Extracellular Vesicles Contribute to Viral-Induced Hepatocellular Carcinoma: Understanding Their Involvement in Viral Hepatitis and Their Potential as Biomarkers for Early Hepatocellular Carcinoma Detection.

The high global prevalence of hepatitis B and hepatitis C and the poor prognosis of hepatitis B and hepatitis C-associated hepatocellular carcinoma (HCC), necessitates the early diagnosis and treatment of the disease. Recent studies show that cell-to-cell communication via extracellular vesicles (EVs) is involved in the HCC progression. The objective of the following study was to explore the role of EVs in the progression of viral-induced HCC and investigate their potential for the early diagnosis of cancer. First, the mRNA derived from EVs of HCC patients was compared to the mRNA derived from EVs from the healthy controls. Expression analysis of ANGPTL3, SH3BGRL3, and IFITM3 genes from the EVs was done. Afterward, to confirm whether hepatocytes can uptake EVs, HuH7 cells were exposed to EVs, and the expression analysis of downstream target genes (AKT, TNF-α, and MMP-9) in Huh7 cells was done. Transcriptional analysis showed that in the EVs from HCC patients, the expression levels of ANGPTL3, SH3BGRL3, and IFITM3 were significantly increased by 2.62-, 4.3-, and 9.03-folds, respectively. The downstream targets, AKT, TNF-α, and MMP-9, also showed a considerable change of 4.1-, 1.46-, and 5.05-folds, respectively, in Huh7 cells exposed to HCC EVs. In conclusion, the following study corroborates the role of EVs in HCC progression. Furthermore, the significant alteration in mRNA levels of the selected genes demonstrates their potential to be used as possible biomarkers for the early diagnosis of HCC.

Autoimmune Neuroinflammatory Diseases: Role of Interleukins.

Autoimmune neuroinflammatory diseases are a group of disorders resulting from abnormal immune responses in the nervous system, causing inflammation and tissue damage. The interleukin (IL) family of cytokines, especially IL-1, IL-6, and IL-17, plays a critical role in the pathogenesis of these diseases. IL-1 is involved in the activation of immune cells, production of pro-inflammatory cytokines, and promotion of blood-brain barrier breakdown. IL-6 is essential for the differentiation of T cells into Th17 cells and has been implicated in the initiation and progression of neuroinflammation. IL-17 is a potent pro-inflammatory cytokine produced by Th17 cells that plays a crucial role in recruiting immune cells to sites of inflammation. This review summarizes the current understanding of the roles of different interleukins in autoimmune neuroinflammatory diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, neuromyelitis optica, and autoimmune encephalitis, and discusses the potential of targeting ILs as a therapeutic strategy against these diseases. We also highlight the need for further research to better understand the roles of ILs in autoimmune neuroinflammatory diseases and to identify new targets for treating these debilitating diseases.

Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action.

Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants' bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals.

Vanishing Bile Duct Syndrome Associated With Non-Hodgkin's Lymphoma and Hepatitis E Virus Infection.

The vanishing bile duct syndrome (VBDS) is a condition secondary to inciting triggers resulting in destruction and eventual disappearance of intrahepatic bile ducts leading to cholestasis. The overall outcome varies and often depends on the nature of the precipitating cause. VBDS has been found to be associated with adverse drug reactions, infectious diseases, autoimmune diseases, ischemia, and humoral factors associated with malignancies and is often irreversible. The objective of this clinical case report is to highlight the need for a broad differential to include VBDS in similar scenarios to aid rapid diagnosis and management. We hope this could lead to a more favourable outcome for patients presenting with VBDS such as the one described in this case report with concurrent non-Hodgkin's lymphoma and infection with hepatitis E virus. To the best of our knowledge, this is the first ever reported case of VBDS associated with non-Hodgkin's lymphoma and hepatitis E virus infection.

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies.

