Spectrum of COVID-19 induced liver injury: A review report.

The coronavirus disease 2019 (COVID-19) pandemic has caused changes in the global health system, causing significant setbacks in healthcare systems worldwide. This pandemic has also shown resilience, flexibility, and creativity in reacting to the tragedy. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection targets most of the respiratory tract, resulting in a severe sickness called acute respiratory distress syndrome that may be fatal in some individuals. Although the lung is the primary organ targeted by COVID-19 viruses, the clinical aspect of the disease is varied and ranges from asymptomatic to respiratory failure. However, due to an unorganized immune response and several affected mechanisms, the liver may also experience liver cell injury, ischemic liver dysfunction, and drug-induced liver injury, which can result in respiratory failure because of the immune system's disordered response and other compromised processes that can end in multisystem organ failure. Patients with liver cirrhosis or those who have impaired immune systems may be more likely than other groups to experience worse results from the SARS-CoV-2 infection. We thus intend to examine the pathogenesis, current therapy, and consequences of liver damage concerning COVID-19.

Challenges in Emerging Vaccines and Future Promising Candidates against SARS-CoV-2 Variants.

Since the COVID-19 outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus has evolved into variants with varied infectivity. Vaccines developed against COVID-19 infection have boosted immunity, but there is still uncertainty on how long the immunity from natural infection or vaccination will last. The present study attempts to outline the present level of information about the contagiousness and spread of SARS-CoV-2 variants of interest and variants of concern (VOCs). The keywords like COVID-19 vaccine types, VOCs, universal vaccines, bivalent, and other relevant terms were searched in NCBI, Science Direct, and WHO databases to review the published literature. The review provides an integrative discussion on the current state of knowledge on the type of vaccines developed against SARS-CoV-2, the safety and efficacy of COVID-19 vaccines concerning the VOCs, and prospects of novel universal, chimeric, and bivalent mRNA vaccines efficacy to fend off existing variants and other emerging coronaviruses. Genomic variation can be quite significant, as seen by the notable differences in impact, transmission rate, morbidity, and death during several human coronavirus outbreaks. Therefore, understanding the amount and characteristics of coronavirus genetic diversity in historical and contemporary strains can help researchers get an edge over upcoming variants.

Analyses of Elaeocarpus sphaericus Extract for Antioxidant, Antiproliferative and Gene Repression Activities against HIF-1α and VEGF.

The study presents antioxidant, phytochemical, anti-proliferative, and gene repression activities against Hypoxia-inducible factor (HIF-1) alpha and Vascular endothelial growth factor (VEGF) of Elaeocarpus sphaericus extract. Elaeocarpus sphaericus dried and crushed plant leaves were extracted using water and methanol by ASE (Accelerated Solvent Extraction) method. Total phenolic content (TPC) and total flavonoid content (TFC) were used to measure the extracts' phytochemical activity (TFC). Antioxidant potential of the extracts was measured through DPPH, ABTS, FRAP, and TRP. Methanolic extract of the leaves of E. sphaericus has shown a higher amount of TPC (94.666±4.040 mg/gm GAE) and TFC value (172.33±3.21 mg/gm RE). The antioxidant properties of extracts in the yeast model (Drug Rescue assay) showed promising results. Ascorbic acid, gallic acid, hesperidin, and quercetin were found in the aqueous and methanolic extracts of E. sphaericus at varying amounts, according to a densiometric chromatogram generated by HPTLC analysis. Methanolic extract of E. sphaericus (10 mg/ml) has shown good antimicrobial potential against all bacterial strains used in the study except E. coli. The anticancer activity of the extract in HeLa cell lines ranged from 77.94±1.03 % to 66.85±1.95 %, while it ranged from 52.83±2.57 % to 5.44 % in Vero cell lines at varying concentration (1000 µg/ml-31.2 µg/ml). A promising effect of extract was observed on the expression activity of HIF-1 and VEGF gene through RT-PCR assay.

Investigating the Performance of a Zinc Oxide Impregnated Polyvinyl Alcohol-Based Low-Cost Cation Exchange Membrane in Microbial Fuel Cells.

