RNA m6A demethylase ALKBH5 regulates the development of γδ T cells.

γδ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N6-methyladenosine (m6A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m6A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γδ T cell early development.

Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation.

BACKGROUND AND AIMS: TGF-ß induces multiple structural and functional changes in quiescent HSCs, including an increase in proliferation, mitochondrial mass, and matrix deposition. HSC transdifferentiation requires significant bioenergetic capacity, and it is not known how TGF-ß-mediated transcriptional upregulation is coordinated with the bioenergetic capacity of HSCs. APPROACH AND RESULTS: Mitochondria are key bioenergetic organelles, and here, we report that TGF-ß induces release of mitochondrial DNA (mtDNA) from healthy HSCs through voltage-dependent anion channels (VDACs), with the formation of an mtDNA-CAP on the external mitochondrial membrane. This stimulates organization of cytosolic cyclic GMP-AMP synthase (cGAS) onto the mtDNA-CAP and subsequent activation of the cGAS-STING-IRF3 pathway. TGF-ß is unable to induce conversion of HSCs from a quiescent to a transdifferentiated phenotype in the absence of mtDNA, VDAC, or stimulator of interferon genes (STING). Transdifferentiation by TGF-ß is blocked by a STING inhibitor, which also reduces liver fibrosis prophylactically and therapeutically. CONCLUSIONS: We have identified a pathway that requires the presence of functional mitochondria for TGF-ß to mediate HSC transcriptional regulation and transdifferentiation and therefore provides a key link between bioenergetic capacity of HSCs and signals for transcriptional upregulation of genes of anabolic pathways.

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response.

Annexin A2 (ANXA2) is widely used as a marker in a variety of tumors. By regulating multiple signal pathways, ANXA2 promotes the epithelial-mesenchymal transition, which can cause tumorigenesis and accelerate thymus degeneration. The elevated ANXA2 heterotetramer facilitates the production of plasmin, which participates in pathophysiologic processes such as tumor cell invasion and metastasis, bleeding diseases, angiogenesis, inducing the expression of inflammatory factors. In addition, the ANXA2 on the cell membrane mediates immune response via its interaction with surface proteins of pathogens, C1q, toll-like receptor 2, anti-dsDNA antibodies and immunoglobulins. Nuclear ANXA2 plays a role as part of a primer recognition protein complex that enhances DNA synthesis and cells proliferation by acting on the G1-S phase of the cell. ANXA2 reduction leads to the inhibition of invasion and metastasis in multiple tumor cells, bleeding complications in acute promyelocytic leukemia, retinal angiogenesis, autoimmunity response and tumor drug resistance. In this review, we provide an update on the pathological effects of ANXA2 in both tumorigenesis and the immune response. We highlight ANXA2 as a critical protein in numerous malignancies and the immune host response.

Fermented Soy Drink (Q-CAN® PLUS) Induces Apoptosis and Reduces Viability of Cancer Cells.

This study tested the ability of a fermented soy product to induce tumor cell toxicity and to assess if this was due to fermentation of soy, and to the genistein content. Four cancer cell lines were cultured without additive, with fermented soy (Q-CAN® PLUS), nonfermented soy, or genistein, and cell viability was examined at 24 h, 48 h, and 72 h. The sensitivity of the cell lines to apoptosis by Q-CAN PLUS was tested with the Annexin V assay. All cell lines demonstrated a dose and time response reduction in tumor cell viability with exposure to Q-CAN PLUS (IC50 at 24 h 3.8 mg/mL to 9 mg/mL). Unfermented soy did not show reduction in viability of any cell line within the same concentration range. The IC50 of genistein for each of the cell lines was significantly greater than for Q-CAN PLUS. All four tumor cell lines demonstrated apoptosis in response to Q-CAN PLUS. Q-CAN PLUS reduces viability and increases apoptosis of cancer cells in a concentration- and fermentation-dependent manner. Taking into consideration the IC50 of genistein and the concentration of genistein in Q-CAN PLUS, the genistein content of Q-CAN PLUS is not responsible for the majority reduction in tumor cell viability. This suggests that fermentation of soy results in the production of metabolites that reduce cancer cell viability and induce cellular apoptosis, and play a major role in addition to any effects produced by their genistein content.

Glycogen synthase kinase-3ß inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction.

