Integration Analysis of Single-Cell Multi-Omics Reveals Prostate Cancer Heterogeneity.

Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, the manner in which heterogeneity is shaped by tumors and stromal cells, or vice versa, remains poorly understood. In this study, single-cell RNA sequencing, spatial transcriptomics, and bulk ATAC-sequence are integrated from a series of patients with PCa and healthy controls. A stemness subset of club cells marked with SOX9highARlow expression is identified, which is markedly enriched after neoadjuvant androgen-deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cells that function as effector T cells is markedly reduced in patients with malignant PCa. For spatial transcriptome analysis, machine learning and computational intelligence are comprehensively utilized to identify the cellular diversity of prostate cancer cells and cell-cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are also examined. Finally, the immunosuppressive microenvironment in advanced PCa is found to be associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. In summary, the cellular heterogeneity is delineated in the stage-specific PCa microenvironment at single-cell resolution, uncovering their reciprocal crosstalk with disease progression, which can be helpful in promoting PCa diagnosis and therapy.

Qualitative and quantitative evaluations of Chuanxiong dispensing granules by using chemical fingerprint in combination with chemometrics methods.

To better elucidate the chemical constituents and evaluate the quality consistency of Chuanxiong dispensing granules (CDG), qualitative and quantitative analyses were performed in this study. Firstly, a high-performance liquid chromatography-diode array detector (HPLC-DAD) based fingerprint was constructed by 12 batches of CDGs from different manufacturers, in which 16 common peaks were assigned. Then, two of them were directionally isolated for structural elucidation. According to the nuclear magnetic resonance (NMR) and mass spectrometry (MS) spectra, 5,6-dihydrophthalic acid was identified as novel compound, and 8-O-4/8-O-4-dehydrotriferulic acid was firstly discovered in plant belonging to the genus Ligusticum. Secondly, a total of 46 components were detected in CDG using high performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (HPLC-Q-TOF-MS), and 14 of them were unambiguously identified by comparing with reference standards. Additionally, a HPLC-DAD method was firstly established to quantify 10 characteristic peaks specified in the China National Standard of CDG, and the results revealed that ferulic acid (1.71 mg/g), chlorogenic acid (1.14 mg/g), 5,6-dihydrophthalic acid (1.13 mg/g), and senkyunolide I (1.13 mg/g) are the major components in CDGs. Chemometrics analyses suggested that phenolic acids are more important than phthalides in discrimination of CDGs from different manufacturers.

Piper nigrum Extract Inhibits the Growth of Human Colorectal Cancer HT-29 Cells by Inducing p53-Mediated Apoptosis.

Colorectal cancer (CRC) is a prevalent malignancy of the digestive tract with the second highest mortality rate globally. Piper nigrum is a widely used traditional medicinal plant, exhibiting antitumor activity against various tumor cells. At present, research on the effect of Piper nigrum on CRC is limited to in vitro cytotoxicity, lacking comprehensive mechanism investigations. This study aimed to explore the inhibitory effect and mechanism of Piper nigrum extract (PNE) on HT-29 cells. Firstly, we identified the chemical components of PNE. Then, MTT assay, colony formation assay, JC-1 staining, and flow cytometry were used to analyze the effect of PNE on HT-29 cells in vitro. A xenograft model, histopathological examination, immunohistochemistry, and western blot were used to evaluate the tumor growth inhibitory activity and mechanism of PNE in vivo. The results indicated that PNE could inhibit cell proliferation and colony formation, reduce mitochondrial membrane potential, induce cell apoptosis in vitro, and inhibit tumor growth in vivo. Furthermore, PNE could regulate p53 and its downstream proteins, and subsequently activate the caspase-3 pathway. In summary, PNE probably induced apoptosis of HT-29 cells through the mitochondrial pathway mediated by p53. All these results suggested that PNE might be a potential natural-origin anti-CRC drug candidate.

Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1+ Macrophage Subpopulation as a Target for Alleviating Fibrosis.

