Buqi Huoxue Tongnao prescription protects against chronic cerebral hypoperfusion via regulating PI3K/AKT and LXRα/CYP7A1 signaling pathways.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms. PURPOSE: To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo. METHODS: In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs. RESULTS: Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1ß, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process. CONCLUSION: In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH.

Tanreqing Injection Inhibits Activation of NLRP3 Inflammasome in Macrophages Infected with Influenza A Virus by Promoting Mitophagy.

OBJECTIVE: To investigate the inhibitory effect of Tanreqing Injection (TRQ) on the activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome in macrophages infected with influenza A virus and the underlying mechanism based on mitophagy pathway. METHODS: The inflammatory model of murine macrophage J774A.1 induced by influenza A virus [strain A/Puerto Rico/8/1934 (H1N1), PR8] was constructed and treated by TRQ, while the mitochondria-targeted antioxidant Mito-TEMPO and autophagy specific inhibitor 3-methyladenine (3-MA) were used as controls to intensively study the anti-inflammatory mechanism of TRQ based on mitophagy-mitochondrial reactive oxygen species (mtROS)-NLRP3 inflammasome pathway. The levels of NLRP3, Caspase-1 p20, microtubule-associated protein 1 light chain 3 II (LC3II) and P62 proteins were measured by Western blot. The release of interleukin-1ß (IL-1ß) was tested by enzyme linked immunosorbent assay, the mtROS level was detected by flow cytometry, and the immunofluorescence and co-localization of LC3 and mitochondria were observed under confocal laser scanning microscopy. RESULTS: Similar to the effect of Mito-TEMPO and contrary to the results of 3-MA treatment, TRQ could significantly reduce the expressions of NLRP3, Caspase-1 p20, and autophagy adaptor P62, promote the expression of autophagy marker LC3II, enhance the mitochondrial fluorescence intensity, and inhibit the release of mtROS and IL-1ß (all P<0.01). Moreover, LC3 was co-localized with mitochondria, confirming the type of mitophagy. CONCLUSION: TRQ could reduce the level of mtROS by promoting mitophagy in macrophages infected with influenza A virus, thus inhibiting the activation of NLRP3 inflammasome and the release of IL-1ß, and attenuating the inflammatory response.

Effects of Three Kinds of Carbohydrate Pharmaceutical Excipients-Fructose, Lactose and Arabic Gum on Intestinal Absorption of Gastrodin through Glucose Transport Pathway in Rats.

BACKGROUND: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway. METHODS: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry. RESULTS: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability. CONCLUSION: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.

TPP-Based Microfluidic Chip Design and Fabrication Method for Optimized Nerve Cells Directed Growth.

Microfluidic chips offer high customizability and excellent biocompatibility, holding important promise for the precise control of biological growth at the microscale. However, the microfluidic chips employed in the studies of regulating cell growth are typically fabricated through 2D photolithography. This approach partially restricts the diversity of cell growth platform designs and manufacturing efficiency. This paper presents a method for designing and manufacturing neural cell culture microfluidic chips (NCMC) using two-photon polymerization (TPP), where the discrete and directional cell growth is optimized through studying the associated geometric parameters of on-chip microchannels. This study involves simulations and discussions regarding the effects of different hatching distances on the mold surface topography and printing time in the Describe print preview module, which determines the appropriate printing accuracy corresponding to the desired mold structure. With the assistance of the 3D maskless lithography system, micron-level rapid printing of target molds with different dimensions were achieved. For NCMC with different geometric parameters, COMSOL software was used to simulate the local flow velocity and shear stress characteristics within the microchannels. SH-SY5Y cells were selected for directional differentiation experiments on NCMC with different geometric parameters. The results demonstrate that the TPP-based manufacturing method efficiently constructs neural microfluidic chips with high precision, optimizing the discrete and directional cell growth. We anticipate that our method for designing and manufacturing NCMC will hold great promise in construction and application of microscale 3D drug models.

Pilose antler extract promotes hair growth in androgenic alopecia mice by promoting the initial anagen phase.

