The gut-immune-liver axis in patients with alcohol use disorder and clinically low serum zinc levels.

BACKGROUND: Alcohol use disorder (AUD) with chronic and heavy alcohol consumption causes alcohol-associated liver disease (ALD). Early-stage ALD exhibits dyshomeostasis of zinc. We investigated the role of zinc deficiency in gut-barrier dysfunction, proinflammatory response, hepatocyte injury, and death, as well as potential sex differences in AUD patients. METHODS: Thirty-nine male and female AUD patients were grouped by normal [≥71 µg/dL (Group 1, number (n) = 26)] and low [<71 µg/dL (Group 2, n = 13)] serum zinc levels. Demographics, alcohol intake markers [Lifetime Drinking History (LTDH), heavy drinking days in the past 90-days (HDD90), total drinks in the past 90-days (TD90), number of drinking days in the past 90-days (NDD90), average drinks per day in the past 90 days (AvgDPD90)] were collected. Blood samples were tested for complete blood count (CBC), comprehensive metabolic panel (CMP), coagulation markers, gut-barrier dysfunction markers, cytokines, and hepatocyte death markers. RESULTS: Group 2 females exhibited lower LTDH than Group 2 males (p = 0.028), but higher recent drinking. Aspartate transaminase: alanine transaminase (AST:ALT) ratio was higher (p = 0.049) in Group 2 males compared to Group 1 males. Overall, Group 2 showed threefold higher interleukin 8 (IL-8) levels than Group 1 (p = 0.92); these were sevenfold higher in Group 2 females than Group 1 females. Group 2 females also had higher K18M65, but lower K18M30 than Group 1 females. Necrotic type of cell death (K18M65) was well-described only in Group 2 by the arrangement of lipopolysaccharide (LPS), soluble cluster of differentiation 14 (sCD14), and tumor necrosis factor alpha (TNF-α) (R2 = 0.633, p = 0.037). CONCLUSION: Our findings demonstrated the role of the gut-immune-liver axis in describing hepatocyte injury and death in zinc-deficient AUD patients. These patients represented an arrangement of gut-barrier dysfunction and an exacerbated immune response. Shift in the cell-death mechanism from apoptosis in zinc-replete females to necrosis in zinc-deficient females suggests a subclinical to clinical transition of ALD associated with zinc status.

Stem Cell Therapy for Myocardial Infarction and Heart Failure: A Comprehensive Systematic Review and Critical Analysis.

In exploring therapeutic options for ischemic heart disease (IHD) and heart failure, cell-based cardiac repair has gained prominence. This systematic review delves into the current state of knowledge surrounding cell-based therapies for cardiac repair. Employing a comprehensive search across relevant databases, the study identifies 35 included studies with diverse cell types and methodologies. Encouragingly, these findings reveal the promise of cell-based therapies in cardiac repair, demonstrating significant enhancements in left ventricular ejection fraction (LVEF) across the studies. Mechanisms of action involve growth factors that stimulate angiogenesis, differentiation, and the survival of transplanted cells. Despite these positive outcomes, challenges persist, including low engraftment rates, limitations in cell differentiation, and variations in clinical reproducibility. The optimal dosage and frequency of cell administration remain subjects of debate, with potential benefits from repeated dosing. Additionally, the choice between autologous and allogeneic stem cell transplantation poses a critical decision. This systematic review underscores the potential of cell-based therapies for cardiac repair, bearing implications for innovative treatments in heart diseases. However, further research is imperative to optimize cell type selection, delivery techniques, and long-term efficacy, fostering a more comprehensive understanding of cell-based cardiac repair.

Detergent induced structural perturbations in peanut agglutinin: insights from spectroscopic and molecular dynamic simulation studies.

