Glycosylphosphatidylinositol anchor lipid remodeling directs proteins to the plasma membrane and governs cell wall mechanics.

Glycosylphosphatidylinositol (GPI) anchoring is a common protein modification that targets proteins to the plasma membrane (PM). Knowledge about the GPI lipid tail, which guides the secretion of GPI-anchored proteins (GPI-APs), is limited in plants. Here, we report that rice (Oryza sativa) BRITTLE CULM16 (BC16), a membrane-bound O-acyltransferase (MBOAT) remodels GPI lipid tails and governs cell wall biomechanics. The bc16 mutant exhibits fragile internodes, resulting from reduced cell wall thickness and cellulose content. BC16 is the only MBOAT in rice and is located in the endoplasmic reticulum and Golgi apparatus. Yeast gup1Δ mutant restoring assay and GPI lipid composition analysis demonstrated BC16 as a GPI lipid remodelase. Loss of BC16 alters GPI lipid structure and disturbs the targeting of BC1, a GPI-AP for cellulose biosynthesis, to the PM lipid nanodomains. Atomic force microscopy revealed compromised deposition of cellulosic nanofibers in bc16, leading to an increased Young's modulus and abnormal mechanical properties. Therefore, BC16-mediated lipid remodeling directs the GPI-APs, such as BC1, to the cell surface to fulfill multiple functions, including cellulose organization. Our work unravels a mechanism by which GPI lipids are remodeled in plants and provides insights into the control of cell wall biomechanics, offering a tool for breeding elite crops with improved support strength.

Effects of different natural products in patients with non-alcoholic fatty liver disease-A network meta-analysis of randomized controlled trials.

Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.

Synthesis and Characterizations of MoS2 Nanoflowers and Spectroscopic Study of their Interaction with Bovine Serum Albumin.

Molybdenum disulfide nanoflowers (MoS2 NFs) were prepared by hydrothermal method. The prepared MoS2 NFs was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), specific surface areas, Raman and X-ray photoelectron spectroscopy (XPS). The characterization results show that the flower-like spherical MoS2 is composed of many ultra-thin nanosheets with an average diameter of about 300-400 nm. MoS2 NFs also exhibits excellent UV-vis absorption and high fluorescence intensity. In order to explore the biological behavior of MoS2 NFs, the interaction between MoS2 NFs and bovine serum albumin (BSA) was studied by UV-Vis absorption, fluorescence, synchronous fluorescence spectra, and cyclic voltammetry. The results of absorption and fluorescence show that MoS2 NFs and BSA interact strongly through the formation of complexes in the ground state, and the static quenching is the main mechanism. The Stern-Volmer constant and the quenching constant was calculated about 3.79×107 L mol-1 and 3.79×1015 L mol-1 s-1, respectively. The synchronous fluorescence implied that MoS2 in the complex may mainly bind to tryptophan residues of BSA. The cyclic voltammograms indicated that the addition of BSA makes electron reduction of MoS2 NFs more difficult than the corresponding free state. The results show that hydrophobic forces play a major role in the binding interaction between BSA and MoS2 NFs.

The effect of hyperthyroidism on cognitive function, neuroinflammation, and necroptosis in APP/PS1 mice.

BACKGROUND: Increasing evidence has linked the thyroid dysfunction to the pathogenesis of dementia. Evidence from clinical studies has demonstrated that hypothyroidism is related to an increased risk of dementia. But the association of hyperthyroidism with dementia is largely unknown. METHODS: We used the adenovirus containing thyrotropin receptor (TSHR) amino acid residues 1-289 (Ad-TSHR289)-induced Graves' disease (GD) phenotype in Alzheimer's disease (AD) model mice (APP/PS1 mice) to evaluate the effect of hyperthyroidism on the cognitive function and ß-amyloid (Aß) accumulation. RESULTS: GD mice exhibited a stable long-term hyperthyroidism and cognitive deficits. Single Cell RNA-sequencing analysis indicated that microglia function played a critical role in the pathophysiological processes in GD mice. Neuroinflammation and polarization of microglia (M1/M2 phenotype) and activated receptor-interacting serine/threonine protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudo-kinase (MLKL)-mediated necroptosis contributed to the pathological process, including Aß deposition and neuronal loss. RIPK3 inhibitor could inhibit GD-mediated Aß accumulation and neuronal loss. CONCLUSIONS: Our findings reveal that GD hyperthyroidism aggravates cognitive deficits in AD mice and induces Aß deposition and neuronal loss by inducing neuroinflammation and RIPK3/MLKL-mediated necroptosis.

