Membrane-targeting, ultrashort lipopeptide acts as an antibiotic adjuvant and sensitizes MDR gram-negative pathogens toward narrow-spectrum antibiotics.

Globally, infections due to multi-drug resistant (MDR) Gram-negative bacterial (GNB) pathogens are on the rise, negatively impacting morbidity and mortality, necessitating urgent treatment alternatives. Herein, we report a detailed bio-evaluation of an ultrashort, cationic lipopeptide 'SVAP9I' that demonstrated potent antibiotic activity and acted as an adjuvant to potentiate existing antibiotic classes towards GNBs. Newly synthesized lipopeptides were screened against ESKAPE pathogens and cytotoxicity assays were performed to evaluate the selectivity index (SI). SVAP9I exhibited broad-spectrum antibacterial activity against critical MDR-GNB pathogens including members of Enterobacteriaceae (MIC 4-8 mg/L), with a favorable CC50 value of ≥100 mg/L and no detectable resistance even after 50th serial passage. It demonstrated fast concentration-dependent bactericidal action as determined via time-kill analysis and also retained full potency against polymyxin B-resistant E. coli, indicating distinct mode of action. SVAP9I targeted E. coli's outer and inner membranes by binding to LPS and phospholipids such as cardiolipin and phosphatidylglycerol. Membrane damage resulted in ROS generation, depleted intracellular ATP concentration and a concomitant increase in extracellular ATP. Checkerboard assays showed SVAP9I's synergism with narrow-spectrum antibiotics like vancomycin, fusidic acid and rifampicin, potentiating their efficacy against MDR-GNB pathogens, including carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO critical priority pathogen. In a murine neutropenic thigh infection model, SVAP9I and rifampicin synergized to express excellent antibacterial efficacy against MDR-CRAB outcompeting polymyxin B. Taken together, SVAP9I's distinct membrane-targeting broad-spectrum action, lack of resistance and strong in vitro andin vivopotency in synergism with narrow spectrum antibiotics like rifampicin suggests its potential as a novel antibiotic adjuvant for the treatment of serious MDR-GNB infections.

Amyloid Mimicking Assemblies Formed by Glutamine, Glutamic Acid, and Aspartic Acid.

The aggregation of amino acids into amyloid-like structures is a critical phenomenon for understanding the pathophysiology of various diseases, including inborn errors of metabolism (IEMs) associated with amino acid imbalances. Previous studies have primarily focused on self-assembly of aromatic amino acids, leading to a limited understanding of nonaromatic, polar amino acids in this context. To bridge this gap, our study investigates the self-assembly and aggregation behavior of specific nonaromatic charged and uncharged polar amino acids l-glutamine (Gln), l-aspartic acid (Asp), and l-glutamic acid (Glu), which have not been reported widely in the context of amyloid aggregation. Upon aging these amino acids under controlled conditions, we observed the formation of uniform, distinct aggregates, with Gln forming fibrillar gel-like structures and Glu exhibiting fibrous globular morphologies. Computational simulations validated these findings, identifying Gln as the most potent in forming stable aggregates, followed by Glu and Asp. These simulations elucidated the driving forces behind the distinct morphologies and stabilities of the aggregates. Thioflavin T assays were employed to confirm the amyloid-like nature of these aggregates, suggesting their potential cytotoxic impact. To assess toxicity, we performed in vitro studies on neural cell lines and in vivo experiments in Caenorhabditis elegans (C. elegans), which demonstrated measurable cytotoxic effects, corroborated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and heat shock survival assays. Importantly, this study fills a critical gap in our understanding on the role of nonaromatic amino acids in amyloidogenesis and its implications for IEMs. Our findings provide a foundation for future investigations into the mechanisms of diseases associated with amino acid accumulation and offer potential avenues for the development of targeted therapeutic strategies.

Anti-proliferative, -migratory and -clonogenic effects of long-lasting nitric oxide release in HepG2 cells.