The current study investigated the development and application of lithium (Li)-doped zinc oxide (ZnO)-impregnated polyvinyl alcohol (PVA) proton exchange membrane separator in a single chambered microbial fuel cell (MFC). Physiochemical analysis was performed via FT-IR, XRD, TEM, and AC impedance analysis to characterize thus synthesized Li-doped ZnO. PVA-ZnO-Li with 2.0% Li incorporation showed higher power generation in MFC. Using coulombic efficiency and current density, the impact of oxygen crossing on the membrane cathode assembly (MCA) area was evaluated. Different amounts of Li were incorporated into the membrane to optimize its electrochemical behavior and to increase proton conductivity while reducing biofouling. When acetate wastewater was treated in MFC using a PVA-ZnO-Li-based MCA, the maximum power density of 6.3 W/m3 was achieved. These observations strongly support our hypothesis that PVA-ZnO-Li can be an efficient and affordable separator for MFC.

Prevalence of pre-perimetric primary open angle glaucoma in hypertensives of North India.

Background: Systemic hypertension is alleged to increase the risk of glaucoma. As clinically Primary Open angle Glaucoma (POAG) is diagnosed only after approximately 40% of ganglion cell loss has occurred, therefore this study was commenced with an aim to determine the prevalence of pre-perimetric glaucomatous damage and its association with systemic hypertension using optical coherence tomography (OCT). Materials and Methods: A total of 680 study participants were enrolled in this cross-sectional study. Among them 340 patients were of systemic hypertension (Group 1) and 340 patients without hypertension (Group 2). All patients underwent detailed history, ocular and systemic examination including slit lamp examination, fundus examination by +90 D lens, Humphrey field analyser for field charting and OCT for nerve fiber analysis. For glaucomatous nerve damage. Results: Group 1 and Group 2 had Male: Female ratio of 1:8 and 1:9, respectively (P = 0.809). Maximum participants 48.8% and 54.4% in Group 1 and Group 2, respectively, were in age group 50-59 years. Statistically significant difference was seen in the percentage of pre-perimetric glaucomatous patients between the two groups (P < 0.001). On OCT analysis between pre-perimetric glaucomatous eyes and healthy eyes significant difference in thickness was seen in temporal inner macula, inferior outer macula, temporal outer macula, superior outer macula and nasal outer macula. Significant difference in volume was seen for inferior temporal and nasal outer macula (P < 0.001). Conclusion: In hypertensives, glaucomatous optic nerve damage starts much earlier before the obvious clinical signs of POAG appear, as compared to normotensive individuals.

Posttranslational modifications of α-conotoxins: sulfotyrosine and C-terminal amidation stabilise structures and increase acetylcholine receptor binding.

Conotoxins are peptides found in the venoms of marine cone snails. They are typically highly structured and stable and have potent activities at nicotinic acetylcholine receptors, which make them valuable research tools and promising lead molecules for drug development. Many conotoxins are also highly modified with posttranslational modifications such as proline hydroxylation, glutamic acid gamma-carboxylation, tyrosine sulfation and C-terminal amidation, amongst others. The role of these posttranslational modifications is poorly understood, and it is unclear whether the modifications interact directly with the binding site, alter conotoxin structure, or both. Here we synthesised a set of twelve conotoxin variants bearing posttranslational modifications in the form of native sulfotyrosine and C-terminal amidation and show that these two modifications in combination increase their activity at nicotinic acetylcholine receptors and binding to soluble acetylcholine binding proteins, respectively. We then rationalise how these functional differences between variants might arise from stabilization of the three-dimensional structures and interactions with the binding sites, using high-resolution nuclear magnetic resonance data. This study demonstrates that posttranslational modifications can modulate interactions between a ligand and receptor by a combination of structural and binding alterations. A deeper mechanistic understanding of the role of posttranslational modifications in structure-activity relationships is essential for understanding receptor biology and could help to guide structure-based drug design.

Hyaluronate-functionalized hydroxyapatite nanoparticles laden with methotrexate and teriflunomide for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.

Co-Delivery of Teriflunomide and Methotrexate from Hydroxyapatite Nanoparticles for the Treatment of Rheumatoid Arthritis: In Vitro Characterization, Pharmacodynamic and Biochemical Investigations.