Abnormal Local Brain Activity and Cognitive Impairments in Young Non-Disabled Patients With Intracerebral Hemorrhage: A Resting-State Functional MRI Study.

BACKGROUND: Resting-state functional MRI (rs-fMRI) has identified static changes of local brain activity among patients with intracerebral hemorrhage (ICH). However, the dynamic and concordance-related characteristics of brain activity remain unclear. PURPOSE: To investigate static, dynamic, and concordance-related features of the regional brain activity of young non-disabled ICH patients. STUDY TYPE: Prospective. SUBJECTS: Thirty-three ICH patients (modified Rankin Scale score ≤2, 21% female, 46.36 ± 6.53) and 33 matched healthy controls (HCs) (21% female, 47.64 ± 6.16). FIELD STRENGTH/SEQUENCE: 3-T, rs-fMRI using gradient echo-planar imaging, T1-weighted imaging. ASSESSMENT: Neuropsychological and rs-fMRI data were acquired from all participants. Amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity, global signal correlation (GSCorr) and degree centrality (DC), and their dynamic and concordance-related changes with sliding window analysis were calculated based on rs-fMRI data at a whole-brain level. The burden of cerebral small vascular diseases (cSVD) was assessed by cSVD scores. All hemorrhage lesions were delineated on normalized T1 images. STATISTICAL TESTS: Multiple regression models, a voxel-level uncorrected P < 0.001, a cluster-level false discovery rate (FDR) corrected q < 0.05, a re-corrected qFDR <0.05 were considered significant. Pearson or Spearman correlation analyses between fMRI data and neurocognitive performance were performed. RESULTS: Compared to HCs, ICH patients showed significant abnormal changes of ALFF, dynamic ALFF, fALFF, ReHo, dynamic ReHo, GSCorr, DC, and voxel-wise concordance in multiple brain regions mainly including the bilateral cerebellar hemispheres, ipsilesional thalamus, and bilateral middle cingulum gyrus. The ALFF in the cerebellar posterior lobe and thalamus were significantly associated with attention (r = -0.481) and executive function (rho = -0.521) in ICH patients. DATA CONCLUSION: Young non-disabled ICH patients exhibit static, dynamic, and concordance-related alterations of local brain activity, part of which shows associations with cognitive functions. These findings may help comprehensively understand the mechanism of cognitive impairment after ICH. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Competing endogenous RNA network construction based on long non-coding RNAs, microRNAs, and mRNAs related to fat deposition in Songliao black swine.

China has a long history of pig breeding and a number of local breeds. The Songliao Black pig, bred in China in 2009, shows high variation in backfat thickness and therefore is well-suited to fat deposition research. Fat deposition is a complex trait, and the underlying regulatory factors are not fully characterized. In this study, the molecular basis of fat deposition traits was evaluated by comparisons between three individuals with extremely high-backfat thickness and three with extremely low-backfat thickness selected from 53 gilts. Subcutaneous adipose tissues of the back were collected for strand-specific library RNA sequencing (RNA-seq) and small RNA-seq. We identified 13 184 mRNAs, 2046 long non-coding (lnc)RNAs, and 494 micro (mi)RNAs by high-throughput sequencing. Furthermore, we detected 150 differentially expressed mRNAs, 66 differentially expressed lncRNAs, and eight differentially expressed miRNAs. A functional enrichment analysis indicated that these genes are involved in multiple fat metabolism-related pathways, including positive regulation of fat cell differentiation, and fat digestion and absorption. We used various algorithms (miRanda, TargetScan, and RNAhybrid) to predict targeting relationships and constructed a competing endogenous RNA network containing seven lncRNAs, three miRNAs, and six mRNAs. All these genes were differentially expressed between the extremely high and low backfat thickness groups or enriched in pathways related to fat metabolism. Our results provide insight into the regulatory mechanisms by which non-coding RNAs and their target genes influence backfat deposition in pigs. Furthermore, our newly constructed competing endogenous RNA (lncRNA-miRNA-mRNA) network provides a basis for further exploration of fat deposition traits and non-coding RNA functions.