Inflammasome-promoted sterile inflammation following cardiac damage is critically implicated in heart dysfunction after myocardial infarction (MI). Glycogen synthase kinase-3 (GSK-3ß) is a prominent mediator of the inflammatory response, and high GSK-3 activity is associated with various heart diseases. We investigated the regulatory mechanisms of GSK-3ß in activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model with successful induction of MI on days 2-28. An in vitro investigation was performed using newborn rat/human cardiomyocytes and fibroblast cultures under typical inflammasome stimulation and hypoxia treatment. GSK-3ß inhibition markedly improved myocardial dysfunction and prevented remodeling, with parallel reduction in the parameters of NLRP3 inflammasome activation after MI. GSK-3ß inhibition reduced NLRP3 inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes. GSK-3ß's interaction with activating signal cointegrator (ASC) as well as GSK-3ß inhibition reduced ASC phosphorylation and oligomerization at the tissues and cellular levels. Taken together, these data show that GSK-3ß directly mediates NLRP3 inflammasome activation, causing cardiac dysfunction in MI.

Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation.

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH.NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.

The Reduced Expression of EOLA1 May Be Related to Refractory Diabetic Foot Ulcer.

BACKGROUND: Chronic diabetic foot ulcer (DFU) is one of the most intractable complications of diabetes mellitus (DM). Its pathogenesis is complex, and uncontrolled chronic inflammation is an important factor. Endothelial overexpressed lipopolysaccharide-associated factor 1 (EOLA1) discovered in our laboratory is an intracellular protein with the function of inflammatory regulation. This study was aimed at observing the expression of EOLA1 in DFU skin tissues and its relationship with inflammation and at exploring the possible role of EOLA1 in DFU and its mechanism. METHODS: The patients with DFU were divided into 2 groups based on the formation time of ulcer: the acute wound (AW) group with the course of disease ≤ 4 weeks and the chronic wound (CW) group with the course of disease > 4 weeks. The relevant clinical data of patients were collected, and the skin tissues around the ulcer were used for immunofluorescence detection and immunohistochemical staining to observe inflammation. The expression levels of EOLA1, metallothionein 2A (MT2A), nuclear factor-κB (NF-κB), and interleukin-6 (IL-6) were detected by western blot. RESULTS: A total of 79 patients were enrolled in the study. The results of immunofluorescence and immunohistochemistry showed that EOLA1 was expressed in the epithelial tissues of DFU. However, the expression of EOLA1 in the CW group was significantly lower than that in the AW group (P < 0.05), and the expression of NF-κB and IL-6 was obviously increased (P < 0.05). CONCLUSION: The refractory wounds in patients with DFU may be closely related to the uncontrolled activation of inflammatory pathways in cells caused by the reduced expression of negative regulators of inflammation (e.g., EOLA1), and such decreased expression may be also strongly linked to the persistent state of inflammation.

ß-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway.

BACKGROUND & AIMS: Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by ß-hydroxybutyrate (BHB). We aimed to determine the relevance of the BHB-Hcar2 pathway in alcoholic liver disease. METHODS: We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation is protective in AH through interaction with Hcar2, and analyzed the immune and cellular basis for protection. RESULTS: Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol-induced AH, with higher plasma alanine aminotransferase levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced alanine aminotransferase levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver Il10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (Δψ) induced by BHB. CONCLUSIONS: Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway. This introduces the concept of metabolite-based therapy for AH. LAY SUMMARY: Alcoholic hepatitis is a life-threatening condition with no approved therapy that occurs unexpectedly in people who consume excess alcohol. The liver makes many metabolites, and we demonstrate that loss of one such metabolite ß-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and ß-hydroxybutyrate can protect from alcohol-induced liver injury via a receptor on liver macrophages. This opens the possibility of metabolite-based therapy for alcoholic hepatitis.

Na(+) /H(+) exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury.

UNLABELLED: The intercellular adhesion molecule 1 (ICAM-1) is induced in mouse liver after bile duct ligation (BDL) and plays a key role in neutrophil-mediated liver injury in BDL mice. ICAM-1 has been shown to interact with cytoskeletal ezrin-radixin-moesin (ERM) proteins that also interact with the PDZ protein, Na(+) /H(+) exchanger regulatory factor 1 (NHERF-1/EBP50). In NHERF-1(-/-) mice, ERM proteins are significantly reduced in brush-border membranes from kidney and small intestine. ERM knockdown reduces ICAM-1 expression in response to tumor necrosis factor alpha. Here we show that NHERF-1 assembles ERM proteins, ICAM-1 and F-actin into a macromolecule complex that is increased in mouse liver after BDL. Compared to wild-type (WT) mice, both sham-operated and BDL NHERF-1(-/-) mice have lower levels of activated ERM and ICAM-1 protein in the liver accompanied by significantly reduced hepatic neutrophil accumulation, serum alanine aminotransferase, and attenuated liver injury after BDL. However, total bile acid concentrations in serum and liver of sham and BDL NHERF-1(-/-) mice were not significantly different from WT controls, although hepatic tetrahydroxylated bile acids and Cyp3a11 messenger RNA levels were higher in NHERF-1(-/-) BDL mice. CONCLUSION: NHERF-1 participates in the inflammatory response that is associated with BDL-induced liver injury. Deletion of NHERF-1 in mice leads to disruption of the formation of ICAM-1/ERM/NHERF-1 complex and reduction of hepatic ERM proteins and ICAM-1, molecules that are up-regulated and are essential for neutrophil-mediated liver injury in cholestasis. Further study of the role of NHERF-1 in the inflammatory response in cholestasis and other forms of liver injury should lead to discovery of new therapeutic targets in hepatic inflammatory diseases.

