Immunoglobulins: Mechanistic Approaches in Moderation of Various Inflammatory and Anti-Inflammatory Pathways.

Immunoglobulins (Ig) are proteins that help fight infections. IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA, IgD, and IgE are the five immunoglobulin subtypes that make up the majority of our immune system. Beneficial effects have been observed on the administration of Ig in diseases like Kawasaki, multiple myositis, chronic inflammatory demyelinating polyneuropathy (CIDP), and immune thrombocytopenia purpura (ITP). The Fc region, FcγRs, and FcRn of the IgG interact to provide both pro- and anti-inflammatory effects. IgM blocks immune-mediated inflammation using N-like glycans. It has been demonstrated that IgM demonstrates its antiinflammatory activity through IgM anti-leukocyte auto-antibodies (IgM-ALA). Since IgA is the second most prevalent and important Ig that operates on the primary objective in the immune system, which exhibits inhibitory signals in the body and generates inflammation in host cells, it plays a critical role in controlling mucosal homeostasis in the gastrointestinal (GI) tract. Additionally, it has been discovered that activating FcαRI boosts cytokine responses at different levels. IgD, a mysterious class of Ig once discovered, has a role in many disorders, including myeloma and Hodgkin's disease. The stability of IgD with development shows a different role, which has an advantage for the host's survival. IgE is mainly associated with many allergic diseases (food allergies), mediates type 1 responses, and has defenses against parasitic infections, which makes it an important parameter for monoclonal antibodies. Studies showed the possible roles of immunoglobulins, from which it came to light that immunoglobulins have their functions as agonists and antagonists in inflammation.

Upregulation of Neuroinflammation-Associated Genes in the Brain of SARS-CoV-2-Infected Mice.

Neurological manifestations are a significant complication of coronavirus disease 2019 (COVID-19), but the underlying mechanisms are yet to be understood. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced neuroinvasion and encephalitis were observed in K18-hACE2 mice, leading to mortality. Our goal in this study was to gain insights into the molecular pathogenesis of neurological manifestations in this mouse model. To analyze differentially expressed genes (DEGs) in the brains of mice following SARS-CoV-2 infection, we performed NanoString gene expression analysis using three individual animal samples at 1, 3, and 6 days post-infection. We identified the DEGs by comparing them to animals that were not infected with the virus. We found that genes upregulated at day 6 post-infection were mainly associated with Toll-like receptor (TLR) signaling, RIG-I-like receptor (RLR) signaling, and cell death pathways. However, downregulated genes were associated with neurodegeneration and synaptic signaling pathways. In correlation with gene expression profiles, a multiplexed immunoassay showed the upregulation of multiple cytokines and chemokines involved in inflammation and cell death in SARS-CoV-2-infected brains. Furthermore, the pathway analysis of DEGs indicated a possible link between TLR2-mediated signaling pathways and neuroinflammation, as well as pyroptosis and necroptosis in the brain. In conclusion, our work demonstrates neuroinflammation-associated gene expression profiles, which can provide key insight into the severe disease observed in COVID-19 patients.

Dysregulated gene subnetworks in breast invasive carcinoma reveal novel tumor suppressor genes.