N6-methyladenosine methylation regulator RBM15 promotes the progression of diabetic nephropathy by regulating cell proliferation, inflammation, oxidative stress, and pyroptosis through activating the AGE-RAGE pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world, and m6A modification plays a critical role in the progression of DN. We aimed to find m6A-related genes and their regulatory mechanisms in DN. METHODS: The expression levels of four important m6A-related genes (METTL16, RBM15, IGF2BP1, and ALKBH5) were detected by quantitative real-time PCR (RT-qPCR). RBM15 was chosen and its function was explored. The downstream pathway of RBM15 was screened by transcriptome sequencing. The levels of AGE, inflammation, and oxidative stress were determined with enzyme-linked immunosorbent assay, and the expression of AGE-RAGE pathway-related proteins were detected by Western blot (WB). Cell proliferation was assessed by Cell counting Kit-8 (CCK-8). The levels of pyroptosis-related proteins were evaluated by RT-qPCR or WB. RESULTS: METTL16 and RBM15 were up regulated in the mouse model of DN, in which RBM15 was more significant. Silencing RBM15 recovered cell proliferation, reduced the levels of inflammation factors, and inhibited cell pyroptosis in high glucose-induced HK-2 cells. Transcriptome sequencing suggested that the AGE-RAGE pathway might be downstream of RBM15. RBM15 knockdown reduced AGE level and the expression of AGE-RAGE pathway-related proteins. After silencing RBM15, we found that activating the AGE-RAGE pathway inhibited cell proliferation, increased the levels of inflammation factors, promoted oxidative stress, and induced cell pyroptosis in HK-2 cell model of DN. CONCLUSION: The m6A-related gene RBM15 inhibited cell proliferation, promoted inflammation, oxidative stress, and cell pyroptosis, thereby facilitating the progression of DN through the activation of the AGE-RAGE pathway.

Heteromerization of short-chain trans-prenyltransferase controls precursor allocation within a plastidial terpenoid network.

Terpenes are the largest and most diverse class of plant specialized metabolites. Sesterterpenes (C25), which are derived from the plastid methylerythritol phosphate pathway, were recently characterized in plants. In Arabidopsis thaliana, four genes encoding geranylfarnesyl diphosphate synthase (GFPPS) (AtGFPPS1 to 4) are responsible for the production of GFPP, which is the common precursor for sesterterpene biosynthesis. However, the interplay between sesterterpenes and other known terpenes remain elusive. Here, we first provide genetic evidence to demonstrate that GFPPSs are responsible for sesterterpene production in Arabidopsis. Blockage of the sesterterpene pathway at the GFPPS step increased the production of geranylgeranyl diphosphate (GGPP)-derived terpenes. Interestingly, co-expression of sesterTPSs in GFPPS-OE (overexpression) plants rescued the phenotypic changes of GFPPS-OE plants by restoring the endogenous GGPP. We further demonstrated that, in addition to precursor (DMAPP/IPP) competition by GFPPS and GGPP synthase (GGPPS) in plastids, GFPPS directly decreased the activity of GGPPS through protein-protein interaction, ultimately leading to GGPP deficiency in planta. Our study provides a new regulatory mechanism of the plastidial terpenoid network in plant cells.

[Effect of diosgenin on mTOR/FASN/HIF-1α/VEGFA expression in rats with non-alcoholic fatty liver disease].