Androgenetic alopecia (AGA) is a prevalent disease in worldwide, local application or oral are often used to treat AGA, however, effective treatments for AGA are currently limited. In this work, we observed the promoting the initial anagen phase effect of pilose antler extract (PAE) on hair regeneration in AGA mice. We found that PAE accelerated hair growth and increased the degree of skin blackness by non-invasive in vivo methods including camera, optical coherence tomography and dermoscopy. Meanwhile, HE staining of sagittal and coronal skin sections revealed that PAE augmented the quantity and length of hair follicles, while also enhancing skin thickness and hair papilla diameter. Furthermore, PAE facilitated the shift of the growth cycle from the telogen to the anagen phase and expedited the proliferation of hair follicle stem cells and matrix cells in mice with AGA. This acceleration enabled the hair follicles to enter the growth phase at an earlier stage. PAE upregulated the expression of the sonic hedgehog (SHH), smoothened receptor, glioma-associated hemolog1 (GLI1), and downregulated the expression of bone morphogenetic protein 4 (BMP4), recombinant mothers against decapentaplegic homolog (Smad) 1 and 5 phosphorylation. This evidence suggests that PAE fosters hair growth and facilitates the transition of the growth cycle from the telogen to the anagen phase in AGA mice. This effect is achieved by enhancing the proliferation of follicle stem cells and matrix cells through the activation of the SHH/GLI pathway and suppression of the BMP/Smad pathway.

Seasonal dynamics of the microbial community in a strong-flavor baijiu fermentation.

BACKGROUND: The microbial community plays a crucial role in Chinese strong-flavor baijiu (SFB) fermentation. However, the seasonal dynamics of the microbial community in the SFB fermentation system and its contribution to the unique flavor of SFB have not been fully elucidated. In this study, we investigated the seasonal dynamics of the microbial community through 16S rRNA and ITS gene sequencing. RESULTS: The results revealed significant temporal dynamics of microbial communities and environmental variables throughout the four seasons. The influence of seasons on fungal communities was found to be more significant than on bacterial communities. The diversity of bacteria was higher during the winter and summer, whereas fungal diversity was more prominent in summer and autumn. Stochastic processes maintained their dominance in microbial assembly throughout all four seasons but the significance of heterogeneous selection increased during summer for both bacteria and fungi, whereas homogeneous selection became more pronounced during winter for fungi. The pH and environmental temperature were important drivers of microbial community assembly across different seasons, primarily impacting the core genera responsible for the production of major volatile flavor compounds (VFCs), especially ethyl caproate. CONCLUSION: These findings provide new insights into the impact of seasons on microbial communities and hold promise for improving the quality-control measures for SFB brewed in different seasons. © 2024 Society of Chemical Industry.

The longitudinal relationship between loneliness and both social anxiety and mobile phone addiction among rural left-behind children: A cross-lagged panel analysis.

INTRODUCTION: Left-behind children are a special group that needs urgent attention. Due to enduring separation from their parents, loneliness is considered the most common and prevalent developmental hurdle in the experiences of left-behind children. This longitudinal cross-lagged study examined the direction of the association between loneliness and both internalizing and externalizing symptoms, with considering gender and left-behind status differences. METHODS: A total of 1175 rural Chinese children (48.3% boys, 39.9% left-behind children, Mage = 14.54 ± 1.18 at baseline) completed self-reported loneliness, social anxiety, and mobile phone addiction at two-time points with 6 months intervals. Descriptive statistics, cross-lagged panel analysis, and multiple group analysis were estimated in the present study. RESULTS: Loneliness exacerbated social anxiety and mobile phone addiction, and vice versa. In addition, gender and left-behind status moderated these relationships, with boys more likely to be mobile phone addicted due to loneliness and girls more likely to be lonely due to mobile phone addiction. More importantly, left-behind children with loneliness are more prone to social anxiety and mobile phone addiction, and vice versa, compared with non-left-behind children. CONCLUSIONS: The targeted interventions should be carried out for different genders and left-behind statuses. Particularly for left-behind children, neglecting to address both the symptoms of loneliness and both social anxiety and mobile phone addiction could significantly undermine the efficacy of intervention programs that solely target either one of these afflictions.

A cytochrome c551 mediates the cyclic electron transport chain of the anoxygenic phototrophic bacterium Roseiflexus castenholzii.