PURPOSE: The present investigation was aimed at developing Teriflunomide (TEF) and Methotrexate (MTX) loaded hydroxyapatite nanoparticles and increasing tolerability towards combination therapy against rheumatoid arthritis by reducing hepatotoxicity. METHODS: Drug-loaded HAp-NPs were synthesized by wet-chemical precipitation method and optimized by Box-Behnken experimental design. The developed NPs were subjected to in vitro and in vivo characterization. In-vivo pharmacodynamics and biochemical studies were performed on adjuvant- induced arthritis model treated with different formulations; MTX-TEF-SOL, TEF-HAp-NP, MTX-HAp-NP, TEF-MTX-HAp-NP, FOLITRAX-10 and AUBAGIO. RESULTS: The size of the optimized formulations, TEF-HAp-NP and MTX-HAp-NP, was found to be 224.3 ± 83.80 nm and 268.3 ± 73.86 nm with drug loading 53.11 ± 0.84% and 67.04 ± 1.12% respectively. In vitro release of TEF from TEF-HAp-NP (70.41 ± 1.22%) and MTX from MTX-HAp-NP (82.43 ± 1.31%) up to 24 h revealed sustained release pattern. Results of the arthritic assessment study showed a significant (P < 0.05) reduction in ankle diameter (61.30 ± 7.42) and arthritis score (2.35 ± 0.24) with a marked restoration of ankle joint micro-architecture in TEF-MTX-HAp-NP treated group. During Hepatotoxicity studies, liver histopathology revealed that the formulation MTX-TEF-HAp-NP was least hepatotoxic with less hepatocyte swelling and fibrous connective tissue proliferation while Folitrax-10 was found to be most hepatotoxic. Biochemical studies revealed that Folitrax-10 significantly (P < 0.05) increased the GOT (313.64 ± 16) and GPT level (334.46 ± 13) while insignificant (P > 0.05) change in GOT (263.68 ± 17) and GPT (229.38 ± 10) level was recorded with TEF-MTX-HAp-NP. CONCLUSIONS: We report that the subcutaneous delivery of TEF-MTX-HAp-NP was most effective as it successfully reduced the dosage by half for maximizing therapeutic efficacy and minimizing side effects. Graphical Abstract ᅟ.

Emerging Role of CD44 Receptor as a Potential Target in Disease Diagnosis: A Patent Review.

BACKGROUND: The CD44 receptor is a cell surface glycoprotein, which mediates many physiological and pathological activities. Its key role is to provide defence against inflammatory reactions by cellular transmigration and cell signalling. In pathological conditions, it gives destructive outcomes by mediating migration of pathogenic cells to vital organs resulting in tissue and organ damage. It binds to several ligands principally the hyaluronan. OBJECTIVE: This review explores CD44 structure, functions, and its potential as a disease indicator and therapeutic target. METHOD: From a thorough literature review on the CD44 receptor, several patents of targeting approaches have been identified and herewith reviewed which recommend CD44-binding proteins, CD44-binding antibodies, antibody fragments, pharmaceutical compositions, as well as nucleic acids as a targeting moiety. RESULT: Applicability of CD44 overexpression and its targeting has now been extensively utilized in the disease diagnosis and real-time bio imaging of pathologic cells. CONCLUSION: A thorough understanding of CD44-receptor structure, expression and diverse functions towards different cell types would offer an opportunity to develop better therapeutic approaches in the near future by overcoming all the shortcomings of toxicity and efficacy. The present review includes recent patents of CD44 receptor targeting approaches that have been presented in the different agencies: European (EP), US, and World Intellectual Property Organization (WIPO) and a general analysis of the future developments and trends in this emerging area.

Experimental studies on possible regulatory role of nitric oxide on the differential effects of chronic predictable and unpredictable stress on adaptive immune responses.

The present study was designed to investigate the effects of chronic predictable stress (CPS) and chronic unpredictable stress (CUS) on immunological responses in KLH-sensitized rats and involvement of NOergic signaling pathways mediating such responses. Male Wistar rats (200-250g) were exposed to either CPS or CUS for 14days and IgG antibody levels and delayed type hypersensitivity (DTH) response was determined to assess changes in adaptive immunity. To evaluate the role of nitric oxide during such immunomodulation, biochemical estimation of stable metabolite of nitric oxide (NOx) and 3-nitrotyrosine (3-NT, a marker of peroxynitrite formation) were done in both blood and brain. Chronic stress exposure resulted in suppression of IgG and DTH response and elevated NOx and 3-NT levels, with a difference in magnitude of response in CPS vs CUS. Pretreatment with aminoguanidine (iNOS inhibitor) caused further reduction of adaptive immune responses and attenuated the increased NOx and 3-NT levels in CPS or CUS exposed rats. On the other hand 7-NI (nNOS inhibitor) did not significantly affect these estimated parameters. The results suggest involvement of iNOS and lesser/no role of nNOS during modulation of adaptive immunity to stress. Thus, the result showed that predictability of stressors results in differential degree of modulation of immune responses and complex NO-mediated signaling mechanisms may be involved during responses.

Nanofacilitated synergistic treatment for rheumatoid arthritis: A 'three-pronged' approach.