BACKGROUND: Perivascular adipose tissue (PVAT) is vital for vascular homeostasis, and PVAT dysfunction is associated with increased atherosclerotic plaque burden. But the mechanisms underlining coronary PVAT dysfunction in coronary atherosclerosis remain elusive. METHODS: We performed single-cell RNA sequencing of the stromal vascular fraction of coronary PVAT from 3 groups of heart transplant recipients with end-stage heart failure, including 3 patients with nonobstructive coronary atherosclerosis, 3 patients with obstructive coronary artery atherosclerosis, and 4 nonatherosclerosis control subjects. Bioinformatics was used to annotate the cellular populations, depict the cellular developmental trajectories and interactions, and explore the differences among 3 groups of coronary PVAT at the cellular and molecular levels. Pathological staining, quantitative real-time polymerase chain reaction, and in vitro studies were performed to validate the key findings. RESULTS: Ten cell types were identified among 67 936 cells from human coronary PVAT. Several cellular subpopulations, including SPP1+ (secreted phosphoprotein 1) macrophages and profibrotic fibroadipogenic progenitor cells, were accumulated in PVAT surrounding atherosclerotic coronary arteries compared with nonatherosclerosis coronary arteries. The fibrosis percentage was increased in PVAT surrounding atherosclerotic coronary arteries, and it was positively associated with the grade of coronary artery stenosis. Cellular interaction analysis suggested OPN (osteopontin) secreted by SPP1+ macrophages interacted with CD44 (cluster of differentiation 44)/integrin on fibroadipogenic progenitor cells. Strikingly, correlation analyses uncovered that higher level of SPP1 in PVAT correlates with a more severe fibrosis degree and a higher coronary stenosis grade. In vitro studies showed that conditioned medium from atherosclerotic coronary PVAT promoted the migration and proliferation of fibroadipogenic progenitor cells, while such effect was prevented by blocking CD44 or integrin. CONCLUSIONS: SPP1+ macrophages accumulated in the PVAT surrounding atherosclerotic coronary arteries, and they promoted the migration and proliferation of fibroadipogenic progenitor cells via OPN-CD44/integrin interaction and thus aggravated the fibrosis of coronary PVAT, which was positively correlated to the coronary stenosis burden. Therefore, SPP1+ macrophages in coronary PVAT may participate in the progression of coronary atherosclerosis.

Association of dietary inflammatory index with helicobacter pylori infection and mortality among US population.

BACKGROUND: Limited research has been conducted on the potential relationship between the dietary inflammation index (DII) and mortality, particularly in individuals with Helicobacter pylori (H. pylori) infection. This study aimed to investigate the association between the DII and H. pylori infection, as well as their respective impacts on all-cause mortality in a cohort of individuals with or without H. pylori infection. METHODS: Data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) were utilized for this study, with a final of 4370 participants included. Both univariable and multivariable-adjusted logistic regression analyses were employed to explore the relationship between H. pylori infection and pertinent covariates. Cox regression analysis, as well as restricted regression cubic spline analysis, were utilized to assess the association between DII and all-cause mortality among individuals with or without H. pylori infection. RESULTS: The findings demonstrated a positive correlation between DII scores and H. pylori infection, even after adjusting for potential confounding factors. Moreover, higher DII scores were significantly associated with an elevated risk of mortality exclusively in individuals with H. pylori infection, while no such association was observed in the uninfected population. Additional analysis using restricted cubic spline modeling revealed a positive linear relationship between DII scores as a continuous variable and the adjusted risk of all-cause mortality specifically in H. pylori-infected patients. CONCLUSION: The results of this study indicated that DII was positively correlated with an increased risk of H. pylori infection and was associated with a heightened risk of all-cause mortality solely in individuals with H. pylori infection. Consequently, DII might serve as a useful tool for risk stratification in the H. pylori-infected population among U.S. adults. Further research is warranted to elucidate the underlying mechanisms and potential clinical implications of these findings.

Molecular-Cling-Effect of Fluoroethylene Carbonate Characterized via Ethoxy(pentafluoro)cyclotriphosphazene on SiOx/C Anode Materials - A New Perspective for Formerly Sub-Sufficient SEI Forming Additive Compounds.