The present study aimed to investigate the effect of diosgenin on mammalian target of rapamycin(mTOR), fatty acid synthase(FASN), hypoxia inducible factor-1α(HIF-1α), and vascular endothelial growth factor A(VEGFA) expression in liver tissues of rats with non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin on lipogenesis and inflammation in NAFLD. Forty male SD rats were divided into a normal group(n=8) fed on the normal diet and an experimental group(n=32) fed on the high-fat diet(HFD) for the induction of the NAFLD model. After modeling, the rats in the experimental group were randomly divided into an HFD group, a low-dose diosgenin group(150 mg·kg~(-1)·d~(-1)), a high-dose diosgenin group(300 mg·kg~(-1)·d~(-1)), and a simvastatin group(4 mg·kg~(-1)·d~(-1)), with eight rats in each group. The drugs were continuously given by gavage for eight weeks. The levels of triglyceride(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were detected by the biochemical method. The content of TG and TC in the liver was detected by the enzyme method. Enzyme-linked immunosorbent assay(ELISA) was used to measure interleukin 1ß(IL-1ß) and tumor necrosis factor α(TNF-α) in the serum. Lipid accumulation in the liver was detected by oil red O staining. Pathological changes of liver tissues were detected by hematoxylin-eosin(HE) staining. The mRNA and protein expression levels of mTOR, FASN, HIF-1α, and VEGFA in the liver of rats were detected by real-time fluorescence-based quantitative polymerase chain reaction(PCR) and Western blot, respectively. Compared with the normal group, the HFD group showed elevated body weight and levels of TG, TC, LDL-C, ALT, AST, IL-1ß, and TNF-α(P<0.01), increased lipid accumulation in the liver(P<0.01), obvious liver steatosis, up-regulated mRNA expression levels of mTOR, FASN, HIF-1α, and VEGFA(P<0.01), and increased protein expression levels of p-mTOR, FASN, HIF-1α, and VEGFA(P<0.01). Compared with the HFD group, the groups with drug treatment showed lowered body weight and levels of TG, TC, LDL-C, ALT, AST, IL-1ß, and TNF-α(P<0.05, P<0.01), reduced lipid accumulation in the liver(P<0.01), improved liver steatosis, decreased mRNA expression levels of mTOR, FASN, HIF-1α, and VEGFA(P<0.05, P<0.01), and declining protein expression levels of p-mTOR, FASN, HIF-1α, and VEGFA(P<0.01). The therapeutic effect of the high-dose diosgenin group was superior to that of the low-dose diosgenin group and the simvastatin group. Diosgenin may reduce liver lipid synthesis and inflammation and potentiate by down-regulating the mTOR, FASN, HIF-1α, and VEGFA expression, playing an active role in preventing and treating NAFLD.

[Diosgenin alleviates NAFLD induced by a high-fat diet in rats via mTOR/SREBP-1c/HSP60/MCAD/SCAD signaling pathway].

This study aims to observe the effects of diosgenin on the expression of mammalian target of rapamycin(mTOR), sterol regulatory element-binding protein-1c(SREBP-1c), heat shock protein 60(HSP60), medium-chain acyl-CoA dehydrogenase(MCAD), and short-chain acyl-CoA dehydrogenase(SCAD) in the liver tissue of the rat model of non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin in alleviating NAFLD. Forty male SD rats were randomized into five groups: a control group, a model group, low-(150 mg·kg~(-1)·d~(-1)) and high-dose(300 mg·kg~(-1)·d~(-1)) diosgenin groups, and a simvastatin(4 mg·kg~(-1)·d~(-1)) group. The rats in the control group were fed with a normal diet, while those in the other four groups were fed with a high-fat diet. After feeding for 8 weeks, the body weight of rats in the high-fat diet groups increased significantly. After that, the rats were administrated with the corresponding dose of diosgenin or simvastatin by gavage every day for 8 weeks. The levels of triglyceride(TG), total cholesterol(TC), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were determined by the biochemical method. The levels of TG and TC in the liver were measured by the enzyme method. Oil-red O staining was employed to detect the lipid accumulation, and hematoxylin-eosin(HE) staining to detect the pathological changes in the liver tissue. The mRNA and protein levels of mTOR, SREBP-1c, HSP60, MCAD, and SCAD in the liver tissue of rats were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. Compared with the control group, the model group showed increased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lipid deposition in the liver, obvious hepatic steatosis, up-regulated mRNA and protein expression levels of mTOR and SREBP-1c, and down-regulated mRNA and protein expression levels of HSP60, MCAD, and SCAD. Compared with the model group, the rats in each treatment group showed obviously decreased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lessened lipid deposition in the liver, ameliorated hepatic steatosis, down-regulated mRNA and protein le-vels of mTOR and SREBP-1c, and up-regulated mRNA and protein levels of HSP60, MCAD, and SCAD. The high-dose diosgenin outperformed the low-dose diosgenin and simvastatin. Diosgenin may prevent and treat NAFLD by inhibiting the expression of mTOR and SREBP-1c and promoting the expression of HSP60, MCAD, and SCAD to reduce lipid synthesis, improving mitochondrial function, and promoting fatty acid ß oxidation in the liver.

