Single-cell profile reveals the landscape of cardiac immunity and identifies a cardio-protective Ym-1hi neutrophil in myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a major hindrance to the success of cardiac reperfusion therapy. Although increased neutrophil infiltration is a hallmark of MIRI, the subtypes and alterations of neutrophils in this process remain unclear. Here, we performed single-cell sequencing of cardiac CD45+ cells isolated from the murine myocardium subjected to MIRI at six-time points. We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI. Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations, including Ccl3hi Neu and Ym-1hi Neu, which were increased at 6 h and 1 d after reperfusion, respectively. Ym-1hi Neu selectively expressed genes with protective effects and was, therefore, identified as a novel specific type of cardiac cell in the injured heart. Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues, especially instructing the response of macrophages. The abundance of Ym-1hi Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D (Ly6G) or anti-Intercellular cell adhesion molecule-1 (ICAM-1) neutralizing antibodies. In addition, a neutrophil subtype with the same phenotype as Ym-1hi Neu was detected in clinical samples and correlated with prognosis. Ym-1 inhibition exacerbated myocardial injury, whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice, which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue. Overall, our findings reveal the anti-inflammatory phenotype of Ym-1hi Neu and highlight its critical role in myocardial protection during the early stages of MIRI.

Interplay of G-proteins and Serotonin in the Neuroimmunoinflammatory Model of Chronic Stress and Depression: A Narrative Review.

INTRODUCTION: This narrative review addresses the clinical challenges in stress-related disorders such as depression, focusing on the interplay between neuron-specific and pro-inflammatory mechanisms at the cellular, cerebral, and systemic levels. OBJECTIVE: We aim to elucidate the molecular mechanisms linking chronic psychological stress with low-grade neuroinflammation in key brain regions, particularly focusing on the roles of G proteins and serotonin (5-HT) receptors. METHODS: This comprehensive review of the literature employs systematic, narrative, and scoping review methodologies, combined with systemic approaches to general pathology. It synthesizes current research on shared signaling pathways involved in stress responses and neuroinflammation, including calcium-dependent mechanisms, mitogen-activated protein kinases, and key transcription factors like NF-κB and p53. The review also focuses on the role of G protein-coupled neurotransmitter receptors (GPCRs) in immune and pro-inflammatory responses, with a detailed analysis of how 13 of 14 types of human 5-HT receptors contribute to depression and neuroinflammation. RESULTS: The review reveals a complex interaction between neurotransmitter signals and immunoinflammatory responses in stress-related pathologies. It highlights the role of GPCRs and canonical inflammatory mediators in influencing both pathological and physiological processes in nervous tissue. CONCLUSION: The proposed Neuroimmunoinflammatory Stress Model (NIIS Model) suggests that proinflammatory signaling pathways, mediated by metabotropic and ionotropic neurotransmitter receptors, are crucial for maintaining neuronal homeostasis. Chronic mental stress can disrupt this balance, leading to increased pro-inflammatory states in the brain and contributing to neuropsychiatric and psychosomatic disorders, including depression. This model integrates traditional theories on depression pathogenesis, offering a comprehensive understanding of the multifaceted nature of the condition.

Computational Analysis of CD46 Protein Interaction with SARS-CoV-2 Structural Proteins: Elucidating a Putative Viral Entry Mechanism into Human Cells.

This study examines an unexplored aspect of SARS-CoV-2 entry into host cells, which is widely understood to occur via the viral spike (S) protein's interaction with human ACE2-associated proteins. While vaccines and inhibitors targeting this mechanism are in use, they may not offer complete protection against reinfection. Hence, we investigate putative receptors and their cofactors. Specifically, we propose CD46, a human membrane cofactor protein, as a potential putative receptor and explore its role in cellular invasion, acting possibly as a cofactor with other viral structural proteins. Employing computational techniques, we created full-size 3D models of human CD46 and four key SARS-CoV-2 structural proteins-EP, MP, NP, and SP. We further developed 3D models of CD46 complexes interacting with these proteins. The primary aim is to pinpoint the likely interaction domains between CD46 and these structural proteins to facilitate the identification of molecules that can block these interactions, thus offering a foundation for novel pharmacological treatments for SARS-CoV-2 infection.