Effective electrolyte compositions are of primary importance in raising the performance of lithium-ion batteries (LIBs). Recently, fluorinated cyclic phosphazenes in combination with fluoroethylene carbonate (FEC) have been introduced as promising electrolyte additives, which can decompose to form an effective dense, uniform, and thin protective layer on the surface of electrodes. Although the basic electrochemical aspects of cyclic fluorinated phosphazenes combined with FEC were introduced, it is still unclear how these two compounds interact constructively during operation. This study investigates the complementary effect of FEC and ethoxy(pentafluoro)cyclotriphosphazene (EtPFPN) in aprotic organic electrolyte in LiNi0.5 Co0.2 Mn0.3 O ∥ SiOx /C full cells. The formation mechanism of lithium ethyl methyl carbonate (LEMC)-EtPFPN interphasial intermediate products and the reaction mechanism of lithium alkoxide with EtPFPN are proposed and supported by Density Functional Theory calculations. A novel property of FEC is also discussed here, called molecular-cling-effect (MCE). To the best knowledge, the MCE has not been reported in the literature, although FEC belongs to one of the most investigated electrolyte additives. The beneficial MCE of FEC toward the sub-sufficient solid-electrolyte interphase forming additive compound EtPFPN is investigated via gas chromatography-mass spectrometry, gas chromatography high resolution-accurate mass spectrometry, in situ shell-isolated nanoparticle-enhanced Raman spectroscopy, and scanning electron microscopy.

Research progress on pesticide residue detection based on microfluidic technology.

The problem of pesticide residue contamination has attracted widespread attention and poses a risk to human health. The current traditional pesticide residue detection methods have difficulty meeting rapid and diverse field screening requirements. Microfluidic technology integrates functions from sample preparation to detection, showing great potential for quick and accurate high-throughput detection of pesticide residues. This paper reviews the latest research progress on microfluidic technology for pesticide residue detection. First, the commonly used microfluidic materials are summarized, including silicon, glass, paper, polydimethylsiloxane, and polymethyl methacrylate. We evaluated their advantages and disadvantages in pesticide residue detection applications. Second, the current pesticide residue detection technology based on microfluidics and its application to real samples are summarized. Finally, we discuss this technology's present challenges and future research directions. This study is expected to provide a reference for the future development of microfluidic technology for pesticide residue detection.

The interplay between herbal medicines and gut microbiota in metabolic diseases.

Globally, metabolic diseases are becoming a major public health problem. Herbal medicines are medicinal materials or preparations derived from plants and are widely used in the treatment of metabolic diseases due to their good curative effects and minimal side effects. Recent studies have shown that gut microbiota plays an important role in the herbal treatment of metabolic diseases. However, the mechanisms involved are still not fully understood. This review provides a timely and comprehensive summary of the interactions between herbal medicines and gut microbiota in metabolic diseases. Mechanisms by which herbal medicines treat metabolic diseases include their effects on the gut microbial composition, the intestinal barrier, inflammation, and microbial metabolites (e.g., short-chain fatty acids and bile acids). Herbal medicines can increase the abundance of beneficial bacteria (e.g., Akkermansia and Blautia), reduce the abundance of harmful bacteria (e.g., Escherichia-Shigella), protect the intestinal barrier, and alleviate inflammation. In turn, gut microbes can metabolize herbal compounds and thereby increase their bioavailability and bioactivity, in addition to reducing their toxicity. These findings suggest that the therapeutic effects of herbal medicines on metabolic diseases are closely related to their interactions with the gut microbiota. In addition, some methods, and techniques for studying the bidirectional interaction between herbal medicines and gut microbiota are proposed and discussed. The information presented in this review will help with a better understanding of the therapeutic mechanisms of herbal medicines and the key role of gut microbiota.

Senkyunolide I: A Review of Its Phytochemistry, Pharmacology, Pharmacokinetics, and Drug-Likeness.

Senkyunolide I (SI) is a natural phthalide that has drawn increasing interest for its potential as a cardio-cerebral vascular drug candidate. In this paper, the botanical sources, phytochemical characteristics, chemical and biological transformations, pharmacological and pharmacokinetic properties, and drug-likeness of SI are reviewed through a comprehensive literature survey, in order to provide support for its further research and applications. In general, SI is mainly distributed in Umbelliferae plants, and it is relatively stable to heat, acid, and oxygen, with good blood-brain barrier (BBB) permeability. Substantial studies have established reliable methods for the isolation, purification, and content determination of SI. Its pharmacological effects include analgesic, anti-inflammatory, antioxidant, anti-thrombotic, anti-tumor effects, alleviating ischemia-reperfusion injury, etc. Pharmacokinetic parameters indicate that its metabolic pathway is mainly phase Ⅱ metabolism, and it is rapidly absorbed in vivo and widely distributed in the kidneys, liver, and lungs.