Roseiflexus castenholzii is a gram-negative filamentous phototrophic bacterium that carries out anoxygenic photosynthesis through a cyclic electron transport chain (ETC). The ETC is composed of a reaction center (RC)-light-harvesting (LH) complex (rcRC-LH); an alternative complex III (rcACIII), which functionally replaces the cytochrome bc1/b6f complex; and the periplasmic electron acceptor auracyanin (rcAc). Although compositionally and structurally different from the bc1/b6f complex, rcACIII plays similar essential roles in oxidizing menaquinol and transferring electrons to the rcAc. However, rcACIII-mediated electron transfer (which includes both an intraprotein route and a downstream route) has not been clearly elucidated, nor have the details of cyclic ETC. Here, we identify a previously unknown monoheme cytochrome c (cyt c551) as a novel periplasmic electron acceptor of rcACIII. It reduces the light-excited rcRC-LH to complete a cyclic ETC. We also reveal the molecular mechanisms involved in the ETC using electron paramagnetic resonance (EPR), spectroelectrochemistry, and enzymatic and structural analyses. We find that electrons released from rcACIII-oxidized menaquinol are transferred to two alternative periplasmic electron acceptors (rcAc and cyt c551), which eventually reduce the rcRC to form the complete cyclic ETC. This work serves as a foundation for further studies of ACIII-mediated electron transfer in anoxygenic photosynthesis and broadens our understanding of the diversity and molecular evolution of prokaryotic ETCs.

Asperulosidic Acid Ameliorates Renal Interstitial Fibrosis via Removing Indoxyl Sulfate by Up-Regulating Organic Anion Transporters in a Unilateral Ureteral Obstruction Mice Model.

Asperulosidic acid is a bioactive iridoid isolated from Hedyotis diffusa Willd. with anti-inflammatory and renal protective effects. However, its mechanism on renal interstitial fibrosis has not been elucidated yet. The present study aims to explore whether asperulosidic acid could retard renal fibrosis by reducing the circulating indoxyl sulfate (IS), which is a uremic toxin and accelerates chronic kidney disease progression by inducing renal fibrosis. In this paper, a unilateral ureteral obstruction (UUO) model of Balb/C mice was established. After the mice were orally administered with asperulosidic acid (14 and 28 mg/kg) for two weeks, blood, liver and kidney were collected for biochemical, histological, qPCR and Western blot analyses. Asperulosidic acid administration markedly reduced the serum IS level and significantly alleviated the histological changes in glomerular sclerosis and renal interstitial fibrosis. It is noteworthy that the mRNA and protein levels of the organic anion transporter 1 (OAT1), OAT3 and hepatocyte nuclear factor 1α (HNF1α) in the kidney were significantly increased, while the mRNA expressions of cytochrome P450 2e1 (Cyp2e1) and sulfotransferase 1a1 (Sult1a1) in the liver were not altered after asperulosidic acid administration. These results reveal that asperulosidic acid could accelerate the renal excretion of IS by up-regulating OATs via HNF1α in UUO mice, thereby alleviating renal fibrosis, but did not significantly affect its production in the liver, which might provide important information for the development of asperulosidic acid.

The response of LncRNAs associated with photosynthesis-and pigment synthesis-related genes to green light in Chlamydomonas reinhardtii.

The quality of light is an important abiotic factor that affects the growth and development of green plants. Ultraviolet, red, blue, and far-red light all have demonstrated roles in regulating green plant growth and development, as well as light morphogenesis. However, the mechanism underlying photosynthetic organism responses to green light throughout the life of them are not clear. In this study, we exposed the unicellular green alga Chlamydomonas reinhardtii to green light and analyzed the dynamics of transcriptome changes. Based on the whole transcriptome data from C. reinhardtii, a total of 9974 differentially expressed genes (DEGs) were identified under green light. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these DEGs were mainly related to "carboxylic acid metabolic process," "enzyme activity," "carbon metabolism," and "photosynthesis and other processes." At the same time, 253 differentially expressed long non-coding RNAs (DELs) were characterized as green light responsive. We also made a detailed analysis of the responses of photosynthesis- and pigment synthesis-related genes in C. reinhardtii to green light and found that these genes exhibited obvious dynamic expression. Lastly, we constructed a co-expression regulatory network, comprising 49 long non-coding RNAs (lncRNAs) and 20 photosynthesis and pigment related genes, of which 9 mRNAs were also the predicted trans/cis-targets of 8 lncRNAs, these results suggested that lncRNAs may affect the expression of mRNAs related to photosynthesis and pigment synthesis. Our findings give a preliminary explanation of the response mechanism of C. reinhardtii to green light at the transcriptional level.

Non-invasive assessment of hair regeneration in androgenetic alopecia mice in vivo using two-photon and second harmonic generation imaging.

