Functional role of autophagy in testicular and ovarian steroidogenesis.

Autophagy is an evolutionarily conserved cellular recycling process that maintains cellular homeostasis. Despite extensive research in endocrine contexts, the role of autophagy in ovarian and testicular steroidogenesis remains elusive. The significant role of autophagy in testosterone production suggests potential treatments for conditions like oligospermia and azoospermia. Further, influence of autophagy in folliculogenesis, ovulation, and luteal development emphasizes its importance for improved fertility and reproductive health. Thus, investigating autophagy in gonadal cells is clinically significant. Understanding these processes could transform treatments for endocrine disorders, enhancing reproductive health and longevity. Herein, we provide the functional role of autophagy in testicular and ovarian steroidogenesis to date, highlighting its modulation in testicular steroidogenesis and its impact on hormone synthesis, follicle development, and fertility therapies.

Multifaceted role of TRIM21 in inflammation.

Tripartite motif (TRIM) family members participate in a variety of cellular activities, such as intracellular signaling, development, cellular death, protein quality control, immunological defense, waste degradation, and the emergence of cancer. These proteins usually act as E3 ubiquitin ligase. The final line of resistance against infectious viruses is a cytosolic ubiquitin ligase and antibody receptor called TRIM containing 21. TRIM21, a protein with a tripartite structure, has been linked to autoimmune erythematosus, Sjogren's disorder, and innate immunity. TRIM21 may either promote the formation of specific cancer-activating proteins, resulting in their proteasomal degradation, or it may do neither, depending on the kind of cancer and cancer-causing trigger. The current research has shown that the antiviral action of TRIM mostly depends on their role as E3-ubiquitin ligases and a significant portion of the TRIM family mediates the transmission of innate immune cell signals and the subsequent production of cytokines. We highlighted the function of TRIM family members in various inflammatory diseases.

Circulating tumor DNA and its role in detection, prognosis and therapeutics of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is considered the fifth most prevalent cancer among all types of cancers and has the third most morbidity value. It has the most frequent duplication time and a high recurrence rate. Recently, the most unique technique used is liquid biopsies, which carry many markers; the most prominent is circulating tumor DNA (ctDNA). Varied methods are used to investigate ctDNA, including various forms of polymerase chain reaction (PCR) [emulsion PCR (ePCR), digital PCR (dPCR), and bead, emulsion, amplification, magnetic (BEAMing) PCR]. Hence ctDNA is being recognized as a potential biomarker that permits early cancer detection, treatment monitoring, and predictive data on tumor burden are subjective to therapy or surgery. Numerous ctDNA biomarkers have been investigated based on their alterations such as 1) single nucleotide variations (either insertion or deletion of a nucleotide) markers including TP53, KRAS, and CCND1; 2) copy number variations which include markers such as CDK6, EFGR, MYC and BRAF; 3) DNA methylation (RASSF1A, SEPT9, KMT2C and CCNA2); 4) homozygous mutation includes ctDNA markers as CDKN2A, AXIN1; and 5) gain or loss of function of the genes, particularly for HCC. Various researchers have conducted many studies and gotten fruitful results. Still, there are some drawbacks to ctDNA namely low quantity, fragment heterogeneity, less stability, limited mutant copies and standards, and differential sensitivity. However, plenty of investigations demonstrate ctDNA's significance as a polyvalent biomarker for cancer and can be viewed as a future diagnostic, prognostic and therapeutic agent. This article overviews many conditions in genetic changes linked to the onset and development of HCC, such as dysregulated signaling pathways, somatic mutations, single-nucleotide polymorphisms, and genomic instability. Additionally, efforts are also made to develop treatments for HCC that are molecularly targeted and to unravel some of the genetic pathways that facilitate its early identification.

Emerging role of lipophagy in liver disorders.

Lipophagy is a selective degradation of lipids by a lysosomal-mediated pathway, and dysregulation of lipophagy is linked with the pathological hallmark of many liver diseases. Downregulation of lipophagy in liver cells results in abnormal accumulation of LDs (Lipid droplets) in hepatocytes which is a characteristic feature of several liver pathologies such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Contrarily, upregulation of lipophagy in activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and cirrhosis. Lipid metabolism reprogramming in violent cancer cells contributes to the progression of liver cancer. In this review, we have summarized the recent studies focusing on various components of the lipophagic machinery that can be modulated for their potential role as therapeutic agents against a wide range of liver diseases.