The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE-/- Mice.

Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism. Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE-/- mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fat metabolism, IL-1ß, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1ß production in culturing primary macrophages of wild type and NLRP3-/- knockout mice were investigated for mechanism analyses. Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1ß, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway. Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1ß by macrophages via the ROS-NLRP3-caspase-1 pathway.

Inflammasome biology in fibrogenesis.

Pathogens and sterile insults both result in an inflammatory response. A significant part of this response is mediated by cytosolic machinery termed as the inflammasome which results in the activation and secretion of the cytokines interleukin-1ß (IL-1ß) and IL-18. Both of these are known to result in the activation of an acute inflammatory response, resulting in the production of downstream inflammatory cytokines such as tumor necrosis factor (TNF-α), interferon-gamma (IFN-γ), chemotaxis of immune cells, and induction of tissue injury. Surprisingly this very acute inflammatory pathway is also vital for the development of a full fibrogenic response in a number of organs including the lung, liver, and skin. There is evidence for the inflammasome having a direct role on tissue specific matrix producing cells such as the liver stellate cell, and also indirectly through the activation of resident tissue macrophage populations. The inflammasome requires stimulation of two pathways for full activation, and initiating stimuli include Toll-like receptor (TLR) agonists, adenosine triphosphate (ATP), particulates, and oxidative stress. Such a role for an acute inflammatory pathway in fibrosis runs counter to the prevailing association of TGF-ß driven anti-inflammatory and pro-fibrotic pathways. This identifies new therapeutic targets which have the potential to simultaneously decrease inflammation, tissue injury and fibrosis. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a ß-arrestin-2 pathway.

Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-d-aspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a ß-arrestin-2 NF-kß and JNK pathway and not via Ca(2+) mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.

Effect of osteopontin in regulating bone marrow mesenchymal stem cell treatment of skin wounds in diabetic mice.

BACKGROUND: We aimed to investigate the role of osteopontin in regulating mesenchymal stem cells transplanted to promote wound healing in diabetic mice. METHODS: The mesenchymal stem cells of osteopontin knock-out (KO) and wild-type (WT) mice were isolated separately for in vitro culture and characterization. A skin wound on the back of mice was established by skin punching. In 27 osteopontin KO male mice, induced diabetes mellitus was via intraperitoneal injection of streptozotocin. 9 normal mice were used as controls. The mice were divided into four groups and injected with Dulbecco's modified Eagle's medium (DMEM) or mesenchymal stem cells via the tail vein: A (diabetic mice injected with DMEM), B (diabetic mice injected with osteopontin KO mesenchymal stem cells), C (diabetic mice injected with WT mesenchymal stem cells), D (normal mice injected with DMEM). The healing times and closure rates of skin wounds were recorded. The microvessel density of healing wounds was measured, and the localized expression of osteopontin was identified by western blotting and immunohistochemistry. The migration of mesenchymal stem cells was observed on normal mice with skin wound injected with mesenchymal stem cells of C57BL6~GFP transgenic mice, which show green fluorescent under UV light. RESULTS: Compared with normal mice, the healing time of wounds in the mice with diabetes and osteopontin KO was significantly prolonged (p < 0.01). After transplanting osteopontin KO mesenchymal stem cells, the healing time was slightly shorter. Meanwhile, the healing time was significantly shorter after transplanted with WT mesenchymal stem cells and more significant neovascularization at healing wounds (p < 0.05). The expression of osteopontin in local healing wounds after transplantation of WT mesenchymal stem cells was demonstrated with western blotting and immunohistochemistry. After 4 days, the green fluoresces were noted on the wounds of mice injected with mesenchymal stem cells of fluorescent mice. CONCLUSIONS: Mesenchymal stem cells can migrate to wound sites, and osteopontin plays a regulatory role in mesenchymal stem cells promoting the healing of diabetic skin wounds.

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response.