The three dimensional structure of a protein is very important for its structure. Studies relating to protein structure have been numerous and the effect of denaturants on proteins can help understand the process of protein folding and misfolding. Detergents are important denaturants and play important roles in various fields. Here we explored the effect of sodium dodecyl sulphate (SDS) and cetyltrimethylammonium bromide (CTAB) on the structure of peanut agglutinin (PNA). The protein was purified from its natural source and impact of SDS and CTAB was studied by circular dichroism, intrinsic fluorescence, 8-anilino-1-napthalenesulfonic acid, molecular docking and molecular dynamics simulation. Pure peanut agglutinin showed a trough at 220 nm and positive ellipticity peak at 195 nm, specific for lectins. Results from the experimental and simulation studies suggest how oppositely charged detergents can interact differently and lead to varied structural perturbations in PNA. Both the surfactants induce all α protein-like circular dichroism in the protein, above its critical micelle concentrations, with significant change in accessible surface area that became more hydrophobic upon the treatment. Major interactions between the surfactants and protein, resulting in PNA conformational rearrangement, are electrostatic and van der Waals interactions. However, CTAB, a cationic surfactant, has similar effects as anionic surfactant (SDS) but at significantly very low concentration. Though the effects followed same pattern in both the surfactant treatment, i.e. above respective CMC, the surfactants were inducing all α protein-like conformation in PNA.Communicated by Ramaswamy H. Sarma.

Methotrexate-Induced Mucositis: A Consequence of Medication Error in a Rheumatoid Arthritis Patient.

Methotrexate (MTX) is a commonly prescribed medication for the treatment of rheumatoid arthritis (RA). Although effective in managing rheumatoid arthritis symptoms, methotrexate can have adverse effects, including mucositis. This study highlights a case of methotrexate-induced mucositis resulting from a medication error in a patient with rheumatoid arthritis. The 69-year-old patient recently diagnosed with rheumatoid arthritis was receiving methotrexate therapy as a part of his treatment plan. The patient, however, unintentionally ingested an excessive dose of methotrexate because of a communication error that occurred during the medication administration process. He started displaying signs of oral mucositis, characterized by uncomfortable ulcers and oral mucosa inflammation, within a short period. The buccal mucosa, tongue, and gingiva of the patient's oral cavity displayed numerous ulcerative lesions upon examination. Due to the mucositis's severity, it was challenging to eat, speak, and perform regular oral hygiene procedures. The patient described severe discomfort that had a detrimental effect on his general quality of life. This case serves as a reminder of the importance of accurate medication administration and communication in the management of rheumatoid arthritis. Healthcare professionals should ensure proper dosing and monitoring to minimize the risk of medication errors and associated complications. Additionally, patients should be educated about the potential side effects of methotrexate, including mucositis, to enable early recognition and timely intervention. In conclusion, this study emphasizes the occurrence of methotrexate-induced mucositis because of medication administration errors in a patient with rheumatoid arthritis. By increasing awareness of this potential complication, healthcare providers can improve patient safety and enhance the overall management of rheumatoid arthritis treatment.

An Uncommon Side Effect of Rivaroxaban: A Drug-Induced Liver Injury.

Rivaroxaban is rarely associated with drug-induced liver injury (DILI). A 57-year-old male was sent to the emergency room from an endocrine clinic for a presyncope evaluation. His exam was non-focal, and his laboratory work was remarkable for the hepatocellular pattern of liver injury. Upon detailed assessment, he was found to have DILI due to rivaroxaban. The liver function tests improved after its discontinuation. This case emphasizes the need for early recognition and timely intervention to prevent further hepatotoxicity from the culprit drug.

A Rare Case of Elevated Transaminases With Incomplete Abortion Due to Cytomegalovirus Infection: An Experience From a Resource-Limited Setting.

Cytomegalovirus (CMV) infection during pregnancy may cause spontaneous abortion, stillbirth, and death of newborns. CMV is the most common congenital infection in newborns. It generally has a benign course in immunocompetent individuals, while the severe disease is usually seen in immunocompromised patients. Most of the published studies about CMV infection describe congenital abnormalities in newborns. Only a handful of case reports mention CMV infection associated with elevated transaminases during pregnancy. Here, we present a case of incomplete abortion with elevated liver enzymes in a 26-year-old female caused by CMV infection. Our case report illustrates the importance of considering CMV infection as a differential in an incomplete abortion associated with elevated liver enzymes.

