mechanisms involved in them; the impact of treatment with replacement GSH; the signaling pathways impacted; and the issues with alternative therapies. The utilization of nano-materials and liposomes as potential new approaches to solving these issues is being considered.

Genetic Variants Impacting Angiogenesis Signaling Pathways in Glioblastoma Multiforme: A Systematic Review of Mutations and Polymorphisms.

BACKGROUND: Several signaling pathways are involved in the process of angiogenesis, which is one of the most important hallmarks of glioblastoma multiforme (GBM). Identifying related gene variants can help researchers work out what causes anti-angiogenesis drug resistance. OBJECTIVE: The goal of this systematic analysis was to identify all mutations and polymorphisms involved in angiogenesis pathways in GBM and their impact on clinical outcomes. METHODS: The keywords include glioblastoma, angiogenesis, signaling pathway, mutation, polymorphism, and related terms used to search ISI, PubMed, and Scopus for relevant articles published up to January 2022. The PRISMA protocol was used to conduct our systematic review. The related articles were taken into consideration. The risk of bias in the associated articles was surveyed, as well as the article scoring. Two authors collaborated on data extraction. RESULTS: The inclusion criteria were included in 32 articles out of a total of 787 articles. VEGF, HIF1a, EGFR, PI3K, and MAPK are the pathways that have been studied the most. IDH1, VEGF, VEGFR, EGFR, and HIF1a are the genes with the highest frequency of mutations or polymorphisms. CONCLUSION: In conclusion, this study found that angiogenesis in primary or recurrent GBM is linked to gene changes in eleven signaling pathways. However, some of these gene mutations have been researched numerous times in relation to angiogenesis, while others have only been studied once. Understanding these changes will help us employ combination therapies more effectively for GBM patients' survival and personal medicine.

Epigenetic drugs as new emerging therapeutics: What is the scale's orientation of application and challenges?

Epigenetics is the study of heritable changes in gene expression or function without altering the DNA sequence. Important factors are part of epigenetic events, such as methylation, DNA histone rearrangements, nucleosome transposition, and non-coding RNAs. Dysregulated epigenetic mechanics are associated with various cancers' initiation, development, and metastasis. It is known that the occurrence and development of cancer can be controlled by regulating unexpected epigenetic events. Epi-drugs are used singly or in combination with chemotherapy and enhance antitumor activity, reduce drug resistance, and stimulate the host immune response. Despite these benefits, epigenetic therapy as a single therapy or in combination with other drugs leads to adverse effects. This review article introduces and compares the advantages, disadvantages, and side effects of using these drugs for the first time since their introduction. Also, this article describes the mechanism of action of various epigenetic drugs. Recommendations for future use of epigenetic drugs as cancer therapeutics are suggested as an overall conclusion.

Various Effects of the GABAergic System on Cancer: The Conditions and Specificities of its use in the Treatment of Some Cancers.

GABA is an essential neurotransmitter in tissues other than the brain and has different functions. Cancer displays dysfunctional GABAergic system roles, comprising GAD, GABA, and GABA receptors. Both tumor-suppressing and carcinogenic characteristics of the GABAergic system have been reported in several malignancies. In the development of cancer cells, it plays oncogenesis- related roles. However, in some tumors, such as pancreatic cancer, it exhibits anti-cancer benefits in numerous human trials and animal models. As a result, GABAergic therapy may be used to treat cancer. The oxidative condition and the status of several malignant circumstances significantly influence the final GABAergic function in many tumors. Depending on the type of malignant tissue and other modifications, these roles manifest differently in malignancies. In this review, we, for the first time, concentrated on the oncogenic and tumor suppressor functions of GABA in various neoplasms, as well as its potential therapeutic implications. The significance of tumor suppressor function and the conditions that promote its function as a cancer genesis factor in cancer are discussed in this article.

Anti-angiogenic Drug Resistance: Roles and Targeting of Non-coding RNAs (microRNAs and long non-coding RNAs).

Cancers with a high capability for angiogenesis are frequently regarded as being difficult to treat. Anti-angiogenesis drugs are considered the primary therapy for these types of cancers. Due to intrinsic or acquired anti-angiogenesis resistance, therapies result in moderate clinical consequences, despite some hopeful findings. The importance of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding (lncRNAs), and circular RNAs (circRNAs) in drug resistance mechanisms in cancer treatment has been discovered in the previous decade. Anti-angiogenic drug resistance can be influenced by ncRNA dysregulation. Hence, ncRNAs are potential drug resistance targets for new anti-angiogenic drugs in the inhibition of angiogenesis in tumors. Furthermore, some ncRNAs can be employed as biomarkers for anti-angiogenic drug responses and can be used to monitor cancer non-invasively. Combination treatment approaches, combined with routine anti-angiogenesis and some drugs that target the ncRNAs causing resistance, can be potential ways to overcome anti-angiogenesis resistance. For the first time, we explain the mechanisms of anti-angiogenic drug resistance and the related miRNAs and lncRNAs and their signaling pathways in commonly used antiangiogenic drugs implicated in this review article. These ncRNAs could be suggestions for targeting and reducing anti-angiogenic drugs in the future.