Breast invasive carcinoma (BRCA) is the most malignant and leading cause of death in women. Global efforts are ongoing for improvement in early detection, prevention, and treatment. In this milieu, a comprehensive analysis of RNA-sequencing data of 1097 BRCA samples and 114 normal adjacent tissues is done to identify dysregulated genes in major molecular classes of BRCA in various clinical stages. Significantly enriched pathways in distinct molecular classes of BRCA have been identified. Pathways such as interferon signaling, tryptophan degradation, granulocyte adhesion & diapedesis, and catecholamine biosynthesis were found to be significantly enriched in Estrogen/Progesterone Receptor positive/Human Epidermal Growth Factor Receptor 2 negative, pathways such as RAR activation, adipogenesis, the role of JAK1/2 in interferon signaling, TGF-ß and STAT3 signaling intricated in Estrogen/Progesterone Receptor negative/Human Epidermal Growth Factor Receptor 2 positive and pathways as IL-1/IL-8, TNFR1/TNFR2, TWEAK, and relaxin signaling were found in triple-negative breast cancer. The dysregulated genes were clustered based on their mutation frequency which revealed nine mutated clusters, some of which were well characterized in cancer while others were less characterized. Each cluster was analyzed in detail which led to the identification of NLGN3, MAML2, TTN, SYNE1, ANK2 as candidate genes in BRCA. They are central hubs in the protein-protein-interaction network, indicating their important regulatory roles. Experimentally, the Real-Time Quantitative Reverse Transcription PCR and western blot confirmed our computational predictions in cell lines. Further, immunohistochemistry corroborated the results in ~ 100 tissue samples. We could experimentally show that the NLGN3 & ANK2 have tumor-suppressor roles in BRCA as shown by cell viability assay, transwell migration, colony forming and wound healing assay. The cell viability and migration was found to be significantly reduced in MCF7 and MDA-MB-231 cell lines in which the selected genes were over-expressed as compared to control cell lines. The wound healing assay also demonstrated a significant decrease in wound closure at 12 h and 24 h time intervals in MCF7 & MDA-MB-231 cells. These findings established the tumor suppressor roles of NLGN3 & ANK2 in BRCA. This will have important ramifications for the therapeutics discovery against BRCA.

Pathological insights into activin A: Molecular underpinnings and therapeutic prospects in various diseases.

Activin A (Act A) is a member of the TGFß (transforming growth factor ß) superfamily. It communicates via the Suppressor of Mothers against Decapentaplegic Homolog (SMAD2/3) proteins which govern processes such as cell proliferation, wound healing, apoptosis, and metabolism. Act A produces its action by attaching to activin receptor type IIA (ActRIIA) or activin receptor type IIB (ActRIIB). Increasing circulating Act A increases ActRII signalling, which on phosphorylation initiates the ALK4 (activin receptor-like kinase 4) type 1 receptor which further turns on the SMAD pathway and hinders cell functioning. Once triggered, this route leads to gene transcription, differentiation, apoptosis, and extracellular matrix (ECM) formation. Act A also governs the immunological and inflammatory responses of the body, as well as cell death. Moreover, Act A levels have been observed to elevate in several disorders like renal fibrosis, CKD, asthma, NAFLD, cardiovascular diseases, cancer, inflammatory conditions etc. Here, we provide an update on the recent studies relevant to the role of Act A in the modulation of various pathological disorders, giving an overview of the biology of Act A and its signalling pathways, and discuss the possibility of incorporating activin-A targeting as a novel therapeutic approach for the control of various disorders. Pathways such as SMAD signaling, in which SMAD moves to the nucleus by making a complex and leads to tissue fibrosis in CKD, STAT3, which drives renal fibroblast activity and the production of ECM, Kidney injury molecule (KIM-1) in the synthesis, deposition of ECM proteins, SERCA2a (sarcoplasmic reticulum Ca2+ ATPase) in cardiac dysfunction, and NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) in inflammation are involved in Act A signaling, have also been discussed.

Fluorine Rich Borate Salt Anion Based Electrolyte for High Voltage Sodium Metal Battery Development.

This study demonstrates the enhanced performance in high-voltage sodium full cells using a novel electrolyte composition featuring a highly fluorinated borate ester anion (1 M Na[B(hfip)4].3DME) in a binary carbonate mixture (EC:EMC), compared to a conventional electrolyte (1 M Na[PF6] EC:EMC). The prolonged cycling performance of sodium metal battery employing high voltage cathodes (NVPF@C@CNT and NFMO) is attributed to uniform and dense sodium deposition along with the formation of fluorine and boron-rich solid electrolyte interphase (SEI) on the sodium metal anode. Simultaneously, a robust cathode electrolyte interphase (CEI) is formed on the cathode side due to the improved electrochemical stability window and superior aluminum passivation of the novel electrolyte. The CEIs on high-voltage cathodes are discovered to be abundant in C-F, B-O, and B-F components, which contributes to long-term cycling stability by effectively suppressing undesirable side reactions and mitigating electrolyte decomposition. The participation of DME in the primary solvation shell coupled with the comparatively weaker interaction between Na+ and [B(hfip)4]- in the secondary solvation shell, provides additional confirmation of labile desolvation. This, in turn, supports the active participation of the anion in the formation of fluorine and boron-rich interphases on both the anode and cathode.