Association of triglyceride-glucose index with atherosclerotic cardiovascular disease and mortality among familial hypercholesterolemia patients.

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited metabolic disorder with a high level of low-density lipoprotein cholesterol and the worse prognosis. The triglyceride-glucose (TyG) index, an emerging tool to reflect insulin resistance (IR), is positively associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) in healthy individuals, but the value of TyG index has never been evaluated in FH patients. This study aimed to determine the association between the TyG index and glucose metabolic indicators, insulin resistance (IR) status, the risk of ASCVD and mortality among FH patients. METHODS: Data from National Health and Nutrition Examination Survey (NHANES) 1999-2018 were utilized. 941 FH individuals with TyG index information were included and categorized into three groups: < 8.5, 8.5-9.0, and > 9.0. Spearman correlation analysis was used to test the association of TyG index and various established glucose metabolism-related indicators. Logistic and Cox regression analysis were used to assess the association of TyG index with ASCVD and mortality. The possible nonlinear relationships between TyG index and the all-cause or cardiovascular death were further evaluated on a continuous scale with restricted cubic spline (RCS) curves. RESULTS: TyG index was positively associated with fasting glucose, HbA1c, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) index (all p < 0.001). The risk of ASCVD increased by 74% with every 1 unit increase of TyG index (95%CI: 1.15-2.63, p = 0.01). During the median 114-month follow-up, 151 all-cause death and 57 cardiovascular death were recorded. Strong U/J-shaped relations were observed according to the RCS results (p = 0.0083 and 0.0046 for all-cause and cardiovascular death). A higher TyG index was independently associated with both all-cause death and cardiovascular death. Results remained similar among FH patients with IR (HOMA-IR ≥ 2.69). Moreover, addition of TyG index showed helpful discrimination of both survival from all-cause death and cardiovascular death (p < 0.05). CONCLUSION: TyG index was applicable to reflect glucose metabolism status in FH adults, and a high TyG index was an independent risk factor of both ASCVD and mortality.

Revealing the Effect of High Ni Content in Li-Rich Cathode Materials: Mitigating Voltage Decay or Increasing Intrinsic Reactivity.

Li-rich layered oxides are considered as one of the most promising cathode materials for secondary lithium batteries due to their high specific capacities, but the issue of continuous voltage decay during cycling hinders their market entry. Increasing the Ni content in Li-rich materials is assumed to be an effective way to address this issue and attracts recent research interests. However, a high Ni content may induce increased intrinsic reactivity of materials, resulting in severe side reactions with the electrolyte. Thus, a comprehensive study to differentiate the two effects of the Ni content on the cell performance with Li-rich cathode is carried out in this work. Herein, it is demonstrated that a properly dosed amount of Ni can effectively suppress the voltage decay in Li-rich cathodes, while over-loading of Ni, on the contrary, can cause structural instability, Ni dissolution, and nonuniform Li deposition during cycling as well as severe oxygen loss. This work offers a deep understanding on the impacts of Ni content in Li-rich materials, which can be a good guidance for the future design of such cathodes for high energy density lithium batteries.

Serum glycolipids mediate the relationship of urinary bisphenols with NAFLD: analysis of a population-based, cross-sectional study.