Nitric oxide (NO) holds promise as a cytotoxic agent against tumors, but its gaseous nature and short half-life hinder direct administration to tumor tissues. Herein, we present novel 6,9-disubstituted purine derivatives designed to ensure sustained NO release, followed by study of their significant anti-proliferative, anti-migratory, and anti-clonogenic effects on HepG2 cell lines, highlighting NO release as a potent effector for treating hepatocellular carcinoma.

Peptide-triggered IL-12 and IFN-γ mediated immune response in CD4+ T-cells against Leishmania donovani infection.

Leishmania donovani are intracellular, human blood parasites that cause visceral leishmaniasis or kala-azar. Cell-penetrating peptides (CPPs) have been shown to modulate intracellular processes and cargo delivery, whereas host defense peptides (HDPs) promote proliferation of both naïve and antigen activated CD4+ T-cells. We report newly designed tripeptides that were able to trigger proinflammatory cytokine (IL-12 and IFN-γ) secretion by CD4+CD44+ T-cells in response to Leishmania donovani infection. These peptides can be used to induce antigen specific TH1 responses to combat obstacles of cytotoxicity and drug resistance associated with current anti-leishmanial drugs. Furthermore, these peptides can also be used as adjuvants to develop an effective immunoprophylactic approach for immunity restoration against visceral leishmaniasis.

Peptide Dendrimer-Based Antibacterial Agents: Synthesis and Applications.

Pathogenic bacteria cause the deaths of millions of people every year. With the development of antibiotics, hundreds and thousands of people's lives have been saved. Nevertheless, bacteria can develop resistance to antibiotics, rendering them insensitive to antibiotics over time. Peptides containing specific amino acids can be used as antibacterial agents; however, they can be easily degraded by proteases in vivo. To address these issues, branched peptide dendrimers are now being considered as good antibacterial agents due to their high efficacy, resistance to protease degradation, and low cytotoxicity. The ease with which peptide dendrimers can be synthesized and modified makes them accessible for use in various biological and nonbiological fields. That is, peptide dendrimers hold a promising future as antibacterial agents with prolonged efficacy without bacterial resistance development. Their in vivo stability and multivalence allow them to effectively target multi-drug-resistant strains and prevent biofilm formation. Thus, it is interesting to have an overview of the development and applications of peptide dendrimers in antibacterial research, including the possibility of employing machine learning approaches for the design of AMPs and dendrimers. This review summarizes the synthesis and applications of peptide dendrimers as antibacterial agents. The challenges and perspectives of using peptide dendrimers as the antibacterial agents are also discussed.

Amyloidogenic Propensity of Metabolites in the Uric Acid Pathway and Urea Cycle Critically Impacts the Etiology of Metabolic Disorders.

Novel insights into the etiology of metabolic disorders have recently been uncovered through the study of metabolite amyloids. In particular, inborn errors of metabolism (IEMs), including gout, Lesch-Nyhan syndrome (LNS), xanthinuria, citrullinemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, are attributed to the dysfunction of the urea cycle and uric acid pathway. In this study, we endeavored to understand and mechanistically characterize the aggregative property exhibited by the principal metabolites of the urea cycle and uric acid pathway, specifically hypoxanthine, xanthine, citrulline, and ornithine. Employing scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM), we studied the aggregation profiles of the metabolites. Insights obtained through molecular dynamics (MD) simulation underscore the vital roles of π-π stacking and hydrogen bonding interactions in the self-assembly process, and thioflavin T (ThT) assays further corroborate the amyloid nature of these metabolites. The in vitro MTT assay revealed the cytotoxic trait of these assemblies, a finding that was substantiated by in vivo assays employing the Caenorhabditis elegans (C. elegans) model, which revealed that the toxic effects were more pronounced and dose-specific in the case of metabolites that had aged via longer preincubation. We hence report a compelling phenomenon wherein these metabolites not only aggregate but transform into a soft, ordered assembly over time, eventually crystallizing upon extended incubation, leading to pathological implications. Our study suggests that the amyloidogenic nature of the involved metabolites could be a common etiological link in IEMs, potentially providing a unified perspective to study their pathophysiology, thus offering exciting insights into the development of targeted interventions for these metabolic disorders.