Early-life maternal deprivation in rats increases sensitivity to the subsequent stressors: a pilot study.

Early life experiences, particularly maternal deprivation (MD), have long-lasting implications on emotional and cognitive development. Using Wistar rats as a model, this study explores the impact of MD followed by predator stress exposure (PSS) to simulate aspects of post-traumatic stress disorder (PTSD). A cohort of 41 male rat pups underwent MD from postnatal days 2 to 14, followed by PSS at day 90. Female rat pups were not included in the experiment. Behavior was subsequently assessed using the Elevated Plus Maze test 14 days post-PSS. While MD led to subtle changes such as decreased activity and increased anxiety-like behavior, PSS induced pronounced anxiogenic effects. Notably, PSS after MD resulted in decreased basal corticosterone levels, mirroring conditions observed in PTSD. The findings suggest that although MD itself does not induce significant behavioral changes, it predisposes individuals to heightened sensitivity to subsequent stressors. This study underscores the utility of a two-stage PSS model for more accurately reflecting the complexities inherent in stress-related disorders, including PTSD.

JAK-STAT signaling in inflammation and stress-related diseases: implications for therapeutic interventions.

The Janus kinase-signal transducer and transcription activator pathway (JAK-STAT) serves as a cornerstone in cellular signaling, regulating physiological and pathological processes such as inflammation and stress. Dysregulation in this pathway can lead to severe immunodeficiencies and malignancies, and its role extends to neurotransduction and pro-inflammatory signaling mechanisms. Although JAK inhibitors (Jakinibs) have successfully treated immunological and inflammatory disorders, their application has generally been limited to diseases with similar pathogenic features. Despite the modest expression of JAK-STAT in the CNS, it is crucial for functions in the cortex, hippocampus, and cerebellum, making it relevant in conditions like Parkinson's disease and other neuroinflammatory disorders. Furthermore, the influence of the pathway on serotonin receptors and phospholipase C has implications for stress and mood disorders. This review expands the understanding of JAK-STAT, moving beyond traditional immunological contexts to explore its role in stress-related disorders and CNS function. Recent findings, such as the effectiveness of Jakinibs in chronic conditions such as rheumatoid arthritis, expand their therapeutic applicability. Advances in isoform-specific inhibitors, including filgotinib and upadacitinib, promise greater specificity with fewer off-target effects. Combination therapies, involving Jakinibs and monoclonal antibodies, aiming to enhance therapeutic specificity and efficacy also give great hope. Overall, this review bridges the gap between basic science and clinical application, elucidating the complex influence of the JAK-STAT pathway on human health and guiding future interventions.

Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes.

Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).

Sequence Variation of Candida albicans Sap2 Enhances Fungal Pathogenicity via Complement Evasion and Macrophage M2-Like Phenotype Induction.

Candida albicans (C. albicans) is an opportunistic pathogen increasingly causing candidiasis worldwide. This study aims to investigate the pattern of systemic immune responses triggered by C. albicans with disease associated variation of Sap2, identifying the novel evasion strategies utilized by clinical isolates. Specifically, a variation in clinical isolates is identified at nucleotide position 817 (G to T). This homozygous variation causes the 273rd amino acid exchange from valine to leucine, close to the proteolytic activation center of Sap2. The mutant (Sap2-273L) generated from SC5314 (Sap2-273V) background carrying the V273L variation within Sap2 displays higher pathogenicity. In comparison to mice infected with Sap2-273V strain, mice infected with Sap2-273L exhibit less complement activation indicated by less serum C3a generation and weaker C3b deposition in the kidney. This inhibitory effect is mainly achieved by Sap2273L -mediated stronger degradation of C3 and C3b. Furthermore, mice infected with Sap2-273L strain exhibit more macrophage phenotype switching from M0 to M2-like and more TGF-ß release which further influences T cell responses, generating an immunosuppressed cellular microenvironment characterized by more Tregs and exhausted T cell formation. In summary, the disease-associated sequence variation of Sap2 enhances pathogenicity by complement evasion and M2-like phenotype switching, promoting a more efficient immunosuppressed microenvironment.

Timosaponin AIII promotes non-small-cell lung cancer ferroptosis through targeting and facilitating HSP90 mediated GPX4 ubiquitination and degradation.