The identification of crucial targets for hair regrowth in androgenetic alopecia (AGA) involves determining important characteristics and different stages during the process of hair follicle regeneration. Traditional methods for assessing key features and different stages of hair follicle primarily involve taking skin tissue samples and determining them through various staining or other methods. However, non-invasive assessment methods have been long sought. Therefore, in this study, endogenous fluorescence signals from skin keratin and second harmonic signals from skin collagen fibers were utilized as probes, two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) imaging techniques were employed to non-invasively assess hair shafts and collagen fibers in AGA mice in vivo. The TPEF imaging technique revealed that the alternation of new and old hair shafts and the different stages of the growth period in AGA mice were delayed. In addition, SHG imaging found testosterone reduced hair follicle area and miniaturized hair follicles. The non-invasive TPEF and SHG imaging techniques provided important methodologies for determining significant characteristics and different stages of the growth cycle in AGA mice, which will facilitate future non-invasive assessments on human scalps in vivo and reduce the use of animal testing.

Highly selective and sensitive determination of doxycycline integrating enrichment with thermosensitive magnetic molecular imprinting nanomaterial and carbon dots based fluorescence probe.

Doxycycline (DOX), a typical tetracycline antibiotic, is widely used because of its excellent antibacterial activity. To develop effective method for DOX has attracted much more attention. Herein, a new detection technology integrating magnetic solid phase extraction (MSPE) based on thermosensitive magnetic molecularly imprinted polymers (T-MMIPs) and fluorescence spectrometry based on carbon dots (CDs) was established. Thermosensitive magnetic molecularly imprinted polymers (T-MMIPs) was designed for selective enrichment of trace DOX. The synthesized T-MMIPs showed excellent selectivity for DOX. The adsorption performance of T-MMIPs varied with temperature in different solvents, which could achieve the enrichment and rapid desorption of DOX. In addition, the synthesized CDs had stable fluorescent property and better water-solubility, and the fluorescence of CDs was significantly quenched by DOX due to the internal filtration effect (IFE). Under the optimized conditions, the method resulted in good linearity over the range from 0.5 to 30 µg L-1, and the limit of detection was 0.2 µg L-1. The constructed detection technology was validated with real water samples, and excellent spiked recoveries from 92.5 % to 105.2 % were achieved. These data clearly indicated that the proposed technology was rapid, highly selective, environmentally friendly, and possessed significant potential application and development prospects.

The Extract of Scutellaria baicalensis Attenuates the Pattern Recognition Receptor Pathway Activation Induced by Influenza A Virus in Macrophages.

The dual strategy of inhibiting the viral life cycle and reducing the host inflammatory response should be considered in the development of therapeutic drugs for influenza A virus (IAV). In this study, an extract of Scutellaria baicalinase (SBE) containing seven flavonoids was identified to exert both antiviral and anti-inflammatory effects in macrophages infected with IAV. We performed transcriptome analysis using high-throughput RNA sequencing and identified 315 genes whose transcription levels were increased after IAV infection but were able to be decreased after SBE intervention. Combined with Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, these genes were mainly involved in TLR3/7/8, RIG-I/MDA5, NLRP3 and cGAS pattern recognition receptor (PRR)-mediated signaling pathways. SBE inhibited the transcription of essential genes in the above pathways and nuclear translocation of NF-κB p65 as confirmed by RT-qPCR and immunofluorescence, respectively, indicating that SBE reversed PR8-induced over-activation of the PRR signaling pathway and inflammation in macrophages. This study provides an experimental basis for applying Scutellaria baicalensis and its main effects in the clinical treatment of viral pneumonia. It also provides novel targets for screening and developing novel drugs to prevent and treat IAV infectious diseases.

Potential herb‒drug interactions between anti-COVID-19 drugs and traditional Chinese medicine.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence, hospitalization, and mortality. At present, antiviral drugs including Nirmatrelvir/Ritonavir (PaxlovidTM), Remdesivir, and Molnupiravir have been authorized to treat COVID-19 and become more globally available. On the other hand, traditional Chinese medicine (TCM) has been used for the treatment of epidemic diseases for a long history. Currently, various TCM formulae against COVID-19 such as Qingfei Paidu decoction, Xuanfei Baidu granule, Huashi Baidu granule, Jinhua Qinggan granule, Lianhua Qingwen capsule, and Xuebijing injection have been widely used in clinical practice in China, which may cause potential herb-drug interactions (HDIs) in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines. However, information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking, and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19, and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters. These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.