Extracellular Vesicles: the Next Frontier in Pregnancy Research.

Extracellular vehicles (EVs) have been involved in several aspects of pregnancy, including endometrial receptivity, embryo implantation, and embryo-maternal communication showing them associated with pregnancy disorders, such as preeclampsia, gestational diabetes mellitus, and preterm birth. Further research is warranted to fully comprehend the exact pathophysiological roles of EVs and to develop new therapies targeting EVs thereby improving pregnancy outcomes. Herein, we review the recent knowledge on the multifaceted roles of EVs during pregnancy and address the majority of the molecular interactions between EVs, maternal, and fetal cells with an emphasis on disorders of pregnancy under the influence of EVs. Moreover, we also discuss its applications in clinical trials followed by prospects.

Diagnostic and therapeutic value of EVs in lungs diseases and inflammation.

Extracellular vesicles (EVs) are membrane-derived messengers which have been playing an important role in the inflammation and pathogenesis of lung diseases. EVs contain varieties of DNA, RNA, and membrane receptors through which they work as a delivery system for bioactive molecules as well as intracellular communicators. EV signaling mediates tumor progression and metastasis. EVs are linked with many diseases and perform a diagnostic role in lung injury and inflammation so are used to diagnose the severity of diseases. EVs containing a variety of biomolecules communicate with the recipient cells during pathophysiological mechanisms thereby acquiring the attention of clinicians toward the diagnostic and therapeutic potential of EVs in different lung diseases. In this review, we summarize the role of EVs in inflammation with an emphasis on their potential as a novel candidate in the diagnostics and therapeutics of chronic obstructive pulmonary disease, asthma, and sarcoidosis.

Mini-organs with big impact: Organoids in liver cancer studies.

Hepatocellular carcinoma, the most common primary liver cancer and a leading cause of death, is a difficult disease to treat due to its heterogeneous nature. Traditional models, such as 2D culture and patient-derived xenografts, have not proven effective. However, the development of 3D culture techniques, such as organoids, which can mimic the tumor microenvironment (TME) and preserve heterogeneity and pathophysiological properties of tumor cells, offers new opportunities for treatment and research. Organoids also have the potential for biomarker detection and personalized medication, as well as genome editing using CRISPR/Cas9 to study the behavior of certain genes and therapeutic interventions. This review explores to-the-date development of organoids with a focus on TME modeling in 3D organoid cultures. Further, it discusses gene editing using CRISPR/Cas9 in organoids, the challenges faced, and the prospects in the field of organoids.

Microplastics: unraveling the signaling pathways involved in reproductive health.

Microplastics (MPs) are biologically active environmental pollutants having significant impact on the ecosystem and human health. MPs have been reported to increase oxidative stress, resulting in tissue damage, developmental abnormalities, metabolic disorders, epigenetic changes, abnormal reproduction, and reduced gamete quality. At present, most of the existing literature has focused on the effects of MPs on the reproduction of various aquatic organisms; however, the effects of MPs on mammalian reproduction specifically humans are least studied except a few ones fragmentally discussing the effects of MPs on gametogenesis in human. This review discusses effects of MPs on male and female reproduction with a focus on different metabolic pathways involved in compromised gamete quality, gamete toxicity, apoptosis, and DNA damage.

Effect of heterologous platelet-rich plasma on liver and modulation of glucose metabolism and Wnt signalling pathways in diabetic mice.

BACKGROUND: The current study was designed to highlight the effects of heterologous platelet-rich plasma (PRP) on deteriorated hepatic tissues and impaired glucose metabolism of alloxan-induced diabetic mice. METHODS: 30 male mice were divided into a control (CG), PRP (PG), diabetic (DG), and two treated groups (T1G and T2G). PG was given PRP treatment (0.5 ml/kg body weight) twice a week for four weeks. DG, T1G and T2G were given alloxan (150 mg/kg) to induce diabetes. After confirmation, PRP treatment was given to T1G and T2G for two and four weeks respectively while DG was left untreated. Upon completion of the said experimental period, liver samples were taken for histological and gene expression analyses. RESULTS: The study found that the liver tissue of the DG group showed signs of damage, including hepatocyte ballooning, sinusoid dilatation, and collagen deposition. However, these changes were significantly reduced in both T1G and T2G groups. The expression of several genes related to liver function was also affected, with upregulation of Fbp1 and Pklr, and downregulation of Pck1 in the DG group. PRP treatment restored Fbp1 expression and also increased the expression of glycolytic pathway genes Hk1 and Gck, as well as Wnt signalling pathway genes Wnt2, Wnt4, and Wnt9a in both treated groups. CONCLUSION: Current study revealed that heterologous PRP may partly alleviate high glucose levels in diabetics possibly by mediating glucose metabolism via inhibition of Wnt signalling pathway.