Timosaponin AIII (Tim-AIII), a steroid saponin, exhibits strong anticancer activity in a variety of cancers, especially breast cancer and liver cancer. However, the underlying mechanism of the effects of Tim-AIII-mediated anti-lung cancer effects remain obscure. In this study, we showed that Tim-AIII suppressed cell proliferation and migration, induced G2/M phase arrest and ultimately triggered cell death of non-small cell lung cancer (NSCLC) cell lines accompanied by the release of reactive oxygen species (ROS) and iron accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion. Interestingly, we found that Tim-AIII-mediated cell death was reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Meanwhile, the heat shock protein 90 (HSP90) was predicted and verified as the direct binding target of Tim-AIII by SwissTargetPrediction (STP) and surface plasmon resonance (SPR) assay. Further study showed that Tim-AIII promoted HSP90 expression and Tim-AIII induced cell death was blocked by the HSP90 inhibitor tanespimycin, indicating that HSP90 was the main target of Tim-AIII to further trigger intracellular events. Mechanical analysis revealed that the Tim-AIII-HSP90 complex further targeted and degraded glutathione peroxidase 4 (GPX4), and promoted the ubiquitination of GPX4, as shown by an immunoprecipitation, degradation and in vitro ubiquitination assay. In addition, Tim-AIII inhibited cell proliferation, induced cell death, led to ROS and iron accumulation, MDA production, GSH depletion, as well as GPX4 ubiquitination and degradation, were markedly abrogated when HSP90 was knockdown by HSP90-shRNA transfection. Importantly, Tim-AIII also showed a strong capacity of preventing tumor growth by promoting ferroptosis in a subcutaneous xenograft tumor model, whether C57BL/6J or BALB/c-nu/nu nude mice. Together, HSP90 was identified as a new target of Tim-AIII. Tim-AIII, by binding and forming a complex with HSP90, further targeted and degraded GPX4, ultimately induced ferroptosis in NSCLC. These findings provided solid evidence that Tim-AIII can serve as a potential candidate for NSCLC treatment.

Shock-Associated Systemic Inflammation in Amniotic Fluid Embolism, Complicated by Clinical Death.

BACKGROUND: Amniotic fluid embolism (AFE) is one of the main causes of maternal mortality in developed countries. The most critical AFE variants may be considered from the perspective of systemic inflammation (SI), a general pathological process that includes high levels of systemic inflammatory response, neuroendocrine system distress, microthrombosis, and multiple organ dysfunction syndrome (MODS). This research work aimed to characterize the dynamics of super-acute SI using four clinical case studies of patients with critical AFE. METHODS: In all the cases, we examined blood coagulation parameters, plasma levels of cortisol, troponin I, myoglobin, C-reactive protein, IL-6, IL-8, IL-10, and TNF-α, and calculated the integral scores. RESULTS: All four patients revealed the characteristic signs of SI, including increased cytokine, myoglobin, and troponin I levels, changes in blood cortisol, and clinical manifestations of coagulopathy and MODS. At the same time, the cytokine plasma levels can be characterized not only as hypercytokinemia, and not even as a "cytokine storm", but rather as a "cytokine catastrophe" (an increase of thousands and tens of thousands of times in proinflammatory cytokine levels). AFE pathogenesis involves rapid transition from the hyperergic shock phase, with its high levels of a systemic inflammatory response over to the hypoergic shock phase, characterized by the mismatch between low systemic inflammatory response values and the patient's critical condition. In contrast to septic shock, in AFE there is a much more rapid succession of SI phases. CONCLUSION: AFE is one of the most compelling examples for studying the dynamics of super-acute SI.

Berberine plays a cardioprotective role by inhibiting macrophage Wnt5a/ß-catenin pathway in the myocardium of mice after myocardial infarction.