Crystal Engineering and Self-Assembled Nanoring Formation with Purine-CdII/HgII Supramolecular Frameworks.

We report three complexes of CdII and HgII with two purine rare tautomers, N9-(pyridin-2-ylmethyl)-N6-methoxyadenine, L1 and N7-(pyridin-2-ylmethyl)-N6-methoxyadenine, L2, highlighting diverse crystallographic signatures exhibited by them. Influence of substituents, binding sites, steric effects and metal salts on the different modes of binding enabled an insight into metal-nucleobase interactions. L1 interacted with two and three equivalents of Cd(NO3)2.4H2O and HgCl2, respectively, while L2 interacted with two equivalents of HgCl2, altogether leading to three different complexes (1 [C48H48Cd6N34O50], 2 [C12H12Cl4Hg2N6O] and 3 [C12H12Cl2HgN6O]) possessing varied dimensionality and stabilising interactions. The photoluminescent properties of these coordination frameworks have also been probed. Notably, nanoring-like structures were obtained, as a result of self-assembly of 3 when investigated by transmission electron microscopy, additionally supported by molecular dynamics simulations.

Strategies for gaseous neuromodulator release in chemical neuroscience: Experimental approaches and translational validation.

Gasotransmitters are a group of short-lived gaseous signaling molecules displaying diverse biological functions depending upon their localized concentration. Nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO) are three important examples of endogenously produced gasotransmitters that play a crucial role in human neurophysiology and pathogenesis. Alterations in their optimal physiological concentrations can lead to various severe pathophysiological consequences, including neurological disorders. Exogenous administration of gasotransmitters has emerged as a prominent therapeutic approach for treating such neurological diseases. However, their gaseous nature and short half-life limit their therapeutic delivery. Therefore, developing synthetic gasotransmitter-releasing strategies having control over the release and duration of these gaseous molecules has become imperative. However, the complex chemistry of synthesis and the challenges of specific quantified delivery of these gases, make their therapeutic application a challenging task. This review article provides a focused overview of emerging strategies for delivering gasotransmitters in a controlled and sustained manner to re-establish neurophysiological homeostasis.

MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the seventh most common cause of mortality and one of the major causes of disability and vulnerability in the elderly. AD is characterized by gradual cognitive deterioration, the buildup of misfolded amyloid beta (Aß) peptide, and the generation of neurofibrillary tangles. Despite enormous scientific progress, there is no effective cure for AD. Thus, exploring new treatment options to stop AD or at least slow down its progress is important. In this study, we investigated the potential therapeutic effects of MCC950 on NLRP3-mediated inflammasome-driven inflammation and autophagy in AD. Rats treated with streptozotocin (STZ) exhibited simultaneous activation of the NLRP3 inflammasome and autophagy, as confirmed by Western blot, immunofluorescence, and co-immunoprecipitation analyses. MCC950, a specific NLRP3 inhibitor, was intraperitoneally administered (50 mg/kg body weight) to rats with AD-like symptoms induced by intracerebroventricular STZ injections (3 mg/kg body weight). MCC950 effectively suppressed STZ-induced cognitive impairment and anxiety by inhibiting NLRP3-dependent neuroinflammation. Moreover, our findings indicate that MCC950 exerts neuroprotective effects by attenuating autophagy in neuronal cells. The inhibiting effects of MCC950 on inflammasome activation and autophagy were reproduced in vitro, provding further mechansistic insights into MCC950 therapeutic action. Our findings suggest that MCC950 impedes the progression of AD and may also improve cognitive function through the mitigation of autophagy and NLRP3 inflammasome inhibition.

An unnatural amino acid modified human insulin derivative for visual monitoring of insulin aggregation.