BACKGROUND: Bisphenol A (BPA) and its substitutes bisphenol S (BPS) and bisphenol F (BPF) are endocrine-disrupting chemicals widely used in consumer products, which have been proposed to induce various human diseases. In western countries, one of the most common liver diseases is non-alcoholic fatty liver disease (NAFLD). However, studies on the associations of the three bisphenols with NAFLD in human beings are scarce. METHODS: We included 960 participants aged ≥ 20 years from the NHANES 2013-16 who had available data on levels of urinary BPA, BPS and BPF. The hepatic steatosis index (HSI) > 36 was used to predict NAFLD. Logistic regression analysis and mediation effect analysis were used to evaluate the associations among bisphenols, glycolipid-related markers and NAFLD. RESULTS: A total of 540 individuals (56.3%) were diagnosed with NAFLD, who had higher concentrations of BPA and BPS but not BPF than those without NAFLD. An increasing trend in NAFLD risks and HSI levels was observed among BPA and BPS tertiles (p for trend < 0.05). After adjustment for confounders, elevated levels of BPA or BPS but not BPF were significantly associated with NAFLD. The odds ratio for NAFLD was 1.581 (95% confidence intervals [CI]: 1.1-2.274, p = 0.013) comparing the highest with the lowest tertile of BPA and 1.799 (95%CI: 1.2462.597, p = 0.002) for BPS. Mediation effect analysis indicated that serum high-density lipoprotein cholesterol and glucose had a mediating effect on the relationships between bisphenols and NAFLD. CONCLUSIONS: The present study showed that high exposure levels of BPA and BPS increased NAFLD incidence, which might be mediated through regulating glycolipids metabolism. Further studies on the role of bisphenols in NAFLD are warranted.

Biobased Self-Growing Approach toward Tailored, Integrated High-Performance Flexible Lithium-Ion Battery.

Here we present an innovative, universal, scalable, and straightforward strategy for cultivating a resilient, flexible lithium-ion battery (LIB) based on the bacterial-based self-growing approach. The electrodes and separator layers are integrated intrinsically into one unity of sandwich bacterial cellulose integrated film (SBCIF), with various active material combinations and tailored mechanical properties. The flexible LIB thereof showcases prominent deformation tolerance and multistage foldability due to the unique self-generated wavy-like structure. The LTO|LFP (Li4Ti5O12 and LiFePO4) SBCIF-based flexible LIB demonstrates reliable long-term electrochemical stability with high flexibility, by exhibiting a high capacity retention (>95%) after 500 cycles at 1C/1C after experiencing a 10 000 bending/flattening treatment. The LTO|LFP SBCIF battery subjected to a simultaneous bending/flattening and cycling experiment shows an extraordinary capacity retention rate (>68%) after 200 cycles at 1C/1C. The biobased self-growing approach offers an exciting and promising pathway toward the tailored, integrated high-performance flexible LIBs.

Michael acceptor molecules in natural products and their mechanism of action.

Purpose: Michael receptor molecules derived from plants are biologically active due to electrophilic groups in their structure. They can target nucleophilic residues on disease-related proteins, with significant therapeutic effects and low toxicity for many diseases. They provide a good option for relevant disease treatment. The aim of this study is to summarize the existing MAMs and their applications, and lay a foundation for the application of Michael receptor molecules in life science in the future. Methods: This review summarizes the published studies on Michael receptor molecules isolated from plants in literature databases such as CNKI, Wanfang Data, PubMed, Web of Science, ScienceDirect, and Wiley. Latin names of plants were verified through https://www.iplant.cn/. All relevant compound structures were verified through PubChem and literature, and illustrated with ChemDraw 20.0. Result: A total of 50 Michael receptor molecules derived from various plants were discussed. It was found that these compounds have similar pharmacological potential, most of them play a role through the Keap1-Nrf2-ARE pathway and the NF-κB pathway, and have biological activities such as antioxidant and anti-inflammatory. They can be used to treat inflammatory diseases and tumors. Conclusion: The Michael receptor molecule has electrophilicity due to its unsaturated aldehyde ketone structure, which can combine with nucleophilic residues on the protein to form complexes and activate or inhibit the protein pathway to play a physiological role. Michael receptor molecules can regulate the Keap1-Nrf2-ARE pathway and the NF-κB pathway. Michael receptor molecules can be used to treat diseases such as inflammation, cancer, oxidative stress, etc.

Trimetazidine Reduces Cardiac Fibrosis in Rats by Inhibiting NOX2-Mediated Endothelial-to-Mesenchymal Transition.