Modified Erchen decoction ameliorates cognitive dysfunction in vascular dementia rats via inhibiting JAK2/STAT3 and JNK/BAX signaling pathways.

BACKGROUND: Vascular dementia (VaD) is one of the most common clinical syndromes of progressive neurocognitive dysfunction with uncertain mechanisms. Modified Erchen decoction (MECD), developed from "Erchen decoction (ECD)" recorded in "Taiping Huimin Heji Jufang", showed a good effect in the treatment of VaD. However, its therapeutic mechanism is still unclear. PURPOSE: This study aimed to elucidate the multi-target mechanisms of MECD against VaD in vivo and in vitro. METHODS: VaD model was established by two-vessel obstruction (2-VO) in Sprague-Dawley rats. Six groups, including the control, 2-VO operation, MECD treatment (2.5, 5.0 and 10.0 g kg-1 d-1), donepezil hydrochloride (positive control, 0.45 g kg-1 d-1) were designed in the whole experiment. After oral administration for 4 weeks, the effects of MECD were verified by behavioral experiments, histological observation, and biochemical index analysis. The chemical profiling of MECD was performed by UHPLC-Orbitrap Fusion-HRMS, and a "compound-target-pathway" multivariate network was constructed to validate and elucidate its pharmacological mechanisms. RESULTS: Compared with 2-VO group, MECD treatment significantly alleviated anxiety and improved spatial memory in VaD rats according to the open field test (OFT) and Y-maze test. A significant increase in neuron number was observed from hematoxylin and eosin (H&E) stained images in cornu ammonis 1 (CA1) of the hippocampal region after MECD treatment. On the one hand, MECD reduced the plasma levels of triglyceride (TG), low-density lipoprotein (LDL), malondialdehyde (MDA), and amyloid-beta 42 (Aß42), and inhibited mRNA expression of interleukin-1 beta (Il-1ß) and Il-6 in the hippocampus. On the other hand, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly increased after treatment with MECD. Moreover, MECD reduced the mRNA expression and protein expression of janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and BCL2-associated X (BAX) in the brain of 2-VO rats. Furthermore, 71 compounds were identified from the extract of MECD. Among them, liquiritin and isochlorogenic acid C gave inhibiting effects on the mRNA expression of Jnk. In addition, liquiritin and hesperetin were conformed with the inhibition of Jak2 transcription level in vitro experiments. CONCLUSION: MECD has demonstrated a significant amelioration effect on cognitive dysfunction in VaD rats via JAK2/STAT3 and JNK/BAX signaling pathways, which represents an innovative insight into the "activate blood and eliminate phlegm" theory.

Dingxin recipe â ¢ ameliorates hyperlipidemia injury in SD rats by improving the gut barrier, particularly the SCFAs/GPR43 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dingxin Recipe Ⅲ (DXR Ⅲ) is a traditional Chinese medicine compound used for hyperlipidemia treatment in clinical practice. However, its curative effects and pharmacological mechanisms in hyperlipidemia have not been clarified to date. AIM OF THE STUDY: Studies have demonstrated that gut barrier was strongly implicated in lipid deposition. Based on gut barrier and lipid metabolism, this study examined the effects and molecular mechanisms of DXR Ⅲ in hyperlipidemia. MATERIALS AND METHODS: The bioactive compounds of DXR Ⅲ were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and its effects were evaluated in high-fat diet-fed rats. Specifically, the serum levels of lipids and hepatic enzymes were measured using the appropriate kits; colon and liver sections were obtained for histological analyses; gut microbiota and metabolites were analyzed by 16S rDNA sequencing and liquid chromatography-MS/MS; and the expression of genes and proteins was determined by real-time quantitative polymerase chain reaction and western blotting and immunohistochemistry, respectively. The pharmacological mechanisms of DXR Ⅲ were further explored by fecal microbiota transplantation and short-chain fatty acid (SCFAs)-based interventions. RESULTS: DXR Ⅲ treatment significantly downregulated serum lipid levels, mitigated hepatocyte steatosis and improved lipid metabolism. Moreover, DXR Ⅲ improved the gut barrier, specifically by improving the physical barrier in the colon, causing part composition changes in the gut microbiota, and increasing the serum SCFAs level. DXR Ⅲ also upregulated the expression of colon GPR43/GPR109A. Fecal microbiota transplantation from rats treated with DXR Ⅲ downregulated part hyperlipidemia-related phenotypes, while the SCFAs intervention significantly improved most of the hyperlipidemia-related phenotypes and upregulated the expression of GPR43. Moreover, both DXR Ⅲ and SCFAs upregulated the expression of colon ABCA1. CONCLUSION: DXR Ⅲ protects against hyperlipidemia by improving the gut barrier, particularly the SCFAs/GPR43 pathway.