The effective factors in human-specific tropism and viral pathogenicity in orthopoxviruses.

The orthopoxvirus (OPV) genus includes several species that infect humans, including variola, monkeypox, vaccinia, and cowpox. Variola and monkeypox are often life-threatening diseases, while vaccinia and cowpox are usually associated with local lesions. The epidemic potential for OPVs may be lower than respiratory-borne viruses or RNA viruses. However, OPVs are notable for their spread and distribution in different environments and among different hosts. The emergence or re-emergence of OPVs in the human population can also occur in wild or domestic animals as intermediate hosts. More effective and safer vaccines for poxvirus can be developed by understanding how immunity is regulated in poxvirus and vaccines for DNA viruses. Downstream events in cells affected by the virus are regulated functionally by a series of characteristics that are affected by host cell interactions and responses of cells against viral infections, including the interferon pathway and apoptosis. Furthermore, infection outcome is greatly influenced by the distinct selection of host-range and immune-modulatory genes that confer the potential for pathogenesis and host-to-host transmission and the distinct host-range properties of each immune-modulatory gene. The present study reviewed the effective factors in human-restricted tropism and virus pathogenicity in OPVs.

CRISPR/Cas9-based Gene Therapies for Fighting Drug Resistance Mediated by Cancer Stem Cells.

Cancer stem cells (CSCs) are cancer-initiating cells found in most tumors and hematological cancers. CSCs are involved in cells progression, recurrence of tumors, and drug resistance. Current therapies have been focused on treating the mass of tumor cells and cannot eradicate the CSCs. CSCs drug-specific targeting is considered as an approach to precisely target these cells. Clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene-editing systems are making progress and showing promise in the cancer research field. One of the attractive applications of CRISPR/Cas9 as one approach of gene therapy is targeting the critical genes involved in drug resistance and maintenance of CSCs. The synergistic effects of gene editing as a novel gene therapy approach and traditional therapeutic methods, including chemotherapy, can resolve drug resistance challenges and regression of the cancers. This review article considers different aspects of CRISPR/Cas9 ability in the study and targeting of CSCs with the intention to investigate their application in drug resistance.

Isolation of Cells and Exosomes from Glioblastoma Tissue to Investigate the Effects of Ascorbic Acid on the c-Myc, HIF-1α, and Lnc-SNHG16 Genes.

Glioblastoma multiforme (GBM) is incurable with routine treatments. Ascorbic acid (Asc) has antioxidant and anti-cancer properties. However, its specific anti-cancer mechanisms are only partially understood. In this study, the effect of Asc on the c-Myc, HIF-1α, and lnc-SNHG16 genes in GBM cells and their exosomes was investigated. Cells isolated from the tissue were characterized by the immunocytochemistry method (GFAP+). The cell-doubling time was determined, and FBS-free medium supplemented with Asc (5 mM) was added to the cells. The extracted exosomes in the cell culture medium were scanned by electron microscopy, Zetasizer, and BCA assay. The expression of lnc-SNHG16 in the exosomes and c-Myc and HIF-1α in the treated and control cells was evaluated by real-time PCR. The interactions between Asc and the c-Myc and HIF-1α proteins were studied using the molecular docking method. The cells showed 90-100% GFAP+ in passage 4, with a cell-doubling time of 4.8 days. Exosomal vesicles measuring 98.25-105.9 were observed. Zetasizer results showed a sharp pick at 90 nm. Protein quantitation showed 3.812 µg/ml protein in the exosomes. Lnc-SNHG16 expression was reduced (P = 0.041), and c-Myc was upregulated (P = 0.002). The expression of HIF-1α was not significant in the treated cells. Also, Asc was able to interact and affect c-Myc and HIF-1α. Asc exerts its effect by reducing lnc-SNHG16 expression in exosomes, upregulating c-Myc in GBM cells, and interacting with HIF-1α and c-Myc. Further research is necessary to achieve a full understanding of these findings.

Novel targets to overcome antiangiogenesis therapy resistance in glioblastoma multiforme: Systems biology approach and suggestion of therapy by galunisertib.