Seipin regulates lipid homeostasis by ensuring calcium-dependent mitochondrial metabolism.

Seipin, the gene that causes Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), is important for adipocyte differentiation and lipid homeostasis. Previous studies in Drosophila revealed that Seipin promotes ER calcium homeostasis through the Ca2+-ATPase SERCA, but little is known about the events downstream of perturbed ER calcium homeostasis that lead to decreased lipid storage in Drosophila dSeipin mutants. Here, we show that glycolytic metabolites accumulate and the downstream mitochondrial TCA cycle is impaired in dSeipin mutants. The impaired TCA cycle further leads to a decreased level of citrate, a critical component of lipogenesis. Mechanistically, Seipin/SERCA-mediated ER calcium homeostasis is important for maintaining mitochondrial calcium homeostasis. Reduced mitochondrial calcium in dSeipin mutants affects the TCA cycle and mitochondrial function. The lipid storage defects in dSeipin mutant fat cells can be rescued by replenishing mitochondrial calcium or by restoring the level of citrate through genetic manipulations or supplementation with exogenous metabolites. Together, our results reveal that Seipin promotes adipose tissue lipid storage via calcium-dependent mitochondrial metabolism.

Single cell sequencing coupled with bioinformatics reveals PHYH as a potential biomarker in kidney ischemia reperfusion injury.

Ischemia reperfusion injury(IRI) is an important factor affecting the early function and long-term survival of transplanted kidney. Single cell RNA sequencing (scRNA-seq) is a powerful method for investigating cell-specific transcriptome changes in the kidney. This study aimed to identify the significant cell type and potential biomarkers in IRI. First, we downloaded the IRI related scRNA dataset GSE139506 from the GEO database. Then, classification of cell type was characterized and proximal tubule cell (PTC) was identified as a significant cell type. The functional enrichment analysis indicated that PTC were related to kidney function and is significant in the ferroptosis of IRI. Analyses of three-dimensional structure and iron binding substructure of protein was carried out basing on SWISS-MODEL database. Finally, we constructed the murine model with IRI and verify the higher expression of PHYH in IRI by PCR, Western blot (WB) and Immunohistochemistry (IHC) experiments. In conclusion, this study provided novel insights on the cell-type-specific expression gene biomarker in IRI pathogenesis.

Hydroxyapatite nanoparticles promote mitochondrial-based pyroptosis via activating calcium homeostasis and redox imbalance in vascular smooth muscle cells.

Hydroxyapatite nanoparticles (HAP) have been widely used in various fields because of their natural biological origin and functional properties. The emerging evidence on their toxicities has attracted research interest. HAP-induced vascular smooth muscle cell (VSMC) damage is a key step in vascular calcification (VC), particularly in patients with chronic kidney disease. However, the injury effects and mechanism of action of HAP on VSMCs have not been extensively investigated. This study comprehensively characterized commercially available HAP and investigated its adverse biological effects in cultured A7R5 cells.In vitroexperiments revealed that internalized HAP was localized in lysosomes, followed by the release of Ca2+owing to the low pH microenvironment. Upon Ca2+homeostasis, Ca2+enters the mitochondria, leading to the simultaneous generation of reactive oxygen species (ROS). ROS subsequently attack mitochondrial transmembrane potentials, promote mitochondrial ROS production, and oxidize mitochondrial DNA (Ox-mtDNA). Mitochondrial permeability-transition pores open, followed by the release of more Ox-mtDNA from the mitochondria into the cytosol due to the redox imbalance. This activates NLRP3/caspase-1/gasdermin D-dependent pyroptosis and finally excretes inflammatory factors to induce VC; an antioxidant could rescue this process. It has been suggested that HAP could induce an imbalance in intracellular Ca2+homeostasis in A7R5 cells, followed by the promotion of mitochondrial dysfunction and cell pyroptosis, finally enhancing VC. To detect thein vivotoxicity of HAP, mice were treated with Cy7-labelled HAP NPs for 24 h.In vivoresults also demonstrated that HAP accumulated in the kidneys, accompined with increased Ca concentration, upregulated oxidative stress-related factor and kidney damage. Overall, our research elucidates the mechanism of calcium homeostasis and redox imbalance, providing insights into the prevention of HAP-induced cell death.