Insulin often forms toxic fibrils during production and transportation, which are deposited as amyloids at repeated injection sites in diabetic patients. Distinguishing early fibrils from non-fibrillated insulin is difficult. Herein, we introduce a chemically modified human insulin derivative with a distinct visual colour transition upon aggregation, facilitating insulin quality assessment.

Bi2Te2Se and Sb2Te3 heterostructure based photodetectors with high responsivity and broadband photoresponse: experimental and theoretical analysis.

Topological insulators have emerged as one of the most promising candidates for the fabrication of novel electronic and optoelectronic devices due to the unique properties of nontrivial Dirac cones on the surface and a narrow bandgap in the bulk. In this work, the Sb2Te3 and Bi2Te2Se materials, and their heterostructure are fabricated by metal-organic chemical vapour deposition and evaporation techniques. Photodetection of these materials and their heterostructure shows that they detect light in a broadband range of 600 to 1100 nm with maximum photoresponse of Sb2Te3, Bi2Te2Se and Sb2Te3/Bi2Te2Se at 1100, 1000, and 1000 nm, respectively. The maximum responsivity values of Sb2Te3, Bi2Te2Se, and their heterostructure are 183, 341.8, and 245.9 A W-1 at 1000 nm, respectively. A computational study has also been done using density functional theory (DFT). Using the first-principles methods based on DFT, we have systematically investigated these topological insulators and their heterostructure's electronic and optical properties. The band structures of Sb2Te3 and Bi2Te2Se thin films (3 QL) and their heterostructure are calculated. The bandgaps of Sb2Te3 and Bi2Te2Se are 26.4 and 23 meV, respectively, while the Sb2Te3/Bi2Te2Se heterostructure shows metallic behaviour. For the optical properties, the dielectric function's real and imaginary parts are calculated using DFT and random phase approximation (RPA). It is observed that these topological materials and their heterostructure are light absorbers in a broadband range, with maximum absorption at 1.90, 2.40, and 3.21 eV.

Kinetic versus thermodynamic polymorph stabilization of a tri-carboxylic acid derivative at the solid-liquid interface.

The carboxylic acid moiety gives rise to structural variability in surface-supported self-assembly due to the common expression of various H-bonding motifs. Self-assembly of 3-fold symmetric tricarboxylic acid derivatives on surfaces typically results in monolayer structures that feature the common 2-fold cyclic R22(8) H-bond motif for at least one of the carboxylic acid groups. Polymorphs that are exclusively based on 3-fold cyclic R33(12) H-bonds were predicted but remained elusive. Here, we show the emergence of such a superflower (SF) structure purely based on R33(12) H-bonds for L-benzene-1,3,5-tricarbonyl phenylalanine (L-BTA), a molecule derived from the well-studied trimesic acid (TMA). In contrast to TMA, L-BTA is not completely planar and is also equipped with additional functional groups for the formation of secondary intermolecular bonds. At the heptanoic acid-graphite interface we transiently observe a SF structure, which is dynamically converted into a chicken-wire structure that only exhibits R22(8) H-bonds. Interestingly, when using nonanoic acid as a solvent the initially formed SF structure remained stable. This unexpected behaviour is rationalized by accompanying force field simulations and experimental determination of solvent-dependent L-BTA solubility.

Single-platform, Attomolar Detection of Multiple Biomarkers by a Flexible SERS Sensor.

Early detection of Alzheimer's disease (AD) is critical for better healthcare management. Herein, we demonstrate a Surface Enhanced Raman Spectroscopy (SERS) active sensor for highly sensitive and selective detection of ß-Amyloid Peptide (Aß1-42 ), a biomarker of Alzheimer's disease. Polyacrylonitrile (PAN) nanofiber mats, containing purine-based ligand (L; 0 mg (P1 ), 50 mg (P2 ), and 100 mg (P3 )) were prepared by electrospinning followed by functionalization with silver nanoparticles (AgNPs). The fabricated SERS sensors were employed for the detection of Rhodamine 6G (Rh-6G) dye for optimization and the highest sensitivity was achieved on P3 /AgNPs SERS sensor. The P3 /AgNPs sensor was chosen for the detection of Aß1-42 and human Insulin (HI). The limit of detection (LoD) was found to be 76×10-18 M and 26×10-18 M for Aß1-42 and HI, respectively. The sensitivity achieved is one order improved for Aß1-42 and four orders for HI when compared with reported values. Also, demonstrated the selectivity of the P3 /AgNPs sensor by testing a simulated cerebrospinal fluid (CSF) and achieved easily identifiable peaks of Aß1-42 among the noise of HI and bovine serum albumin should be written before the acronym of BSA. This approach could be extended to develop ultra-sensitive flexible SERS sensors for the facile detection of multiple biomarkers on a single platform with excellent sensitivity, selectivity and stability.