Unveiling the Role of PAR 1: A Crucial Link with Inflammation in Diabetic Subjects with COVID-19.

Inflammation is a distinguished clinical manifestation of COVID-19 and type 2 diabetes mellitus (T2DM), often associated with inflammatory dysfunctions, insulin resistance, metabolic dysregulation, and other complications. The present study aims to test the hypothesis that serum concentrations of PAR-1 levels differ between COVID-19 diabetic patients (T2DM) and non-diabetic COVID-19 patients and determine their association with different biochemical parameters and inflammatory biomarkers. T2DM patients with COVID-19 (n = 50) with glycated hemoglobin (HbA1c) levels of (9.23 ± 1.66) and non-diabetic COVID-19 patients (n = 50) with HbA1c levels (4.39 ± 0.57) were recruited in this study. The serum PAR-1 levels (ELISA method) were determined in both groups and correlated with parameters such as age, BMI, inflammatory markers including CRP, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), D-dimer, homocysteine, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Demographic variables such as BMI (29.21 ± 3.52 vs. controls 21.30 ± 2.11) and HbA1c (9.23 ± 1.66 vs. controls 4.39 ± 0.57) were found to be statistically elevated in COVID-19 T2DM patients compared to non-diabetic COVID-19 patients. The concentrations of several inflammatory biomarkers and PAR-1 were remarkably increased in the COVID-19 T2DM group when compared with the non-diabetic COVID-19 group. The univariate analysis revealed that increased serum PAR-1 estimations were positively correlated with enhanced HbA1c, BMI, inflammatory cytokines, D-dimer, homocysteine, and NT-proBNP. The findings in the current study suggest that increased levels of serum PAR-1 in the bloodstream could potentially serve as an independent biomarker of inflammation in COVID-19 patients with T2DM.

Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication.

The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (Mpro, also known as 3CLpro or Nsp5) to proteolytically process the polyproteins encoded by the viral genome for the release of functional units in the host cells to initiate viral replication. Mpro also interacts with host proteins of the innate immune pathways, such as IRF3 and STAT1, to suppress their activities and facilitate virus survival and proliferation. To identify the host mechanism for regulating Mpro, we screened various classes of E3 ubiquitin ligases and found that Parkin of the RING-between-RING family can induce the ubiquitination and degradation of Mpro in the cell. Furthermore, when the cells undergo mitophagy, the PINK1 kinase activates Parkin and enhances the ubiquitination of Mpro. We also found that elevated expression of Parkin in the cells significantly decreased the replication of SARS-CoV-2 virus. Interestingly, SARS-CoV-2 infection downregulates Parkin expression in the mouse lung tissues compared to healthy controls. These results suggest an antiviral role of Parkin as a ubiquitin ligase targeting Mpro and the potential for exploiting the virus-host interaction mediated by Parkin to treat SARS-CoV-2 infection.

Clinical Significance of Adropin and Afamin in Evaluating Renal Function and Cardiovascular Health in the Presence of CKD-MBD Biomarkers in Chronic Kidney Disease.