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease of unidentified etiology that affects the joints and causes pain, swelling, stiffness and redness in the joints. The exact cause of rheumatoid arthritis has not yet been discovered and, consequently, treatment methods have not been optimally effective. It has long been treated with anti-inflammatory and immunosupressants including modern biologics either alone or in combination but all of the drugs have severe life threatening consequences with impaired immune function due to nonspecific targeting. Therefore, a three-pronged approach of local, active and synergistic targeting can be used to optimize delivery of therapeutic agents to reduce toxicity and patient outcome without compromising patient's immunity.

Antihypertensive, Amlodipine Besilate Inhibits Growth and Biofilm of Human Fungal Pathogen Candida.

Candida albicans and Candida glabrata are two important human pathogens associated with high mortality. The anti-Candida potential of an antihypertensive drug, amlodipine besilate (AB), was studied against 10 strains of Candida, including 8 clinical isolates. AB is an inhibitor of voltage-gated Ca2+ channel (VGCC) of mammals. CCH1 expresses in a part of Ca2+ channel of Candida, which is a homologue of α subunit of mammalian VGCC. In plate assays, all strains of Candida showed sensitivity to AB on agar media at 256 µg/mL concentration, AB caused lethality at concentrations of 16 and 64 µg/mL in clinical isolates of C. glabrata and all strains of C. albicans, respectively. Minimum fungicidal concentration (MFC) values of AB varied for different strains. The clinical isolates of C. glabrata turned out to be more susceptible to AB than those of C. albicans. At 16 µg/mL, AB showed reduction of biofilm in the range of 41.51%-79.66% for C. glabrata strains and 32.00%-54.06% for C. albicans strains. AB has shown potential antifungal properties against the laboratory strains and clinical isolates of C. glabrata and C. albicans. In conclusion, AB exhibited potential antifungal properties against planktonic form and biofilm of C. glabrata and C. albicans. It was more effective against C. glabrata than against C. albicans in vitro.

Cellular and molecular mechanisms of action of polyherbal preparation UNIM-352 in experimental models of bronchial asthma.

Bronchial asthma is a chronic inflammatory disorder of the airways and pharmacotherapy is dependent on anti-inflammatory and bronchodilator agents. However, adverse effects of these agents on chronic administration and sometimes non-responsiveness to these drugs have prompted the search for viable alternatives from medicinal plant sources. UNIM-352 is a polyherbal preparation traditionally used in the Unani system of Indian medicine for the treatment of bronchial asthma. The present study defines the possible cellular and molecular mechanisms of action of UNIM-352 in experimental models of bronchial asthma and validates the observed therapeutically beneficial effects. Wistar rats were immunized and challenged with ovalbumin, and blood and bronchoalveolar lavage (BAL) fluid were assayed for cytological and biochemical markers. UNIM-352 (200 and 400 mg/kg) markedly reduced the eosinophil and neutrophil counts in both blood and BAL compared to control. The polyherbal agent also attenuated the levels of TNF-α, IL-4, GM-CSF and NF-κB whereas histone deacetylase (HDAC) levels were elevated, in both blood and BAL fluid. All effects of UNIM-352 were comparable with the standard drug, prednisolone. The results demonstrated possible cellular and molecular mechanisms of UNIM-352 and thus explain its beneficial effects in bronchial asthma.

Biochemical characterization and pharmacognostic evaluation of purified catechins in green tea (Camellia sinensis) cultivars of India.

Green tea (GT) is derived from the leaves of Camellia sinensis implicated in a wide range of health attributes. In the present comprehensive study, methanolic, acetone and aqueous extract of leaves of C. sinensis var. sinensis [Kashmir (KW), Uttarakhand (IP & PN)] and C. sinensis var. assamica (Assam, AT) were explored for their phytoconstituents. Solvent extracts of GT cultivars showed rich presence of phytoconstituents in comparison with aqueous extracts. The methanolic extract of AT and acetone extract of KW showed highest total phenol content (18.32 ± 0.357 mg of GAE equivalent/g of sample) and total flavonoid content (29.25 ± 0.015 mg of catechin equivalent/g of sample), respectively. All the cultivars revealed higher free radical scavenging activity in the range of 73.80 ± 0.152 to 82.40 ± 0.004 % confirming antioxidant potentials. The HPLC analysis of purified residue procured from solvent partitioning depicted AT with highest concentration of epigallocatechin gallate (EGCg) i.e., 154.7 ± 4.949 mg/g followed by Kashmir and Uttarakhand GT cultivars. The present study revealed that Assam GT could be a potent herbal candidate with multiple nutraceutical applications. However, significant investigation of the cultivars is to be done to further explore the EGCg-dependent activity of GT for herbal drug development.