From barriers to novel strategies: smarter CAR T therapy hits hard to tumors.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors shows promise, but several hurdles remain. Strategies to overcome barriers such as CAR T therapy-related toxicities (CTT), immunosuppression, and immune checkpoints through research and technology are needed to put the last nail to the coffin and offer hope for previously incurable malignancies. Herein we review current literature and infer novel strategies for the mitigation of CTT while impeding immune suppression, stromal barriers, tumor heterogeneity, on-target/off-tumor toxicities, and better transfection strategies with an emphasis on clinical research and prospects.

Self-assembled and Zn(II)-coordinated dipeptide nanoparticles with membrane-rupturing action on bacteria.

Metal ion-coordinated self-assembled short-chain amino acid peptide molecules with multi-photon excitation wavelengths and their photoluminescence properties are advantageous for fluorescence-based diagnostics and treatments of biological diseases based on their extra features of antibacterial agents. We have designed a novel strategy based on tryptophan molecule coordinated with Zn(II) ions in the form of biocompatible spherical nanoparticles of diameter 30-80 nm which have been used for antibacterial treatments against different kinds of pathogenic bacteria (Escherichia coli, Salmonella typhimurium, and Pseudomonas). Preferably, we have used tryptophan-phenylalanine (Trp-Phe), a dipeptide molecule having tryptophan as principal material against E. coli strains as antimicrobial agents for surface rupturing and killing purposes. Furthermore, based on single amino acid, tryptophan, self-assembled and Zn(II)-coordinated dipeptide nanoparticles (Zn-DPNPs) were studied against three types of multi-drug-resistant bacteria as an active antimicrobial agent. These antibacterial efficient nanoparticles may have best alternative of antibiotic drugs for clinical applications. The capability of self-assembled fluorescence behavior of Zn-coordinated dipeptide molecules and higher hydrophobicity against bacterial cell wall will perform as antimicrobial fluorescent agents. KEY POINTS: • Zn(II) and Cu(II) better coordinated into self-assembled NPs. • Fluorescence signals showed interaction of NPs with gram -ve cell wall. • Significant surface-damaging effects were observed in the case of Cu-DPNPs and Zn-DPNPs.

Recent advances to Neuroprotection: repurposing drugs against neuroinflammatory disorders.

Cell death is a natural mechanism for biological clearance for the maintenance of homeostasis in a dynamic microenvironment of the central nervous system. Stress and various factors can lead to imbalance between cellular genesis and cell death leading to dysfunctionality and a number of neuropathological disorders. Drug repurposing can help bypass development time and cost. A complete understanding of drug actions and neuroinflammatory pathways can lead to effective control of neurodegenerative disorders. This review covers recent advances in various neuroinflammatory pathways understanding, biomarkers, and drug repurposing for neuroprotection.

Inimical impact of high-fat diet on expression of heme oxygenase-1, trace metals content, and associated intestinal histopathology.

A high-fat diet (HFD) is one of the most prominent causative factors for obesity and metabolic inflammation. The effects of HFD overconsumption on intestinal histology, expression of haem oxygenase-1 (HO-1), and transferrin receptor-2 (TFR2) remain elusive. The present study was conducted to analyze the effect of HFD on these parameters. To develop the HFD-induced obese model, rat colonies were divided into 3 groups; the control group was reared on normal rat chow, whereas groups I and II were given HFD for 16 weeks. Hematoxylin and eosin (H & E) staining revealed marked epithelial changes, inflammatory cell infiltrates, and destruction of mucosal architecture in both experimental groups as compared to the control group. Sudan Black B staining showed a high triglyceride deposition in the intestinal mucosa of animals fed on HFD. Atomic absorption spectroscopy revealed a decrease in tissue copper (Cu) and selenium (Se) concentration in both HFD experimental groups. Whereas the cobalt (Co) and manganese (Mn) levels were comparable to controls. The mRNA expression levels of HO-1 and TFR2 were found to be significantly upregulated in HFD groups compared to the control group. Hence, HFD consumption leads to histopathological changes and altered gene expression in the rodent intestine. So, one should remove HFD from daily meals to avoid related metabolic complications.