AIM: The study aims to test the hypothesis that concentrations of adropin and afamin differ between patients in various stages of chronic kidney disease when compared with healthy controls. The study also investigates the association of the biomarkers (adropin and afamin) with CKD-MBD and traditional cardiovascular risk parameters in CKD patients. METHODOLOGY: The cross-sectional study includes the subjects divided into four groups comprising the control group (healthy volunteers = 50), CKD stages 1-2 patients (n = 50), CKD stages 3-4 patients (n = 50), CKD stage 5 patients (n = 50). Serum concentrations of adropin and afamin were determined using ELISA. Clinical variables (renal, lipid, and CKD-MBD parameters) were correlated to adropin and afamin concentrations. RESULTS: Afamin concentration was found to be higher in group IV, followed by groups III and II when compared to the control group, i.e., (83.243 ± 1.46, 64.233 ± 0.99, and 28.948 ± 0.72 vs. 14.476 ± 0.5) mg/L (p < 0.001), and adropin concentration was found to be lower in group IV as compared to groups III, II, and I (200.342 ± 8.37 vs. 284.682 ± 9.89 vs. 413.208 ± 12.32 vs. 706.542 ± 11.32) pg/mL (p < 0.001), respectively. Pearson correlation analysis showed that afamin was positively correlated with traditional cardiovascular risk biomarkers, while adropin showed a negative correlation. CONCLUSIONS: Adropin and afamin may potentially serve as futuristic predictors for the deterioration of renal function and may be involved in the pathological mechanisms of CKD and its associated complications such as CKD-MBD and high lipid levels.

Omental torsion: diagnostic challenge in patients with sclerosing cholangitis and inflammatory bowel disease - case report.

Introduction and importance: The omentum appears as an apron-like extension of the peritoneum. Case presentation: A 30-year-old male patient, presented to the emergency department with the chief complaints of acute nonradiating pain localized in the right-side abdomen for the past 3 days. The patient had a past medical history of sclerosing cholangitis (SC) with inflammatory bowel disease (IBD). The patient reported the pain as persistent, pressure-like, and moderate. The patient also had a low-grade fever and nausea at the time of admission. On examination, the vital signs were found as normal. The patient reported that the abdominal pain gets exacerbated after the meals, and increase in physical activity and movement. Due to the patient's complaints and history of SC and IBD, these were considered as the possible diagnosis. After the diagnostic procedures, the patient was finally diagnosed with OT. Clinical discussion: This report presents a case of a patient suffering from omental torsion having history of SC and IBD. During the laparoscopic procedure, the diagnosis of omental torsion was confirmed. To our knowledge, no case report of omental torsion with IBD and SC is published in the literature. Conclusion: This seems to be a major diagnostic challenge as patients with IBD almost resembles the same clinical signs and symptoms as in the omental torsion. The possibility of misdiagnosis and delayed diagnosis could result in the unfavorable outcome. Therefore, the healthcare fraternities are advised to include the rare diseases such as OT as the differential diagnosis.

ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders.

Leukocyte migration from the vascular compartment is critical fornormal lymphocyte recirculation in specific tissues and immune response in inflammatory locations. Leukocyte recruitment, migration to inflammatory areas, and targeting in the extravascular space are caused by cellular stimulation and local expression of adhesion molecules. Intercellular adhesion molecule 1 (ICAM-1) and Vascular cell adhesion molecule 1 (VCAM-1) belong to the immunoglobulin superfamily of cell adhesion molecules (CAM) with a crucial role in mediating the strong adherence of leukocytes to endothelial cells in numerous acute as well as chronic diseases. ICAM-1 and VCAM-1 mediate inflammation and promote leukocyte migration during inflammation. ICAM-1 and VCAM-1 have a large role in regulating homeostasis and in pathologic states such as cancer, atherosclerosis, atrial fibrillation, myocardial infarction, stroke, asthma, obesity, kidney diseases, and much more. In inflammatory conditions and infectious disorders, leukocytes move and cling to the endothelium via multiple intracellular adhesive interactions. It is suggested that combining membrane-bound and soluble ICAM-1 and VCAM-1 into a single unit functional system will further our understanding of their immunoregulatory role as well as their pathophysiological effects on disease. This review focuses on the pathophysiological roles of ICAM-1 and VCAM-1 in various inflammatory and other diseases as well as their emerging cardiovascular role during the COVID-19 pandemic.

Evolutionary unmasking Resuscitative therapeutics potential of centhaquin citrate in hypovolemic shock.