Myocardial infarction (MI) is one of the diseases with high fatality rate. Berberine (BBR) is a monomer compound with various biological functions. And some studies have confirmed that BBR plays an important role in alleviating cardiomyocyte injury after MI. However, the specific mechanism is unclear. In this study, we induced a model of MI by ligation of the left anterior descending coronary artery and we surprisingly found that BBR significantly improved ventricular remodeling, with a minor inflammatory and oxidative stress injury, and stronger angiogenesis. Moreover, BBR inhibited the secretion of Wnt5a/ß-catenin pathway in macrophages after MI, thus promoting the differentiation of macrophages into M2 type. In summary, BBR effectively improved cardiac function of mice after MI, and the potential protective mechanism was associated with the regulation of inflammatory responses and the inhibition of macrophage Wnt5a/ß-catenin pathway in the infarcted heart tissues. Importantly, these findings supported BBR as an effective cardioprotective drug after MI.

Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy.

Since the discovery of Stimulator of Interferon Genes (STING) as an important pivot for cytosolic DNA sensation and interferon (IFN) induction, intensive efforts have been endeavored to clarify the molecular mechanism of its activation, its physiological function as a ubiquitously expressed protein, and to explore its potential as a therapeutic target in a wide range of immune-related diseases. With its orthodox ligand 2'3'-cyclic GMP-AMP (2'3'-cGAMP) and the upstream sensor 2'3'-cGAMP synthase (cGAS) to be found, STING acquires its central functionality in the best-studied signaling cascade, namely the cGAS-STING-IFN pathway. However, recently updated research through structural research, genetic screening, and biochemical assay greatly extends the current knowledge of STING biology. A second ligand pocket was recently discovered in the transmembrane domain for a synthetic agonist. On its downstream outputs, accumulating studies sketch primordial and multifaceted roles of STING beyond its cytokine-inducing function, such as autophagy, cell death, metabolic modulation, endoplasmic reticulum (ER) stress, and RNA virus restriction. Furthermore, with the expansion of the STING interactome, the details of STING trafficking also get clearer. After retrospecting the brief history of viral interference and the milestone events since the discovery of STING, we present a vivid panorama of STING biology taking into account the details of the biochemical assay and structural information, especially its versatile outputs and functions beyond IFN induction. We also summarize the roles of STING in the pathogenesis of various diseases and highlight the development of small-molecular compounds targeting STING for disease treatment in combination with the latest research. Finally, we discuss the open questions imperative to answer.

Stem cells and cardiac arrhythmias.

Recent discoveries in the physiology and pathology of myocardial progenitor cells have allowed researchers to better understand a variety of cardiac pathologies and look at the pathophysiology of arrhythmias from a different perspective. Since the myocardium is composed of a syncytium of electrically interconnected cells, the process of incorporation of newly formed or imported cells into its structure is particularly important. Progenitor cells are stimulated by spontaneous electrical activity, a lengthy action potential, and easily induced triggering activity. All these can lead to arrhythmias development via the three classical mechanisms (reentrancy, automatism, or triggering activity). Transplanted stem cells can influence the electrophysiological properties of cardiomyocytes, thus creating a proarrhythmic substrate. The islets of unbound cells can form an anatomical block, causing unidirectional blockages and recurrent arrhythmias. Similarly, stem cells are capable of establishing heterotopic excitation foci with cardiac stimulatory activity. Finally, the paracrine factors produced by stem cells can also cause proarrhythmic effects. The review examines the factors that influence the proarrhythmic properties of administered stem cells and the mechanisms of arrhythmia development. The results indicate that further research should be carried out to establish the possible impact of stem cells on the development of arrhythmias.

The Healing Environment of Dental Clinics through the Eyes of Patients and Healthcare Professionals: A Pilot Study.

The physical environment of healthcare settings can promote both the healing process and patient feelings of well-being, as well as instill positive emotions in employees. The present study aimed to evaluate the dental work environment of a typical private and public dental clinic to identify key parameters that determine the perception of health facilities by patients and employees. The study was carried out from 1 to 20 December 2021, in two dental clinics in Ekaterinburg (Russian Federation) using 'ASPECT'. The participants were 58 staff and 94 patients. The results showed that, compared with patients, staff reported higher views scores, nature and outdoors scores, and comfort and control scores. The common criterion that distinguishes private clinics from public ones was comfort and control. Compared with patients in state clinics, patients in private clinics reported higher privacy, company and dignity scores, comfort and control scores, interior appearance scores, and facility scores. In general, while views scores and nature parameters can be singled out as a universal absolute value for everyone in a particular environment, staff pay more attention to factors that contribute to long-term comfortable stay and performance of their duties.