Drinking and laboratory biomarkers, and nutritional status characterize the clinical presentation of early-stage alcohol-associated liver disease.

Chronic and heavy alcohol consumption is commonly observed in alcohol use disorder (AUD). AUD often leads to alcohol-associated organ injury, including alcohol-associated liver disease (ALD). Approximately 10-20% of patients with AUD progress to ALD. Progression of ALD from the development phase to more advanced states involve the interplay of several pathways, including nutritional alterations. Multiple pathologic processes have been identified in the progression and severity of ALD. However, there are major gaps in the characterization and understanding of the clinical presentation of early-stage ALD as assessed by clinical markers and laboratory measures. Several Institutions and Universities, including the University of Louisville, in collaboration with the National Institutes of Health, have published a series of manuscripts describing early-stage ALD over the past decade. Here, we comprehensively describe early-stage ALD using the liver injury and drinking history markers, and the laboratory biomarkers (with a focus on nutrition status) that are uniquely involved in the development and progression of early-stage ALD.

Oxidative stress generated due to photocatalytic activity of biosynthesized selenium nanoparticles triggers cytoplasmic leakage leading to bacterial cell death.

The present work investigates the role of oxidative stress generated at biosynthesized selenium nanoparticles (SeNPs) interface in defining the antimicrobial and anti-biofilm activity. To this end, SeNPs with average size of 119 nm were synthesized rapidly during the growth of Staphylococcus aureus using the principle of green chemistry. The synthesis of SeNPs was confirmed by using different biophysical techniques like UV-vis spectroscopy, X-ray diffraction (XRD), field-emission scanning electron microscope (FE-SEM), EDX and zeta potential analysis. The obtained data from antimicrobial study revealed strong antimicrobial activity against both Gram-positive bacteria like Bacillus subtilis (MTCC 441) and Gram-negative bacteria like Escherichia coli (MTCC 443) and anti-biofilm activity against biofilm forming bacteria. The mechanism behind antimicrobial activity of biosynthesized SeNPs was explored by evaluating the amount of reactive oxygen species (ROS) generated at SeNPs interface due to photocatalytic activity. The experimental data obtained altogether concluded that, the ROS generated at SeNPs interface put stress on bacterial cell membrane causing leakage of cytoplasmic contents, leading to bacterial cell death.

Photocatalytic activity of biosynthesized silver nanoparticle fosters oxidative stress at nanoparticle interface resulting in antimicrobial and cytotoxic activities.

Inside the biological milieu, nanoparticles with photocatalytic activity have potential to trigger cell death non-specifically due to production of reactive oxygen species (ROS) upon reacting with biological entities. Silver nanoparticle (AgNP) possessing narrow band gap energy can exhibit high light absorption property and significant photocatalytic activity. This study intends to explore the effects of ROS generated due to photocatalytic activity of AgNP on antimicrobial and cytotoxic propensities. To this end, AgNP was synthesized using the principle of green chemistry from the peel extract of Punica granatum L., and was characterized using UV-Vis spectroscope, transmission electron microscope and x-ray diffraction, and so forth. The antimicrobial activity of AgNP against studied bacteria indicated that, ROS generated at AgNP interface develop stress on bacterial membrane leading to bacterial cell death, whereas Alamar Blue dye reduction assay indicated that increased cytotoxic activity with increasing concentrations of AgNP. The γH2AX activity assay revealed that increasing the concentrations of AgNP increased DNA damaging activity. The results altogether demonstrated that both antimicrobial and cytotoxic propensities are triggered primarily due interfacial ROS generation by photocatalytic AgNP, which caused membrane deformation in bacteria and DNA damage in HT1080 cells resulting in cell death.

Interplay of lipid head group and packing defects in driving amyloid-beta-mediated myelin-like model membrane deformation.