Integrative analyses of bulk microarray data to discover genes, pathways, and immune infiltration characteristics associated with targeting of Ewing sarcoma.

PURPOSE: To explore transcriptome and immunological features of patients with Ewing sarcoma (ES) using all publicly available microarray data. METHODS: Data of 479 ES tissues were integrated and normalized. Gene expression, immune infiltration, and cancer-specific pathways were analyzed. Genes of interest were knocked down, followed by cell proliferation and colony formation assays. RESULTS: Consistent with the previous reports of differential expressed genes (DEGs) in ES, our analysis identified CCND1, HMCN1, and NKX2-2 were among the most highly expressed, while TWNC1, MYBPC1, and CKM were among the lowest expressed genes. GO, KEGG, and GSEA enrichment analysis identified that the DEGs related to bone and muscle functioning, those that contributed to crucial cellular, and metabolism pathways such as actin binding, apoptosis, TCA cycle, and cell cycle were also significantly enriched. Immune infiltration analysis discovered that many T cell subsets including CD4T, CD8 T, and Gamma delta T cells were highly infiltrated, while monocytes and B cells were less infiltrated in tumors. A total of 138 genes were both significantly up-regulated in tumors and associated with decreased survival, while 38 significantly down-regulated genes were associated with increased survival, many of which were previously reported as oncogenes and tumor suppressors in ES and other cancers. Silencing of four newly identified top ranked up-regulated genes with decreased survivals in ES inhibited proliferation and colony formation of ES cells. CONCLUSION: This study may provide a clear representative transcriptome profile of ES, providing diagnostic biomarkers, pathways, and immune infiltrative characteristics targets for ES.

Gold nanocubes based optical detection of HIV-1 DNA via surface enhanced Raman spectroscopy.

Optical detection of HIV-1 DNA with surface enhanced Raman spectroscopy (SERS) is a quick and versatile method, having great potential in screening and characterization of HIV-1 virus particle. We have synthesized and applied novel gold nanocubes (AuNCs) for signal enhancement of SERS to study HIV-1 DNA strands by taking into account the specific vibrational bands of functional groups. Raman peaks at 562 cm-1, 800 cm-1, 1094 cm-1 were observed in both Human Random Control DNA and HIV-1 DNA, while three new peaks were detected in infected DNA at 421 cm-1, 1069 cm-1 and 1254 cm-1. Raman bands in case of AuNCs coated HIV-1 DNA molecules were observed with enhanced intensity values as compared to the silver nanoparticles-based SERS substrate. In case of silver nanoparticles (AgNPs) conjugate DNA, we get all signatures of HIV-1 virus at almost the same position with peak distortions, peak alterations and intensities reductions. We overall molecularly observed HIV-1 infected DNA and Human Random Control DNA, with high sensitivity and selectivity using highly sensitive and stable AuNCs in SERS. This technique can be utilized to identify molecular structures and chemical identification of biomacromolecules which can further be investigated as biomarkers for the screening of whole-body HIV-1 virus particles.

TLR-8, TNF-α, and ESR-1α Gene Polymorphism Susceptibility in Onset of Arthritis.

Arthritis is a genetic disorder characterized by bones and joint degradation assisted by severe pain and inflammation. It is evident by the studies that 0 candidate genes variations play vital role in its development and progression. Therefore, we investigated the genetic variation of TLR-8, TNF, and ESR-1α genes in the Pakistani population. A case-control study comprising 300 RA, 316 OA, and 412 control subjects was conducted. PCR-RFLP and direct sequencing methods were used for determining genetic variations. Analysis was performed by using PLINK and MEGA 6.0 software. Allelic and genetic frequencies of polymorphisms identified on rs3764879 (TLR-8), rs3764880 (TLR-8), rs5744080 (TLR-8), rs1800629 (TNF), rs2228480 (ESR-1α), and rs1451501590 (ESR-1α) were significantly varied among RA, OA, and controls. Novel functional mutations SCV000844945 and SCV000844946 on TLR-8 as well as a non-functional SCV000804801 and functional variation SCV000804802 on ESR-1α were also identified and reported for the first time in the studied population. Multiple site analyses indicated that polymorphisms on TLR-8 and ESR-1α genes were significant risk factors in disease onset to the next generation. In conclusion, TLR-08 and ESR-1α were significant in the onset of arthritis whereas the TNF was not found as a significant risk factor in the onset of RA and OA.