Flowering in sugarcane-insights from the grasses.

Flowering is a crucial phase for angiosperms to continue their species propagation and is highly regulated. In the current review, flowering in sugarcane and the associated mechanisms are elaborately presented. In sugarcane, flowering has two effects, wherein it is a beneficial factor from the breeder's perspective and crucial for crop improvement, but commercially, it depletes the sucrose reserves from the stalks; hence, less value is assigned. Different species of Saccharum genus are spread across geographical latitudes, thereby proving their ability to grow in multiple inductive daylengths of different locations according in the habituated zone. In general, sugarcane is termed an intermediate daylength plant with quantitative short-day behaviour as it requires reduction in daylength from 12 h 55 min to 12 h or 12 h 30 min. The prime concern in sugarcane flowering is its erratic flowering nature. The transition to reproductive stage which reverts to vegetative stage if there is any deviation from ambient temperature and light is also an issue. Spatial and temporal gene expression patterns during vegetative to reproductive stage transition and after reverting to vegetative state could possibly reveal how the genetic circuits are being governed. This review will also shed a light on potential roles of genes and/or miRNAs in flowering in sugarcane. Knowledge of transcriptomic background of circadian, photoperiod, and gibberellin pathways in sugarcane will enable us to better understand of variable response in floral development.

Targeting multidrug resistant Staphylococcus aureus with cationic chlorpromazine-peptide conjugates.

Antimicrobial resistance is a serious public health risk. Its severity is fueled on an unprecedented scale, necessitating the demand for novel antimicrobial scaffolds aimed at novel targets. Herein, we present cationic chlorpromazine peptide conjugates that are rationally intended to targetmultidrug-resistant (MDR) bacteria. The most potent compound, CPWL, of all the conjugates evaluated, showed promising antibacterial activity against clinical, MDR S. aureus, with no cytotoxicity. The molecular docking experiments confirmed that CPWL possessed a very high affinity for S. aureus enoyl reductase (saFabI). Furthermore, CPWL antibacterial action against saFabI was further corroborated by MD simulation studies. Thus, our findings highlight cationic chlorpromazine as a promising scaffold for the development of saFabI inhibitors to target severe staphylococcal infections.

Aß-oligomers: A potential therapeutic target for Alzheimer's disease.

The cascade of amyloid formation relates to multiple complex events at the molecular level. Previous research has established amyloid plaque deposition as the leading cause of Alzheimer's disease (AD) pathogenesis, detected mainly in aged population. The primary components of the plaques are two alloforms of amyloid-beta (Aß), Aß1-42 and Aß1-40 peptides. Recent studies have provided considerable evidence contrary to the previous claim indicating that amyloid-beta oligomers (AßOs) as the main culprit responsible for AD-associated neurotoxicity and pathogenesis. In this review, we have discussed the primary features of AßOs, such as assembly formation, the kinetics of oligomer formation, interactions with various membranes/membrane receptors, the origin of toxicity, and oligomer-specific detection methods. Recently, the discovery of rationally designed antibodies has opened a gateway for using synthesized peptides as a grafting component in the complementarity determining region (CDR) of antibodies. Thus, the Aß sequence motif or the complementary peptide sequence in the opposite strand of the ß-sheet (extracted from the Protein Data Bank: PDB) helps design oligomer-specific inhibitors. The microscopic event responsible for oligomer formation can be targeted, and thus prevention of the overall macroscopic behaviour of the aggregation or the associated toxicity can be achieved. We have carefully reviewed the oligomer formation kinetics and associated parameters. Besides, we have depicted a thorough understanding of how the synthesized peptide inhibitors can impede the early aggregates (oligomers), mature fibrils, monomers, or a mixture of the species. The oligomer-specific inhibitors (peptides or peptide fragments) lack in-depth chemical kinetics and optimization control-based screening. In the present review, we have proposed a hypothesis for effectively screening oligomer-specific inhibitors using the chemical kinetics (determining the kinetic parameters) and optimization control strategy (cost-dependent analysis). Further, it may be possible to implement the structure-kinetic-activity-relationship (SKAR) strategy instead of structure-activity-relationship (SAR) to improve the inhibitor's activity. The controlled optimization of the kinetic parameters and dose usage will be beneficial for narrowing the search window for the inhibitors.