Taraxasterol Inhibits Tumor Growth by Inducing Apoptosis and Modulating the Tumor Microenvironment in Non-Small Cell Lung Cancer.

Taraxasterol (TAX), one of the active components in Dandelion, demonstrated strong antitumor properties in several cancers. However, the effect and underlying mechanism of TAX in non-small cell lung cancer (NSCLC) is unclear. In this study, we showed that TAX inhibited the proliferation of cells by inducing S-phase cell cycle arrest and prevented cell migration by interfering epithelial-mesenchymal transition (EMT) in Lewis lung cancer (LLC) cells and lung carcinoma SPC-A1 cells. The pharmacological network analysis predicted that induction of apoptosis might be the potential mechanism of TAX-mediated cell deaths. Further in vitro experiments showed that TAX could significantly induce cancer cell apoptosis as verified by increased pro-apoptotic molecules including Bax, caspase-9, and PARP1 downregulated anti-apoptotic protein Bcl-2; and decreased mitochondrial potential. The LLC subcutaneous tumor model demonstrated that TAX inhibited tumor growth by induction of apoptosis and inhibition of proliferation in vivo, which is consistent with the in vitro data. Importantly, TAX administration downregulated the proportion of Treg cells and upregulated CD107a+ NK cells in the tumor microenvironment in the tumor model. Together, these data reveal that TAX performs its antitumor effect by inducing apoptosis and modulating the tumor microenvironment, providing evidence that TAX could serve as a potential natural drug for lung cancer therapy.

Big Five Traits as Predictors of a Healthy Lifestyle during the COVID-19 Pandemic: Results of a Russian Cross-Sectional Study.

The healthy lifestyle of people around the world has changed dramatically during the COVID-19 pandemic. The personality risk factors for these processes from around the world remain understudied. This study aimed to examine the associations of the Big Five traits with a healthy lifestyle during the COVID-19 pandemic. In a cross-sectional study, data from 1215 Russian university students were analyzed. Participants completed the Big Five Inventory-10 and Short Multidimensional Inventory Lifestyle Evaluation. The results showed that personality traits predicted many dimensions of a healthy lifestyle during the COVID-19 pandemic. Diet and nutrition were positively predicted by extraversion, agreeableness, and conscientiousness, and it was negatively predicted by neuroticism. Substance abuse was positively predicted by agreeableness and conscientiousness, and it was negatively predicted by extraversion. Physical activity was positively predicted by extraversion and conscientiousness, and it was negatively predicted by neuroticism. Stress management was positively predicted by extraversion and conscientiousness, and it was negatively predicted by neuroticism. Restorative sleep was positively predicted by extraversion and conscientiousness, and it was negatively predicted by neuroticism. Social support for healthy practices was positively predicted by extraversion, agreeableness, and conscientiousness. Environmental exposures were positively predicted by extraversion, and neuroticism was positively and negatively predicted by conscientiousness. Our findings may be useful for further exploration of personality risk factors for healthy practices in challenging life circumstances.

The Link between Activities of Hepatic 11beta-Hydroxysteroid Dehydrogenase-1 and Monoamine Oxidase-A in the Brain Following Repeated Predator Stress: Focus on Heightened Anxiety.

We investigated the presence of a molecular pathway from hepatic 11-ßHSD-1 to brain MAO-A in the dynamics of plasma corticosterone involvement in anxiety development. During 14 days following repeated exposure of rats to predator scent stress for 10 days, the following variables were measured: hepatic 11-ßHSD-1 and brain MAO-A activities, brain norepinephrine, plasma corticosterone concentrations, and anxiety, as reflected by performance on an elevated plus maze. Anxiety briefly decreased and then increased after stress exposure. This behavioral response correlated inversely with plasma corticosterone and with brain MAO-A activity. A mathematical model described the dynamics of the biochemical variables and predicted the factor(s) responsible for the development and dynamics of anxiety. In the model, hepatic 11-ßHSD-1 was considered a key factor in defining the dynamics of plasma corticosterone. In turn, plasma corticosterone and oxidation of brain ketodienes and conjugated trienes determined the dynamics of brain MAO-A activity, and MAO-A activity determined the dynamics of brain norepinephrine. Finally, plasma corticosterone was modeled as the determinant of anxiety. Solution of the model equations demonstrated that plasma corticosterone is mainly determined by the activity of hepatic 11-ßHSD-1 and, most importantly, that corticosterone plays a critical role in the dynamics of anxiety following repeated stress.

Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Experimental Ulcerative Colitis Mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by many factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR exerts the protective effects. We characterized the therapeutic effects and the potential mechanism of CSR on treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation. CSR administration significantly ameliorated the dextran sodium sulfate (DSS)-induced colitis in mice, which was evidenced by the recovered body weight and colon length as well as the decreased disease activity index (DAI) score and intestinal permeability. Meanwhile, CSR down-regulated the production of pro-inflammatory cytokines and up-regulated the amount of anti-inflammatory mediators at both mRNA and protein levels, and improved the balances of Treg/Th1 and Treg/Th17 to maintain the colonic immune homeostasis. Notably, all the therapeutic effects were exerted in a gut microbiota-dependent manner. Furthermore, CSR treatment increased the gut microbiota diversity and changed the compositions of the gut microbiota and metabolites, which is probably associated with the gut microbiota-mediated protective effects. In conclusion, this study provides the strong evidence that CSR may be a promising therapeutic drug for UC.

Urinalysis, but Not Blood Biochemistry, Detects the Early Renal Impairment in Patients with COVID-19.

BACKGROUND: Coronavirus 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has created a tremendous economic and medical burden. The prevalence and prognostic value of SARS-CoV-2-induced kidney impairment remain controversial. The current study aimed to provide additional evidence on the incidence of acute kidney injury (AKI) in COVID-19 patients and propose the use of urinalysis as a tool for screening kidney impairment. METHODS: 178 patients with confirmed COVID-19 were enrolled in this retrospective cohort study. The laboratory examinations included routine blood tests, blood biochemical analyses (liver function, renal function, lipids, and glucose), blood coagulation index, lymphocyte subset and cytokine analysis, urine routine test, C-reactive protein, erythrocyte sedimentation, and serum ferritin. RESULTS: No patient exhibited a rise in serum creatinine or Cystatin C and occurrence of AKI, and only 2.8% of patients were recorded with an elevated level of blood urea nitrogen among all cases. On the contrary, 54.2% of patients who underwent routine urine testing presented with an abnormal urinalysis as featured by proteinuria, hematuria, and leucocyturia. CONCLUSIONS: Kidney impairment is prevalent among COVID-19 patients, with an abnormal urinalysis as a clinical manifestation, implying that a routine urine test is a stronger indication of prospective kidney complication than a blood biochemistry test.

Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/ß-catenin pathway.

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colon, and it has become one of the world-recognized medical problems as it is recurrent and refractory. Berberine (BBR) is an effective drug for UC treatment. However, the underlying mechanism and targets remain obscure. In this study, we systematically investigated the therapeutic effect and its mechanism of BBR in ameliorating DSS-induced mouse colitis. Expectedly, the colon inflammation was significantly relieved by BBR, and microbiota depletion by antibiotic cocktail significantly reversed the therapeutic effect. Further studies showed that BBR can regulate the abundance and component of bacteria, reestablish the broken chemical and epithelial barriers. Meanwhile, BBR administration dramatically decreased ILC1 and Th17 cells, and increased Tregs as well as ILC3 in colonic tissue of DSS-induced mice, and it was able to regulate the expression of various immune factors at the mRNA level. Moreover, a proteomic study revealed that Wnt/ß-catenin pathway was remarkably enhanced in colonic tissue of BBR-treated mice, and the therapeutic effect of BBR was disappeared after the intervention of Wnt pathway inhibitor FH535. These results substantially revealed that BBR restores DSS-induced colon inflammation in a microbiota-dependent manner, and BBR performs its protective roles in colon by maintaining the structure and function of the intestinal mucosal barrier, regulating the intestinal mucosal immune homeostasis and it works through the Wnt/ß-catenin pathway. Importantly, these findings also provided the proof that BBR serves as a potential gut microbiota modulator and mucosal barrier protector for UC prevention and therapy.