Purpose: Endothelial-to-mesenchymal transition (EndMT) is an important mechanism underlying cardiac fibrosis. The anti-ischemic drug trimetazidine (TMZ) is reportedly useful in ventricular remodeling and associated with NADPH oxidase (NOX) 2. This study aimed to investigate the possible effect of TMZ on cardiac fibrosis exerted via the inhibition of NOX2-mediated EndMT. Methods: A cardiac fibrosis model was established in Sprague-Dawley rats through a subcutaneous injection of isoproterenol (ISO, 5 mg/kg/d). Echocardiographic parameters, myocardial fibrosis, NOX2 expression and EndMT were assessed. An in vitro model of EndMT was developed using human umbilical vein endothelial cells (HUVECs) via treatment with transforming growth factor-ß (TGF-ß) at 10 ng/mL for 24 h. HUVECs were administrated with TMZ or TMZ and lentivirus, the expression of EndMT and related proteins was observed by wound healing assay, immunoblotting, and immunofluorescence. Results: Rats injected with ISO exhibited severe interstitial cardiac fibrosis and perivascular fibrosis, decreased left ventricular ejection fraction, and increased NOX activity. TMZ treatment mitigated cardiac fibrosis, ameliorated left ventricular dysfunction, and reduced NOX activity. In addition, TMZ effectively inhibited EndMT in ISO-treated rat hearts and TGF-ß-treated HUVECs, as manifested by increased CD31 expression, decreased α-SMA expression, and suppressed cell migration. Compared with the control group, the expression of NOX2, nuclear factor-κB (NF-κB), and Snail was increased in vivo and in vitro but decreased with TMZ treatment. Furthermore, the overexpression of NOX2 by lentivirus abolished the protective effects of TMZ on TGF-ß-induced EndMT. Conclusion: TMZ may ameliorate EndMT and ISO-induced cardiac fibrosis through the NOX2/NF-κB/Snail pathway. The findings of the study may provide new insights into the potential role of TMZ in the pathophysiology of cardiac fibrosis.

Targeting HIC1/TGF-ß axis-shaped prostate cancer microenvironment restrains its progression.

Prostate cancer (PCa) is a malignant tumor that seriously threatens men's health worldwide. Recently, stromal cells in the tumor microenvironment (TME) have been reported to contribute to the progression of PCa. However, the role and mechanism of how PCa cells interact with stromal cells to reshape the TME remain largely unknown. Here, using a spontaneous prostate adenocarcinoma (PRAD) model driven by the loss of Pten and Hic1, we found that M2 macrophages markedly infiltrated the stroma of Pten and Hic1 double conditional knockout (dCKO) mice compared with those in control (Ctrl) mice due to higher TGF-ß levels secreted by HIC1-deleted PCa cells. Mechanistically, TGF-ß in TME promoted the polarization of macrophages into "M2" status by activating the STAT3 pathway and modulating c-Myc to upregulate CXCR4 expression. Meanwhile, TGF-ß activated the fibroblasts to form cancer-associated fibroblasts (CAFs) that secrete higher CXCL12 levels, which bound to its cognate receptor CXCR4 on M2 macrophages. Upon interaction with CAFs, M2 macrophages secreted more CXCL5, which promoted the epithelial-mesenchymal transition (EMT) of PCa via CXCR2. Moreover, using the TGF-ß receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-ß in HIC1-deficient PCa and was associated with the progression of PCa.

Gut microbiota-derived metabolites as key actors in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is one of the most risk factors threatening human health. Although genetic and environmental factors contribute to the development of T2DM, gut microbiota has also been found to be involved. Gut microbiota-derived metabolites are a key factor in host-microbe crosstalk, and have been revealed to play a central role in the physiology and physiopathology of T2DM. In this review, we provide a timely and comprehensive summary of the microbial metabolites that are protective or causative for T2DM, including some amino acids-derived metabolites, short-chain fatty acids, trimethylamine N-oxide, and bile acids. The mechanisms by which metabolites affect T2DM have been elaborated. Knowing more about these processes will increase our understanding of the causal relationship between gut microbiota and T2DM. Moreover, some frontier therapies that target gut microbes and their metabolites to improve T2DM, including dietary intervention, fecal microbiota transplantation, probiotics, prebiotics or synbiotics intervention, and drugging microbial metabolism, have been critically discussed. This review may provide novel insights for the development of targeted and personalized treatments for T2DM based on gut microbial metabolites. More high-quality clinical trials are needed to accelerate the clinical translation of gut-targeted therapies for T2DM.

Metabolic profiling in liver microsomes and mice of E28, a potent FLT3 inhibitor.