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

Bioinformatics prediction and experimental verification of a novel microRNA for myocardial fibrosis after myocardial infarction in rats.

Background: MicroRNAs (miRNAs) are endogenous noncoding single-stranded small RNAs. Numerous studies have shown that miRNAs have pivotal roles in the occurrence and development of myocardial fibrosis (MF). However, miRNA expression profile in rats with MF after myocardial infarction (MI) is not well understood. The present study aimed to find the potential miRNA for MF post MI. Methods: SPF male Sprague-Dawley (SD) rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. Hematoxylin-eosin and Masson trichrome staining were used to detect myocardial histopathological changes for model evaluation. The differentially expressed miRNAs were detected by using the Agilent Rat miRNA gene chip in the myocardial tissue of the infarct marginal zone. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed by DAVID. The expression of miR-199a-5p was verified by real-time fluorescence quantitative PCR (qRT-PCR). Transfected miR-199a-5p mimics into cardiac fibroblasts (CFs) to construct cell models of miR-199a-5p overexpression. Dual-luciferase reporter assay was employed to validate the target gene of miR-199a-5p. The protein expression of the target gene in CFs transfected with miR-199a-5p mimics were detected by Western blot. Results: Myocardial fibrosis was exacerbated in the model group compared with the control group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3ß. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3ß was decreased in CFs transfected with miR-199a-5p mimics. Conclusion: Our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3ß, which provides novel targets for diagnosis and treatment of MF.

Water Electrolysis toward Elevated Temperature: Advances, Challenges and Frontiers.

Since severe global warming and related climate issues have been caused by the extensive utilization of fossil fuels, the vigorous development of renewable resources is needed, and transformation into stable chemical energy is required to overcome the detriment of their fluctuations as energy sources. As an environmentally friendly and efficient energy carrier, hydrogen can be employed in various industries and produced directly by renewable energy (called green hydrogen). Nevertheless, large-scale green hydrogen production by water electrolysis is prohibited by its uncompetitive cost caused by a high specific energy demand and electricity expenses, which can be overcome by enhancing the corresponding thermodynamics and kinetics at elevated working temperatures. In the present review, the effects of temperature variation are primarily introduced from the perspective of electrolysis cells. Following an increasing order of working temperature, multidimensional evaluations considering materials and structures, performance, degradation mechanisms and mitigation strategies as well as electrolysis in stacks and systems are presented based on elevated temperature alkaline electrolysis cells and polymer electrolyte membrane electrolysis cells (ET-AECs and ET-PEMECs), elevated temperature ionic conductors (ET-ICs), protonic ceramic electrolysis cells (PCECs) and solid oxide electrolysis cells (SOECs).

Manganese Prussian blue nanozymes with antioxidant capacity prevent acetaminophen-induced acute liver injury.

As one of the leading cases of acute liver failure triggered by excessive Acetaminophen (APAP), breakdown of the antioxidant system, inflammatory response, and inescapable apoptosis following overaccumulation of reactive oxygen species (ROS) play crucial roles in the mechanisms of APAP-induced liver injury (AILI). Therefore, cutting off ROS overproduction at the source is considered promising. Here, manganese Prussian blue nanozymes (MPBZs) with superior antioxidant enzyme-like activity are prepared as an effective strategy for hepatocyte protection, in which MPBZs accumulated in the liver show anti-oxidation properties by scavenging superfluous ROS. Importantly, in addition to alleviating oxidative stress, bioactive MPBZs with abundant variable valence states as a natural antioxidant enzymes mediated the responses of multi-biological signaling pathways in vitro and in vivo, including Nrf2-Keap1, NF-κB, and mitochondrial-induced apoptosis signaling pathways, enhancing tolerance for imminent AILI. Taking nanomedicine, hepatology, and catalytic chemistry into consideration, the revealed superior performance of AILI prevention suggests that MPBZ-based nano-detoxification therapy may offer an effective alternative against AILI.