Routine replacement versus replacement as clinical indicated of peripheral intravenous catheters: A multisite randomised controlled trial.

AIMS AND OBJECTIVES: To compare the safety of replacing peripheral intravenous catheter as clinically indicated versus routine replacement on patient outcomes in the Chinese context. BACKGROUND: Some evidence from developed countries recommend replacing peripheral intravenous catheter as clinically indicated; however, there is limited evidence from developing countries. DESIGN: A multisite randomised controlled trial. METHODS: The 3050 participants from three hospitals in China were randomly assigned to clinically indicated or routine replacement groups. Patients in the clinically indicated group had the catheters kept in situ until any of the following clinical signs appeared: phlebitis, infiltration, occlusion, displacement, local infection and diagnosed catheter-related bloodstream infection. Patients in the routine replacement group had their peripheral intravenous catheters replaced every 96 hours. The outcomes of phlebitis, infiltration, occlusion, displacement; catheter-related bloodstream infection, all-cause bloodstream infection, and local infection were compared. CONSORT checklist was used to guide the reporting of this RCT. RESULTS: The risk of phlebitis, phlebitis per 1000 catheter days, occlusion, dislodgement, all bloodstream infections, local infection and mortality between the two groups were not significantly different. The risk of infiltration was increased in the clinically indicated group (HR 1.29). There was no catheter-related bloodstream infection reported in either group. Patients' first peripheral intravenous catheter dwelling time and cumulative indwelling time of all peripheral intravenous catheters in the clinically indicated group were significantly longer than the routine replacement group. There was no statistical significant difference in survival times from phlebitis between the two groups. CONCLUSIONS: In the Chinese context, removing peripheral catheters as clinical indicated did not increase the risk of phlebitis, occlusion, catheter displacement and catheter infection; however, there was an increased infiltration incidence. RELEVANCE TO CLINICAL PRACTICE: In developing countries, removing peripheral catheters as clinical indicated is feasible, but more frequent observations of infiltration are highly recommended.

Therapeutic potential and research progress of diosgenin for lipid metabolism diseases.

Diosgenin, a steroidal saponin, is a natural product found in many plants. Diosgenin has a wide range of pharmacological activities, and has been used to treat cancer, nervous system diseases, inflammation, and infections. Numerous studies have shown that diosgenin has potential therapeutic value for lipid metabolism diseases via various pathways and mechanisms, such as controlling lipid synthesis, absorption, and inhibition of oxidative stress. These mechanisms and pathways have provided ideas for researchers to develop related drugs. In this review, we focus on data from animal and clinical studies, summarizing the toxicity of diosgenin, its pharmacological mechanism, recent research advances, and the related mechanisms of diosgenin as a drug for the treatment of lipid metabolism, especially in obesity, hyperlipidemia, nonalcoholic fatty liver disease, atherosclerosis, and diabetes. This systematic review will briefly describe the advantages of diosgenin as a potential therapeutic drug and seek to enhance our understanding of the pharmacological mechanism, recipe-construction, and the development of novel therapeutics against lipid metabolism diseases.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

PPBP as a marker of diabetic nephropathy podocyte injury via Bioinformatics Analysis.

Diabetic nephropathy (DN) is a type of kidney injuries associated with diabetes mellitus and the prevalence of DN has increased dramatically. However, DN still pose problems in therapy, and prognosis. Identifying new DN biomarkers would be helpful in reducing morbidity and mortality from DN and developing novel preventive approaches. In the study, from GSE36336 dataset with DN glomeruli samples, we screened for 238 differentially expressed genes. Enrichment analysis were performed to find out biological function and diseases of DEGs. Next, depended on protein-protein interaction network, We identified top 10 hub genes (Serpine1, Cxcl10, Cfd, Ppbp, Retn, Socs2, Ccr5, Mmp8, Pf4, Cxcl9) may played potential roles in DN. Meanwhile, transcriptome sequencing on podocyte were performed to reconfirm the reliability of Ppbp. To verify the efficiency of the selected genes as biomarkers, several experiments like qRT-PCR, renal histologic analysis and immunofluorescence were conducted to validate. Our results showed that PPBP have the potential to become a novel biomarker for DN podocyte injury.