Implantation of biomaterials and devices into soft tissues leads to the development of the foreign body response (FBR), which can interfere with implant function and eventually lead to failure. The FBR consists of overlapping acute and persistent inflammatory phases coupled with collagenous encapsulation and currently there are no therapeutic options. Initiation of the FBR involves macrophage activation, proceeding to giant cell formation, fibroblast activation, and collagen matrix deposition. Despite the recognition of this sequence of events, the molecular pathways required for the FBR have not been elucidated. We have identified that the acute inflammatory response to biomaterials requires nucleotide-binding domain and leucine-rich repeat-containing 3 (Nlrp3), apoptosis-associated speck-like protein containing CARD (Asc), and caspase-1, as well as plasma membrane cholesterol, and Syk signaling. Full development of the FBR is dependent on Asc and caspase-1, but not Nlrp3. The common antiinflammatory drug aspirin can reduce inflammasome activation and significantly reduce the FBR. Taken together, these findings expand the role of the inflammasome from one of sensing damage associated molecular patterns (DAMPs) to sensing all particulate matter irrespective of size. In addition, implication of the inflammasome in biomaterial recognition identifies key pathways, which can be targeted to limit the FBR.

RNA modifications in the progression of liver diseases: from fatty liver to cancer.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern associated with high risk of metabolic syndrome, and has impacted a substantial segment of the population. The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is increasingly becoming a prevalent indication for liver transplantation. The existing therapeutic options for NAFLD, NASH, and HCC are limited, underscoring the urgent need for innovative treatment strategies. Insights into gene expression, particularly RNA modifications such as N6 methyladenosine (m6A), hold promising avenues for interventions. These modifications play integral roles in RNA metabolism and cellular functions, encompassing the entire NAFLD-NASH-HCC progression. This review will encompass recent insights on diverse RNA modifications, including m6A, pseudouridine (ψ), N1-methyladenosine (m1A), and 5-methylcytidine (m5C) across various RNA species. It will uncover their significance in crucial aspects such as steatosis, inflammation, fibrosis, and tumorigenesis. Furthermore, prospective research directions and therapeutic implications will be explored, advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

Digoxin as an emerging therapy in noncardiac diseases.

The cardiac glycoside (CG) digoxin is a generic drug approved for the treatment of heart failure and supraventricular arrhythmias. Over the past few decades, substantial strides have been made toward repurposing digoxin to treat various noncardiac diseases. Here, we evaluate recent insights into basic and clinical work related to noncardiac use of digoxin.

New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders.

Repurposing of the widely available and relatively cheap generic cardiac gly-coside digoxin for non-cardiac indications could have a wide-ranging impact on the global burden of several diseases. Over the past several years, there have been significant advances in the study of digoxin pharmacology and its potential non-cardiac clinical applications, including anti-inflammatory, antineoplastic, metabolic, and antimicrobial use. Digoxin holds promise in the treatment of gastrointestinal disease, including nonalcoholic steatohepatitis and alcohol-associated steatohepatitis as well as in obesity, cancer, and treatment of viral infections, among other conditions. In this review, we provide a summary of the clinical uses of digoxin to date and discuss recent research on its emerging applications.

An analysis of the nutritional effects of Schisandra chinensis components based on mass spectrometry technology.

Objective: Schisandra chinensis (Turcz.) Baill. (S. chinensis) is a Traditional Chinese medicinal herb that can be used both for medicinal purposes and as a food ingredient due to its beneficial properties, and it is enriched with a wide of natural plant nutrients, including flavonoids, phenolic acids, anthocyanins, lignans, triterpenes, organic acids, and sugars. At present, there is lack of comprehensive study or systemic characterization of nutritional and active ingredients of S. chinensis using innovative mass spectrometry techniques. Methods: The comprehensive review was conducted by searching the PubMed databases for relevant literature of various mass spectrometry techniques employed in the analysis of nutritional components in S. chinensis, as well as their main nutritional effects. The literature search covered the past 5 years until March 15, 2023. Results: The potential nutritional effects of S. chinensis are discussed, including its ability to enhance immunity, function as an antioxidant, anti-allergen, antidepressant, and anti-anxiety agent, as well as its ability to act as a sedative-hypnotic and improve memory, cognitive function, and metabolic imbalances. Meanwhile, the use of advanced mass spectrometry detection technologies have the potential to enable the discovery of new nutritional components of S. chinensis, and to verify the effects of different extraction methods on these components. The contents of anthocyanins, lignans, organic acids, and polysaccharides, the main nutritional components in S. chinensis, are also closely associated to its quality. Conclusion: This review will provide guidelines for an in-depth study on the nutritional value of S. chinensis and for the development of healthy food products with effective components.