Accumulating evidence suggests that amyloid plaque-associated myelin lipid loss as a result of elevated amyloid burden might also contribute to Alzheimer's disease. The amyloid fibrils are closely associated with lipids under physiological conditions; however, the progression of membrane remodeling events leading to lipid-fibril assembly remains unknown. Here we first reconstitute the interaction of amyloid Beta 40 (Aß-40) with myelin-like model membrane and show that the binding of Aß-40 induces extensive tubulation. To look into the mechanism of membrane tubulation, we chose a set of membrane conditions varying in lipid packing density and net charge that allows us to dissect the contribution of lipid specificity of Aß-40 binding, aggregation kinetics, and subsequent changes in membrane parameters such as fluidity, diffusion, and compressibility modulus. We show that the binding of Aß-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin-like model membrane during the early phase of amyloid aggregation. Furthermore, elongation of Aß-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the model membrane followed by extensive lipid membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aß-40-myelin-like model membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril-mediated load generation results in the consequent association of lipids with growing amyloid fibrils.

Multiple Hepatic Abscesses Secondary to Streptococcus anginosus Infection: A Case Report and Review of the Literature.

Hepatic abscesses are rare and generally present as solitary lesions in immunocompromised patients. The development of multiple hepatic abscesses in an immunocompetent patient is relatively uncommon. We report a rare case of a 73-year-old woman who presented with fever and right upper quadrant abdominal tenderness. Laboratory findings were significant for leukocytosis, transaminitis, and elevated inflammatory markers. Peripheral blood culture grew Streptococcus anginosus. Computed tomography of the abdomen and pelvis (CT A/P) revealed multiple hypoattenuating ill-defined cystic lesions in the liver consistent with abscesses formation; this was confirmed by magnetic resonance cholangiopancreatography (MRCP). The patient underwent appropriate treatment with antibiotics. Upon a three-week follow-up, the patient's symptoms subsided, and her laboratory parameters normalized. Although Streptococcus anginosus is a normal gastrointestinal flora, it has the potential to form abscesses. Our report indicates the importance of considering Streptococcus anginosus in the differential diagnosis. Management includes four to six weeks of antibiotic therapy together with drainage of larger abscesses.

Zinc oxide nanoparticle interface moderation with tyrosine and tryptophan reverses the pro-amyloidogenic property of the particle.

Zinc oxide nanoparticle with negative surface potential (ZnONP) enhances bovine insulin fibrillation. Here, we are exploring ZnONP with positive surface potential (ZnONPUnc) and surface functionalized with tyrosine and tryptophan amino acids to observe the effects of surface potential and surface functional groups on the fibrillation. ZnONPUnc, despite of inversed surface potential, enhances the insulin fibrillation with increase in the interface concentration at physiological pH. Whereas, the interface moderation with the amino acids mitigates the surface-mediated insulin fibrillation propensity. Additionally, the study indicates that the change in interfacial functional groups at ZnONPUnc significantly reverses the interface-mediated destabilization of insulin conformation. The functional groups from the amino acids, like CO, N-H and aromatic functional groups, are anticipated to further stabilize the insulin conformation by forming hydrogen bond and van der Waals interactions with the key amyloidogenic sequences of insulin, A13-A20 from A-chain and B9-B20 from B-chain. Hence, the altered interaction profile, with change in interfacial functional groups, mitigates the interface-mediated insulin fibrillation and the ZnONPUnc-/fibril-mediated cytotoxicity.

Cardiovascular Complication following Covishield Vaccination in Nepal: A Case Report.

Nepal started the COVID-19 vaccination on 27 January 2021 with AstraZeneca/Oxford Coronavirus Disease-19 AZD1222 (Covishield) vaccine to control the Coronavirus disease pandemic. The vaccine has a good safety profile, with cardiovascular complications being rare. Herein we report a rare case of cardiovascular complication following Covishield vaccination in a 33 years old female who had dizziness and elevated blood pressure immediately following vaccination and abnormal electrocardiogram showing T wave inversions followed by left bundle branch block. The patient was kept on observation, following which the blood pressure and electrocardiogram changes were normal by seven days. This cardiovascular complication following the vaccination demands further investigation into the adverse event of the vaccine. However, since the benefit of the vaccine outweighs the risk, World Health Organization has recommended the continuity of the vaccine as of now.