Hypovolemic shock (HS), a clinical condition of insufficient blood perfusion and oxygenation in body tissues, is associated with immense morbidity and mortality. Treatment approaches include fluid replacement and surgical repair of reversible causes of hemorrhage; however, they cause irreversible blood perfusion loss, systemic inflammation, multiple organ failure, and death. Centhaquin citrate (CC) is an innovative centrally acting cardiovascular active agent that is initially intended as an antihypertensive drug. However, due to its positive ionotropic effect, Centhaquin citrate is being tested clinically as a resuscitative agent for the management of hypovolemic shock It acts at the α2B-adrenergic receptor to produce venous constriction followed by an increase in venous return to the heart. These actions are assumed to be capable of resuscitative activity observed by centhaquin citrate, through an increase in cardiac output and tissue perfusion. Pharmacokinetics investigations in animals and humans have shown that centhaquin citrate is well tolerated and has insignificant side effects. Therefore, centhaquin citrate seems to be a promising entity and gaining the interest of researchers to develop it as a resuscitative agent in HS. The review gives insight into the development of centhaquin citrate as a resuscitative agent and provides insight into the associated mechanism of action and molecular signalling to foster future research on CC for its clinical use in HS.

Phytochemicals: Alternative for Infertility Treatment and Associated Conditions.

Infertility and obstetric complications have become global health issues in the past few years. Infertility is defined as the inability of a couple to conceive even after twelve months or more of regular and unprotected intercourse. According to WHO data published in the year 2020, 186 million people have infertility globally. Factors leading to infertility are variable in both males and females. But some common factors include smoking, alcohol consumption, obesity, and stress. Various synthetic drugs and treatment options are available that are effective in treating infertility, but their prolonged usage produces various unwanted adverse effects like hot flashes, mood swings, headaches, and weight gain. In extreme cases, these may also lead to the development of anxiety and depression. Herbal remedies have gained a lot of popularity over the years, and people's inclination toward them has increased all over the world. The prime reason is that these show significant therapeutic efficacy and have fewer side effects. The therapeutic efficacy of plants can be attributed to the presence of diverse phytochemical classes of constituents like alkaloids, flavonoids, and volatile oils. These secondary metabolites, or phytomolecules, can be used to develop herbal formulations. The review highlights the applications and mechanisms of action of various phytochemicals for treating infertility. Also, it focuses on the various future prospects associated with it.

A comprehensive overview of juvenile idiopathic arthritis: From pathophysiology to management.

Rheumatoid Arthritis (RA) is a progressive autoimmune disease. It is among the most widespread chronic illnesses in children, with an annual incidence of 1.6 to 23 new instances per 100,000 adolescents. About 1 child in every 1000 develops Juvenile Idiopathic Arthritis (JIA) type of chronic arthritis. The cause of JIA is not well known but what known is that it involves inflammation of the synovium and destruction of tissues in joints which can cause early-onset of oligo articular JIA. It is challenging to diagnose the condition in some children who initially complain of pain and joint swelling as there is no blood test discovered that can confirm the diagnoses of JIA. As JIA patients are immunosuppressed due to the use of drugs, making them vulnerable to catch infections like COVID-19 which can lead to cardiovascular diseases having high rate of morbidity and mortality. The comorbidity like Diabetes has higher incidence in these patients resulting in synergistic effect on inflammation. Currently, the connection of genetics in JIA provides evidence that HLA Class I and II alleles have a role in the pathophysiology of various subtypes of JIA which includes inflammation in the axial skeletal. The primary objective of therapy in juvenile idiopathic arthritis is the suppression of clinical symptoms. The pharmacological approach includes use of medications like DMARDs, NSAIDs etc. and non-pharmacological approach includes physiotherapy, which helps in restoring normal joint function and herbs as adjuvants which has the benefit of no side effects.

Lower Diffusion-Induced Stress in Nano-Crystallites of P2-Na2/3 Ni1/3 Mn1/2 Ti1/6 O2 Novel Cathode for High Energy Na-ion Batteries.