Multifaceted roles of extracellular RNAs in different diseases.

Extracellular RNAs (exRNAs) are novel circulating factors that can be used as biomarkers in various diseases. Their unique and diverse kinds, as well as their role as biomarkers, make them significant biomarkers. There has been immense work carried out since the discovery of exRNAs in circulation and other biological fluids to catalog and determine whether exRNAs may be utilized as indicators for health and illness. In this review, we aim to understand the current state of exRNAs in relation to various diseases and their potential as biomarkers. We will also review current issues and challenges faced in using exRNAs, with clinical and lab trials, that can be used as viable markers for different diseases.

Neoantigens and NK Cells: "Trick or Treat" the Cancers?

Immunotherapy has become an important treatment strategy for cancer patients nowadays. Targeting cancer neoantigens presented by major histocompatibility complex (MHC) molecules, which emerge as a result of non-synonymous somatic mutations with high immunogenicity, is one of the most promising cancer immunotherapy strategies. Currently, several therapeutic options based on the personalized or shared neoantigens have been developed, including neoantigen vaccine and adoptive T-cell therapy, both of which are now being tested in clinical trials for various malignancies. The goal of this review is to outline the use of neoantigens as cancer therapy targets, with an emphasis on neoantigen identification, clinical usage of personalized neoantigen-based cancer therapy agents, and the development of off-the-shelf products based on shared neoantigens. In addition, we introduce and discuss the potential impact of the neoantigen-MHC complex on natural killer (NK) cell antitumor function, which could be a novel way to boost immune response-induced cytotoxicity against malignancies.

Bisphenol S induced dysregulations in liver; iron regulatory genes and inflammatory mediators in male Wistar rats.

Bisphenol S (BPS), an analog of bisphenol A (BPA), has been frequently detected in consumer products, food wrappers, plastics, and thermal papers. Since the liver is a hub of metabolic and detoxification pathways, thus intimately related to BPS presence in the environment and body. The current study was designed to investigate the effects of BPS administration in an animal model. Twenty-five male Wistar rats weighing 175 ± 25 g were randomly divided into control and treated groups. The control group was further divided into group I (no treatment) and group II (corn oil), whereas the treatment group was divided into D-I (40 mg/kg/day), D-II (200 mg/kg/day), and D-III (400 mg/kg/day) groups, getting oral doses of BPS for 15 days. Data analysis showed a significant statistical increase in hepatic enzymes ALT (33.4%), AST (25.4%), and ALP (529.6%) in the D-III group along with the development of hypercholesterolemia and hypertriglyceridemia in all BPS groups. Aberrant mRNA expressions of some key hepatic iron regulatory genes and inflammatory mediators were evident through qRT-PCR. Bisphenol S caused congestion of central vein from mild to moderate in hepatic sections. In conclusion, our investigation insinuates BPS intoxication potential and therefore may not be a safe alternative to BPA.

Tumor-derived extracellular vesicles: Potential tool for cancer diagnosis, prognosis, and therapy.

Various types of cancer pose a notable threat to human health globally. To date, many researchers have undertaken the search for anticancer therapies. However, many anticancer therapeutic approaches accompany many undesirable hazards. In this respect, extracellular vesicles as a whole gained excessive attention from the research community owing to their remarkable potential for delivery of anticancer agents since they are involved in distal intercellular communication via biological cargoes. With the discovery of the fact that tumor cells discharge huge quantities of EVs, new insights have been developed in cancer diagnosis and treatment. Tumor-derived extracellular vesicles (TD-EVs) can be distinguished from the normal cell-derived EVs due to the presence of specific labels on their surface. TD-EVs carry specific oncogenic proteins and the nucleic acids on their surface membrane that participate in tumor progression. Moreover, the proportion of these nucleic acids and the protein greatly varies among malignant and healthy cell-derived EVs. The diagnostic potential of TD-EVs can be implied for the more precise and early-stage detection of cancer that was impossible in the past. This review examines the recent progress in prognostic, diagnostic, and therapeutic potential of the EVs derived from the tumor cells.