Acid-Base Disorder in the Patients Visiting the Emergency Department of a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

INTRODUCTION: An acid-base disorder is a change in the normal value of extracellular pH that may result when renal or respiratory function is abnormal or when an acid or base load overwhelms their excretory capacity. Clinical acid-base disorders are conventionally defined from the vantage point of their impact on carbonic-acid-bicarbonate buffer system. The aim of the study is to find out the prevalence of acid-base disorder among patients visiting the emergency department of a tertiary care hospital. METHODS: This is a descriptive cross-sectional study conducted among 370 patients who underwent arterial gas analysis at the emergency department of a tertiary care hospital. The study was carried out from 15th July 2016 to 15th July 2017 after receiving ethical approval from Institutional Review Committee. Convenient sampling was done. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. Data were entered in Microsoft-Excel. Statistical Package for Social Sciences version 17 was used for analysis. RESULTS: Out of 370 patients analyzed, 329 (88.91%) (84.68-91.311 at 95% Confidence Interval) had acid-base disorder. The mixed disorder was the most common finding 80 (21.6%), followed by compensated Respiratory Acidosis 56 (17.8%). The mean age group of male patients studied was 50.72±20.586 and among females, it was 49.95±20.908 Among those most common symptoms were shortness of breath 151 (40.81%) followed by vomiting 91 (24.59%). CONCLUSIONS: Most common acid-base disorder was mixed disorder presenting with prominent symptoms of shortness of breathe in non-geriatric patients wherein the geriatric patient, the most common disorder was compensated respiratory acidosis with the prominent symptom of shortness of breath.

Spectroscopic and molecular docking studies for the binding and interaction aspects of curcumin-cysteine conjugate and rosmarinic acid with human telomeric G-quadruplex DNA.

The binding and interaction aspects of potential anticancer ligands like: curcumin-cysteine (CC) and rosmarinic acid (RA) with human telomeric G-quadruplex DNA, a novel anticancer target, have been probed by spectroscopic and molecular docking approach. The circular dichroism study unravels the conformational switching from mixed hybrid to parallel structure for the short sequence of human telomeric G-quadruplex structure in the presence of both the ligands. Further a good correlation for binding affinity has been established from the emission and absorption binding spectrum analysis. Further our spectroscopic and molecular docking studies have suggested that the CC having better binding capability than RA to human telomeric G-quadruplex. The presence of L-cysteine moiety in CC ligand is responsible factor for its binding via both minor as well as major groove of human telomeric G-quadruplex DNA where-as RA binds only via minor groove of telomeric G-DNA.

Kanamycin-Mediated Conformational Dynamics of Escherichia coli Outer Membrane Protein TolC.

TolC is a member of the outer membrane efflux proteins (OEPs) family and acts as an exit duct to export proteins, antibiotics, and substrate molecules across the Escherichia coli cell membrane. Export of these molecules is evidenced to be brought about through the reversible interactions and binding of substrate-specific drug molecules or antibiotics with TolC and by being open for transport, which afterward leads to cross-resistance. Hence, the binding of kanamycin with TolC was monitored through molecular docking (MD), the structural fluctuations and conformational changes to the atomic level. The results were further supported from the steady-state fluorescence binding and isothermal titration calorimetry (ITC) studies. Binding of kanamycin with TolC resulted in a concentration dependent fluorescence intensity quenching with 7 nm blue shift. ITC binding data maintains a single binding site endothermic energetic curve with binding parameters indicating an entropy driven binding process. The confirmational changes resulting from this binding were monitored by a circular dichroism (CD) study, and the results showed insignificant changes in the α-helix and ß-sheets secondary structure contents, but the tertiary structure shows inclusive changes in the presence of kanamycin. The experimental data substaintially correlates the RMSD, R g, and RMSF results. The resulting conformational changes of the TolC-kanamycin complexation was stabilized through H-bonding and other interactions.