P2-type Na2/3 Ni1/3 Mn1/2 Ti1/6 O2 (NMTNO) cathode is a preeminent electrode material for Na-ion batteries owing to its open prismatic framework, air-moisture stability, inexpensiveness, appealing capacity, environmental benignity, and Co-free composition. However, the poor cycling stability, sluggish Na-ion kinetics induced in bulk-sized cathode particles, cracking, and exfoliation in the crystallites remain a setback. To outmaneuver these, a designing strategy of a mechanically robust, hexagonal nano-crystallites of P2-type Na2/3 Ni1/3 Mn1/2 Ti1/6 O2 (NMTNOnano ) electrode via quick, energy-efficient, and low-cost microwave-irradiated synthesis is proposed. For the first time, employing a unified experimental and theoretical approach with fracture mechanics analysis, the mechanism behind the enhanced performance, better structural stability, and lower diffusion-induced stress of NMTNOnano compared to micro-sized Na2/3 Ni1/3 Mn1/2 Ti1/6 O2 is unveiled and the electrochemical shock map is predicted. The NMTNOnano cathode provides 94.8% capacity retention after 100 cycles at 0.1 C with prolonged performance for 1000 cycles at 0.5 C. The practical viability of this cathode, tested in a full cell against a hard carbon anode delivered 85.48% capacity retention at 0.14 mA cm-2 after 200 cycles. This work bridges the gap in correlating the microstructural and electrochemical properties through experimental, theoretical (DFT), and fracture mechanics analysis, thereby tailoring efficient cathode with lower diffusion-induced stress for high-energy Na-ion batteries.

Metformin: Activation of 5' AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action.

Metformin is a plant-based drug belonging to the class of biguanides and is known to treat type-2 diabetes mellitus (T2DM). The drug, combined with controlling blood glucose levels, improves the body's response to insulin. In addition, trials have identified the cardioprotective potential of metformin in the diabetic population receiving the drug. Activation of 5' AMP-activated protein kinase (AMPK) is the major pathway for these potential beneficial effects of metformin. Historically, much emphasis has been placed on the potential indications of metformin beyond its anti-diabetic use. This review aims to appraise other potential uses of metformin primarily mediated by the activation of AMPK. We also discuss various mechanisms, other than AMPK activation, by which metformin could produce beneficial effects for different conditions. Databases including PubMed/MEDLINE and Embase were searched for literature relevant to the review's objective. Reports from both research and review articles were considered. We found that metformin has diverse effects on the human body systems. It has been shown to exert anti-inflammatory, antioxidant, cardioprotective, metabolic, neuroprotective, anti-cancer, and antimicrobial effects and has now even been identified as effective against SARS-CoV-2. Above all, the AMPK pathway has been recognized as responsible for metformin's efficiency and effectiveness. Owing to its extensive potential, it has the capability to become a part of treatment regimens for diseases apart from T2DM.

Study on dengue severity in diabetic and non-diabetic population of tertiary care hospital by assessing inflammatory indicators.

Background: Dengue fever is a highly endemic tropical infectious disease that is quickly spreading over the world. Diabetes Mellitus has been linked to chronic inflammation. This present study was designed to compare the severity of dengue infection among diabetic and non-diabetic populations. Methods: A prospective observational study was conducted on 40 patients (20 diabetic and 20 non-diabetic) who suffered from dengue infection. The study involved the collection of data of the dengue patients includes patient's demographic details, medical condition as well as biochemical investigations. Results: Dengue-infected individuals with diabetes showed greater CRP, Endocan levels, IL-8 and Perfusion Index than those without diabetes (CRP; 35.308 ± 1.32 vs. 18.6365 ± 0.64) mg/dl (p≤ 0.001) (Endocan 42.316 ± 1.46vs. 32.839 ± 0.33), ng/dl (p≤ 0.001), (142.98 ± 1.05 vs 103.69 ± 0.64) (p ≤ 0.001) and (3.695 ± 0.18 vs. 1.98 ± 0.08) (p ≤ 0.001) respectively. Conclusion: In conclusion the results indicate that prognosis of DHF grade II with diabetes mellitus tends to be more prone to bleeding disorder and can result into morbidity and mortality considering by triggering of the various inflammatory cascade resulting in hyperglycaemia and poor glycemic control.