Diosgenin alleviates hypercholesterolemia via SRB1/CES-1/CYP7A1/FXR pathway in high-fat diet-fed rats.

Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150 mg/kg/d), high-dose DG (HDG) group (300 mg/kg) and Simvastatin (Sim) group (4 mg/kg/d). Body weights, serum and hepatic lipid parameters of rats were tested. The expression levels of scavenger receptor class B type I (SRB1), carboxylesterase-1 (CES-1), cholesterol7α- hydroxylase (CYP7A1), and farnesoid X receptor (FXR) were determined. The results showed that DG reduced weight and lowered lipid levels in HFD-fed rats. Pathological morphology analyses revealed that DG notably improved hepatic steatosis and intestinal structure. Further studies showed the increased hepatic SRB1, CES-1, CYP7A1 and inhibited FXR-mediated signaling in DG-fed rats, which contributing to the decrease of hepatic cholesterol. DG also increased intestinal SRB1 and CES-1, inhibiting cholesterol absorption and promoting RCT. The expression levels of these receptors in the HDG group were higher than LDG and Sim groups. These data suggested that DG accelerated reverse cholesterol transport (RCT) and enhanced cholesterol elimination via SRB1/CES-1/CYP7A1/FXR pathway, and DG might be a new candidate for the alleviation of hypercholesterolemia.

Noncatalytic chalcone isomerase-fold proteins in Humulus lupulus are auxiliary components in prenylated flavonoid biosynthesis.

Xanthohumol (XN) and demethylxanthohumol (DMX) are specialized prenylated chalconoids with multiple pharmaceutical applications that accumulate to high levels in the glandular trichomes of hops (Humulus lupulus L.). Although all structural enzymes in the XN pathway have been functionally identified, biochemical mechanisms underlying highly efficient production of XN have not been fully resolved. In this study, we characterized two noncatalytic chalcone isomerase (CHI)-like proteins (designated as HlCHIL1 and HlCHIL2) using engineered yeast harboring all genes required for DMX production. HlCHIL2 increased DMX production by 2.3-fold, whereas HlCHIL1 significantly decreased DMX production by 30%. We show that CHIL2 is part of an active DMX biosynthetic metabolon in hop glandular trichomes that encompasses a chalcone synthase (CHS) and a membrane-bound prenyltransferase, and that type IV CHI-fold proteins of representative land plants contain conserved function to bind with CHS and enhance its activity. Binding assays and structural docking uncover a function of HlCHIL1 to bind DMX and naringenin chalcone to stabilize the ring-open configuration of these chalconoids. This study reveals the role of two HlCHILs in DMX biosynthesis in hops, and provides insight into their evolutionary development from the ancestral fatty acid-binding CHI-fold proteins to specialized auxiliary proteins supporting flavonoid biosynthesis in plants.

An InDel in the Promoter of Al-ACTIVATED MALATE TRANSPORTER9 Selected during Tomato Domestication Determines Fruit Malate Contents and Aluminum Tolerance.

Deciphering the mechanism of malate accumulation in plants would contribute to a greater understanding of plant chemistry, which has implications for improving flavor quality in crop species and enhancing human health benefits. However, the regulation of malate metabolism is poorly understood in crops such as tomato (Solanum lycopersicum). Here, we integrated a metabolite-based genome-wide association study with linkage mapping and gene functional studies to characterize the genetics of malate accumulation in a global collection of tomato accessions with broad genetic diversity. We report that TFM6 (tomato fruit malate 6), which corresponds to Al-ACTIVATED MALATE TRANSPORTER9 (Sl-ALMT9 in tomato), is the major quantitative trait locus responsible for variation in fruit malate accumulation among tomato genotypes. A 3-bp indel in the promoter region of Sl-ALMT9 was linked to high fruit malate content. Further analysis indicated that this indel disrupts a W-box binding site in the Sl-ALMT9 promoter, which prevents binding of the WRKY transcription repressor Sl-WRKY42, thereby alleviating the repression of Sl-ALMT9 expression and promoting high fruit malate accumulation. Evolutionary analysis revealed that this highly expressed Sl-ALMT9 allele was selected for during tomato domestication. Furthermore, vacuole membrane-localized Sl-ALMT9 increases in abundance following Al treatment, thereby elevating malate transport and enhancing Al resistance.