Multiple Actions of H2S-Releasing Peptides in Human ß-Amyloid Expressing C. elegans.

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder characterized by the loss of cognitive function. A major challenge in treating this ailment fully is its multifactorial nature, as it is associated with effects like deposition of Aß plaques, oxidative distress, inflammation of neuronal cells, and low levels of the neurotransmitter acetylcholine (ACh). In the present work, we demonstrate the design, synthesis, and biological activity of peptide conjugates by coupling a H2S-releasing moiety to the peptides known for their Aß antiaggregating properties. These conjugates release H2S in a slow and sustained manner, due to the formation of self-assembled structures and delivered a significant amount of H2S within Caenorhabditis elegans. These conjugates are shown to target multiple factors responsible for the progression of AD: notably, we observed reduction in oxidative distress, inhibition of Aß aggregation, and significantly increased ACh levels in the C. elegans model expressing human Aß.

Metagenomic strain detection with SameStr: identification of a persisting core gut microbiota transferable by fecal transplantation.

BACKGROUND: The understanding of how microbiomes assemble, function, and evolve requires metagenomic tools that can resolve microbiota compositions at the strain level. However, the identification and tracking of microbial strains in fecal metagenomes is challenging and available tools variably classify subspecies lineages, which affects their applicability to infer microbial persistence and transfer. RESULTS: We introduce SameStr, a bioinformatic tool that identifies shared strains in metagenomes by determining single-nucleotide variants (SNV) in species-specific marker genes, which are compared based on a maximum variant profile similarity. We validated SameStr on mock strain populations, available human fecal metagenomes from healthy individuals and newly generated data from recurrent Clostridioides difficile infection (rCDI) patients treated with fecal microbiota transplantation (FMT). SameStr demonstrated enhanced sensitivity to detect shared dominant and subdominant strains in related samples (where strain persistence or transfer would be expected) when compared to other tools, while being robust against false-positive shared strain calls between unrelated samples (where neither strain persistence nor transfer would be expected). We applied SameStr to identify strains that are stably maintained in fecal microbiomes of healthy adults over time (strain persistence) and that successfully engraft in rCDI patients after FMT (strain engraftment). Taxonomy-dependent strain persistence and engraftment frequencies were positively correlated, indicating that a specific core microbiota of intestinal species is adapted to be competitive both in healthy microbiomes and during post-FMT microbiome assembly. We explored other use cases for strain-level microbiota profiling, as a metagenomics quality control measure and to identify individuals based on the persisting core gut microbiota. CONCLUSION: SameStr provides for a robust identification of shared strains in metagenomic sequence data with sufficient specificity and sensitivity to examine strain persistence, transfer, and engraftment in human fecal microbiomes. Our findings identify a persisting healthy adult core gut microbiota, which should be further studied to shed light on microbiota contributions to chronic diseases. Video abstract.

Prevalence of Gastrointestinal Symptoms, Hepatic Dysfunction, and Outcomes in Hospitalized Patients With COVID-19 Infection: An Early Experience.