Interaction with zinc oxide nanoparticle kinetically traps α-synuclein fibrillation into off-pathway non-toxic intermediates.

α-Synuclein is an intrinsically disordered amyloidogenic protein associated with Parkinson's disease (PD). The monomeric α-synuclein transition into amyloid fibril involves multiple steps, which are affected by several intrinsic and extrinsic factors. This increases complexities in development of targeted therapeutics against the pathological intermediate(s). Several studies have been dedicated to find an effective molecule to inhibit the detrimental amyloidogenesis. In recent years, metal oxide nanoparticle interfaces have shown direct effects on protein conformation, hence may be adopted as an alternative potential therapeutic approach against amyloidosis. In this context, our study explores the zinc oxide nanoparticle (ZnONP) with negative surface potential interface interaction with α-synuclein, and subsequent impact of the interaction on the protein fibrillation and the fibril-mediated cytotoxicity. N-terminus amphipathic "KA/TKE/QGV" repeating motifs in α-synuclein primarily interact with the ZnONP interface that enthalpically drives initial adsorption of the protein onto the interface. Whereas, subsequent bulk-protein adsorption onto the hard-corona is entropically driven, leading into flocculation of the complex. The flocs appear as amorphous mesh-like morphology in TEM micrographs, as opposed to the typical fibrils formed by the wild-type protein. Interestingly, α-synuclein in complex with ZnONP shows significantly lowered cytotoxicity against the IMR32 and THP-1 cells in-vitro, as compared to fresh α-synuclein.

Silver nanoparticles fabricated using medicinal plant extracts show enhanced antimicrobial and selective cytotoxic propensities.

Nanoparticles fabricated using medicinal plant extract have great potential in the area of nanomedicine. High surface-to-volume ratio of nanoparticle enhances the local active biomolecules concentration, leading to many fold increase in the medicinal potentials. The silver nanoparticles (AgNPs) fabricated using indigenous medicinal plants of India, Azadirachta indica and Syzygium cumini, have shown a significant effect on the viability of prokaryotic and eukaryotic cells. Biofabrication of AgNP was confirmed using different spectroscopic and microscopic techniques. Extraction and purification of AgNP from non-conjugated plant moieties are done using centrifugation and size exclusion chromatography. The cytotoxic propensity of AgNP formulations was screened against Gram-positive (Bacillus subtilis), Gram-negative (Escherichia coli) bacteria, cancerous (HT1080) and non-cancerous (HEK293) cell lines. The nanoparticle formulations showed a relatively higher cytotoxic propensity against Gram-positive bacteria and cancerous cell lines. In addition, the surface roughness and reactive oxygen species (ROS) measurements indicated that AgNP formulations mediate the cell activity predominantly by ROS-mediated disruptive change in membrane morphology upon direct interaction with the membrane. Hence, the nanoparticle formulations show an enhanced selective cytotoxic propensity towards Gram-positive bacteria and cancerous cell lines.

Attenuation of neuroblastoma cell growth by nisin is mediated by modulation of phase behavior and enhanced cell membrane fluidity.

Antimicrobial peptides have been attracting significant attention as potential anti-cancer therapeutic agents in recent times. Yet most antimicrobial peptides seem to possess cytotoxic effects on non-cancerous cells. Nisin, an antimicrobial peptide and FDA approved food preservative, has recently been found to induce selective apoptotic cell death and reduced cell proliferation in different cancer cell lines. However, the mechanism of nisin interaction with cancer cell membranes remains unexplored. Using potentiometric dye-based fluorescence and monolayer surface pressure-area isotherms we find that nisin interaction enhances the fluidity and reduces the dipole potential of a neuroblastoma cell membrane model. The quantified compressibility modulus suggests that the changes in fluidity are predominantly driven by the nisin interaction with the non-raft like regions. However, the measured positive Gibbs free energy of mixing and enthalpy hints that nisin, owing to its unfavorable mixing with cholesterol, might significantly disrupt the raft-like domains.