Toll-like receptors (TLRs) are the pattern recognition receptors, which are activated by foreign and host molecules in order to initiate the immune response. They play a crucial role in the regulation of innate immunity, and several studies have shown their importance in bacterial, viral, and fungal infections, autoimmune diseases, and cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as a possible therapeutic agent or as a vaccine adjuvant toward cancers or infectious diseases and that TLR inhibitors may be a promising approach to the treatment of autoimmune diseases, some cancers, bacterial, and viral infections. These notions are based on the fact that TLR agonists stimulate the secretion of proinflammatory cytokines and in general, the development of proinflammatory responses. Some of the TLR-based inhibitory agents have shown to be efficacious in preclinical models and have now entered clinical trials. Therefore, TLRs seem to hold the potential to serve as a perfect target in the era of immunotherapies. We offer a perspective on TLR-based therapeutics that sheds light on their usefulness and on combination therapies. We also highlight various therapeutics that are in the discovery phase or in clinical trials.

Role of TMPRSS6 rs855791 (T > C) polymorphism in reproductive age women with iron deficiency anemia from Lahore, Pakistan.

BACKGROUND: Iron deficiency anemia (IDA) is the highest nutritional deficiency worldwide. It is a multifactorial disease, with a higher morbidity rate. TMPRSS6 polymorphisms importantly rs855791 is found to play an essential role in iron homeostasis in the human body. The rs855791 (T > C) polymorphism is highly associated with iron levels, and multiple blood parameters, leading to IDA. The role of TMPRSS6 rs855791 polymorphism and the significance of complete blood count (CBC) parameters in the pathogenesis of IDA is not yet studied in the Pakistani population. METHODS: We enrolled 113 cases and 136 controls to conduct a case control study. Complete blood count (CBC) and iron parameters were analyzed for association studies. PCR-RFLP based genotyping was performed. RESULTS: The TMPRSS6 rs855791 (T > C) polymorphism is significantly associated with IDA pathogenesis as observed in the codominant model and recessive models (P < 0.05, OR: 1.5 and 95% CI: 0.9, 2.6, P < 0.05, OR: 0.5 and 95% CI: 0.2, 0.9 respectively). Elderly women among cases (30-49 years) were found to be more susceptible to IDA (P < 0.05, AOR: 2.1 and 95% CI: 1.0, 4.2). The most significant parameters associated with IDA were red blood cell count (RBC) and hematocrit (Hct%) (P < 0.05, AOR: 16.5, 95% CI: 7.6, 35.9 and P < 0.05, AOR: 10.1, 95% CI: 2.5, 41.6, respectively). CONCLUSION: TMPRSS6 polymorphism at rs855791 (T > C) is significantly associated with IDA susceptibility in reproductive age women in Pakistan. Age, RBC count and Hct% are found to play an important role in IDA pathogenesis in our study population.

A comparative analysis of interferons and direct-acting antivirals on the expression of genes involved in hepatitis C pathogenesis.

The discovery of direct-acting antivirals (DAAs) has revolutionized the treatment of hepatitis C worldwide. In contrast, pegylated interferon-alpha (PEG IFN-α), the older regimen, had limited success. However, the effect of DAAs on the expression of immunomodulatory genes involved in liver pathologies remains ambiguous. The objective of this study was to explore and contrast the effects of DAAs and PEG IFN-α on the expression of selected immunomodulatory genes. Fifty individuals were enrolled in the study and they were divided into five categories; healthy individuals, treatment-naive, DAAs-responders, DAAs-nonresponders, and interferon-relapsers. The effect of the therapies on the expression of transforming growth factor-beta (TGF-ß), tumor necrosis factor-alpha (TNF-α), suppressor of cytokine signaling 3 (SOCS-3), copper/zinc superoxide dismutase (Cu/Zn SOD), interleukin 10 (IL-10), and collagen type 1 was analyzed. Expression analysis of the selected genes was done through real time polymerase chain reaction. A significantly increased expression of TGF-ß was observed in the patients who received DAAs or PEG IFN-α, which suggests that patients receiving anti-HCV therapies are prone to developing fibrosis. Moreover, DAAs-nonresponders had higher expression of TNF-α, SOCS-3, and IL-10. The elevated expression of TNF-α and SOCS-3 insinuates that DAAs-nonresponders may develop insulin resistance and steatosis in the future. Finally, in addition to TGF-ß, high expression of collagen was found in interferon relapsers, which suggests that these patients are the most susceptible to developing cirrhosis.