The objective of this study was to clarify the species differences of metabolic stability of E28 in liver microsomes, and to study metabolic phenotypes of E28 in human liver microsomes by chemical inhibition method.The metabolites in plasma, urine, and faeces samples from mice received caudal vein intravenous were detected and identified by UHPLC-HRMS, and the tissue distribution was studied after oral administration.E28 was metabolised rapidly in liver microsomes of each species with a short half-live T1/2 and a moderate clearance, except for rats. The metabolic properties of E28 were similar in human and mouse liver microsomes. Data from metabolic phenotype studies indicated that CYP2D6, CYP3A4 and CYP2C9 were the main metabolic enzymes participating in the metabolism of E28.The main metabolic pathways implicated include oxidation, methylation, amide hydrolysis, acetylation, glucuronide conjugation.Tissue distribution studies showed that E28 could be detected in all organs and tissues after oral administration, with the highest level in the stomach and the lowest in the brain. In bone marrow cells, the concentration of E28 in all sample points were consistently higher than its half inhibitory concentration against MV4-11 tumour cells.

Seabuckthorn Berries Extract Attenuates Pulmonary Vascular Hyperpermeability in Lipopolysaccharide-Induced Acute Lung Injury in Mice.

OBJECTIVE: To investigate the effect of seabuckthorn berries extract (SBE) on pulmonary vascular hyperpermeability in the mice model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). METHODS: Sixty Kunming mice were allocated into 6 groups by a random number table, including control, LPS, dexamethasone (Dex, 1 mg/kg), and 120, 240 and 480 mg/kg SBE groups, 10 mice in each group. Except the control group, mice were pre-treated with Dex and SBE, respectively, for 7 days before LPS was intraperitoneally injected to induce ALI. Pulmonary vascular hyperpermeability was evaluated by histopathologic observation and transvascular leakage determination. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels in serum were measured using enzyme-linked immunosorbent assay. The expression of nuclear factor-kappa B (NF-κB) p65 in lung cells was determined by immunofluorescence analysis. The contents of cytoplasmic inhibitor of nuclear factor-κB kinase (IKK) and nuclear p65, as well as downstream proteins of E-selectin (CD62E) and intercellular adhesion molecule-1 (ICAM-1), were determined using Western blot analysis. RESULTS: Histopathological observation confirmed SBE treatment alleviated morphological lesion induced by LPS. Compared with the LPS group, 480 mg/kg SBE significantly decreased the water content of lung, Evans blue accumulation in lung tissue, and protein concentration and neutrophils count in bronchoalveolar lavage fluid (P<0.01); moreover, 480 mg/kg SBE significantly suppressed release of TNF-α and IL-6, and down-regulated expressions of IKK, nuclear p65, ICAM-1 and CD62E (P<0.01). CONCLUSION: SBE maintained alveolar-capillary barrier integrity under endotoxin challenge in mice by suppressing the key factors in the pathogenesis of ALI.

Simultaneous Formation of Interphases on both Positive and Negative Electrodes in High-Voltage Aqueous Lithium-Ion Batteries.

The formation of solid-electrolyte interphase (SEI) in "water-in-salt" electrolyte (WiSE) expands the electrochemical stability window of aqueous electrolytes beyond 3.0 V. However, the parasitic hydrogen evolution reaction that drives anode corrosion, cracking, and the subsequent reformation of SEI still occurs, compromising long-term cycling performance of the batteries. To improve cycling stability, an unsaturated monomer acrylamide (AM) is introduced as an electrolyte additive, whose presence in WiSE reduces its viscosity and improves ionic conductivity. Upon charging, AM electropolymerizes into polyacrylamide, as confirmed both experimentally and computationally. The in situ polymer constitutes effective protection layers at both anode and cathode surfaces, and enables LiMn2 O4 ||L-TiO2 full cells with high specific capacity (157 mAh g-1 at 1 C), long-term cycling stability (80% capacity retention within 200 cycles at 1 C), and high rate capability (79 mAh g-1 at 30 C). The in situ electropolymerization found in this work provides an alternative and highly effective strategy to design protective interphases at the negative and positive electrodes for high-voltage aqueous batteries of lithium-ion or beyond.