Glioblastoma multiforme (GBM) is a tumor with high microvessel density. Antiangiogenesis therapy (AAT) resistance occurs due to the complex mechanisms involved in angiogenesis, with increased chances of recurrence. The vascular endothelial growth factor (VEGF) pathway is the main pathway of angiogenesis, and anti-VEGF drugs have been ineffective in controlling it. New oncogenes in the VEGF signaling pathway may be new candidates for angiogenesis targeting. Oncogene candidates were chosen using gene expression profiles and databases. Then oncogenes were subjected to gene set enrichment analysis (GSEA) and survival analysis (SA). Molecular docking was conducted to evaluate the interaction of the oncogenes with galunisertib. NRAS, AKT1, and HSPB1 were the most effective oncogenes upregulating genes that play a role in GBM expression in the VEGF signaling pathway. The VEGF and MAPK signaling pathways were found to be effective using GSEA and Kyoto Encyclopedia Gene and Genome pathway analysis. Survival analyses revealed that patients with high HSPB1 expression had poorer overall survival rates than those with low HSPB1 expression. Galunisertib exhibits intermolecular interactions with 6DV5, 5UHV, and 3O96 (binding energy -8.0, -8.6, and -10.3 kcal/mol, respectively). The current AAT should be restrategized to suppress the numerous angiogenic elements to manage angiogenesis and combat AAT resistance in GBM. In silico analysis indicated that NRAS, AKT1, and HSPB1 genes can be the main oncogenes in the VEGF signaling pathway and galunisertib strongly interacts with these genes. Consequently, the use of galunisertib to overcome AAT in GBM in combination therapy can be assessed.

Efficacy of Anti-VEGF Drugs Based Combination Therapies in Recurrent Glioblastoma: Systematic Review and Meta-Analysis.

BACKGROUND: Recurrent glioblastoma multiforme (rGBM) has a grim prognosis with current therapies offering no survival benefit. Several combination therapies involving anti-VEGF agents have been studied with mixed results. METHODS: A systematic search was performed using five electronic databases: PubMed, Scopus, ISI, Embase, and the Cochrane Library without language limitations. The primary outcome of interest was progression free survival (PFS). Secondary outcomes were overall survival (OS), objective response ratio (ORR), and grade ≥ 3 adverse events. Estimates for PFS, OS were calculated as random effects hazard ratio (HR) with 95% confidence intervals (CIs) using the generic inverse variance method. Estimates for ORR, grade ≥ 3 adverse events were calculated using a random-effects risk ratio (RR) with 95% confidence intervals (CIs) using the Mantel-Haenszel method. RESULTS: Thirteen studies met the inclusion criteria and a total of 1994 patients have been included in the analysis. There was no statistically significant improvement in PFS (HR 0.84; 95% CI (0.68, 1.03); I2=81%), OS (HR 0.99; 95% CI (0.88, 1.12); I2=0%), ORR (RR 1.36; 95% CI (0.96, 1.92); I2=61%) in the combination therapy group when compared to the control group. Significantly higher grade ≥ 3 adverse events (RR 1.30; 95% CI (1.14, 1.48); I2=47%) were seen in the combination therapy when compared to the control group. CONCLUSION: Our analysis showed that the use of combination therapy with anti-VEGF agents did not offer any benefit in PFS, OS, or ORR. In contrast, it had significantly higher grade 3-5 adverse events. Further studies are needed to identify effective therapies in rGBM that can improve survival.

Molecular docking and mouse modeling suggest CMKLR1 and INSR as targets for improving PCOS phenotypes by minocycline.

Polycystic ovary syndrome (PCOS) is the most common cause of women's infertility. Some inflammatory pathways play a pivotal role in the pathogenesis of PCOS. This study aimed to investigate the possible beneficial effects of minocycline on chemokine-like receptor 1 (CMKLR1) and Insulin Receptor (INSR) in a PCOS model. A molecular docking study was implemented using Molecular Operating Environment (MOE) software. The PCOS was induced in NMRI mice (mean body weight 14.47±0.23) by 28 days estradiol valerate injection (2 mg/kg/day). The mice were then divided into six groups (n=8 per group, mean body weight 17.77± 0.26): control (received normal saline), PCOS model, control for minocycline, minocycline treated PCOS (50 mg/kg), letrozole treated PCOS (0.5 mg/kg), and metformin-treated PCOS (300 mg/kg). Serum FSH, LH, estradiol (E2), and testosterone were detected by ELISA. The ovarian tissues were stained by hematoxylin and eosin. The CMKLR1 and INSR expression levels were determined by Real-time-PCR. The molecular docking studies showed scores of -10.92 and -9.30 kcal/mol, respectively, for minocycline with CMKLR1 and INSR. Estradiol valerate treatment led to a significant increase in E2, graffian follicle, and decrease in corpus luteum (CL) numbers (P<0.05), while minocycline treatment improved these PCOS features. The minocycline treatment significantly decreased the CMKLR1 expression and increased the INSR expression (P<0.05) while the CMKLR1 expression was increased in PCOS model. Minocycline may improve ovulation in PCOS model by returning E2 to a normal level and increasing CL number (ovulation signs). These beneficial outcomes may be related to the changes in CMKLR1 and INSR gene expression involved in glucose metabolism and inflammation.