Background and objective Coronavirus disease 2019 (COVID-19) was first reported in China two years ago as primarily a lung infection associated with cough and fever. It spread rapidly across the world and was declared a pandemic in early 2020, with 131 million people infected and 2.85 million deaths worldwide. To date, approximately 550,000 deaths have occurred due to COVID-19 in the United States and the numbers continue to rise. The extrapulmonary manifestations of this disease such as acute kidney injury (AKI), cardiovascular events, and gastrointestinal (GI) indications were not emphasized initially. However, subsequent studies from the United States and Canada have noted GI involvement in this disease in a large number of cases. Our group, taking care of these patients during the early phase of the pandemic in 2020, observed the frequent presentations of GI symptoms such as diarrhea and hepatic dysfunction and this study examines the same. Methods We undertook a retrospective study of 184 consecutive adult patients who were hospitalized at our center with confirmed COVID-19 infection, with a view to further elucidate the GI and hepatic involvement during the early breakout (March 17-May 17, 2020) of this illness. Results Major comorbidities associated with this illness in our cohort of patients included hypertension (HTN, 66%), diabetes mellitus (DM, 44%), obesity (41%), and chronic kidney disease (CKD, 17%). The most common GI manifestation was diarrhea (25%) and, interestingly, more than two-thirds of the patients had at least one liver function abnormality. The most common liver function abnormality was elevated serum aspartate aminotransferase (AST). Elevated AST was significantly correlated (p<0.05) with inflammatory markers such as D-dimer, lactate dehydrogenase (LDH), and ferritin, as well as AKI by bi-variate analysis. Salient observations from our study include higher mortality, frequent AKI, and cardiovascular events in male patients (p<0.05).  The liver injury in our cohort was suspected to be multifactorial, involving excessive cytokine release, viral infiltration of the hepatocytes, and cholangiocytes playing a role in transaminitis. The mean (±SD) duration of hospital stay was 13.5 ±15 days with 33% admissions to the ICU. The overall mortality was around 27%, with no significant difference between African Americans and Caucasians. However, patients admitted to the ICU had a very high mortality rate (54%) compared to those admitted to intermediate care (IMC)/acute care who had less severity of illness and associated pulmonary complications. Conclusions This study evaluates the presence of comorbidities such as DM, HTN, and obesity in patients hospitalized with COVID-19 at a community hospital in the Mid-Atlantic region of the United States. Statistical analysis of the data obtained for this cohort revealed a high frequency of GI symptoms, with diarrhea as the predominant common initial manifestation of the disease. Serum AST elevations were common and correlated with inflammatory markers and AKI. Male gender was also significantly associated with the development of AKI, higher frequency of cardiovascular events, and increased mortality. Overall mortality was noted to be 27%, with higher mortality in patients admitted to the ICU (54%) as compared to the IMC/floor (13%). These observations should spur future investigations into the role of these comorbidities, development of diarrhea, and hepatic dysfunction in COVID-19.

Inhibiting Erastin-Induced Ferroptotic Cell Death by Purine-Based Chelators.

Ferroptosis is a cell death event caused by increased lipid peroxidation leading to iron-dependent oxidative stress and is associated with a wide variety of diseases. In recent years, ferroptosis inhibition has emerged as a novel strategy to target different pathologies. Here, we report the synthesis of two purine derivatives, 1 and 2, for iron chelation strategy and evaluate their potency to inhibit erastin-induced ferroptosis. Both compounds showed efficient iron chelation in solution as well as in cellular environment. The crystal structure of the purine derivatives with iron demonstrated a 2 : 1 (ligand to metal center) stoichiometry for iron and purine derivative complexation. The synthesized compounds also decrease the reactive oxygen species concentration in cell cultures. Compound 2 showed better potency towards the prevention of ferroptotic cell death as compared to commercially available iron chelator in the erastin-induced ferroptosis cell culture model. Such purine analogues are potential functional scaffolds for the development of target molecules for ferroptosis inhibition.