Dynamic alternations of interhemispheric functional connectivity in brachial plexus avulsion injury patients with nerve transfer: a resting state fMRI study.

Brachial plexus avulsion injury (BPAI) is a severe peripheral nerve injury that leads to functional reorganization of the brain. However, the interhemispheric coordination following contralateral cervical 7 nerve transfer remains unclear. In this study, 69 BPAI patients underwent resting-state functional magnetic resonance imaging examination to assess the voxel-mirrored homotopic connectivity (VMHC), which reveals the interhemispheric functional connection. The motor function of the affected upper extremity was measured using the Fugl-Meyer Assessment of Upper Extremity (FMA-UE) scale. The VMHC analysis showed significant differences between the bilateral precentral gyrus, supplementary motor area (SMA), middle frontal gyrus (MFG), and insula. Compared to the preoperative group, the VMHC of the precentral gyrus significantly increased in the postoperative short-term group (PO-ST group) but decreased in the postoperative long-term group (PO-LT group). Additionally, the VMHC of the SMA significantly increased in the PO-LT group. Furthermore, the VMHC of the precentral gyrus in the PO-ST group and the SMA in the PO-LT group were positively correlated with the FMA-UE scores. These findings highlight a positive relationship between motor recovery and increased functional connectivity of precentral gyrus and SMA, which provide possible therapeutic targets for future neuromodulation interventions to improve rehabilitation outcomes for BPAI patients.

Nickel-Based Metal-Organic Frameworks Promote Diabetic Wound Healing via Scavenging Reactive Oxygen Species and Enhancing Angiogenesis.

Chronic diabetic wounds remain a worldwide challenge for both the clinic and research. Given the vicious circle of oxidative stress and inflammatory response as well as the impaired angiogenesis of the diabetic wound tissues, the wound healing process is disturbed and poorly responds to the current treatments. In this work, a nickel-based metal-organic framework (MOF, Ni-HHTP) with excellent antioxidant activity and proangiogenic function is developed to accelerate the healing process of chronic diabetic wounds. The Ni-HHTP can mimic the enzymatic catalytic activities of antioxidant enzymes to eliminate multi-types of reactive species through electron transfer reactions, which protects cells from oxidative stress-related damage. Moreover, this Ni-based MOF can promote cell migration and angiogenesis by activating transforming growth factor-ß1 (TGF-ß1) in vitro and reprogram macrophages to the anti-inflammatory phenotype. Importantly, Ni-HHTP effectively promotes the healing process of diabetic wounds by suppressing the inflammatory response and enhancing angiogenesis in vivo. This study reports a versatile and promising MOF-based nanozyme for diabetic wound healing, which may be extended in combination with other wound dressings to enhance the management of diabetic or non-healing wounds.

Right ventricular-pulmonary arterial coupling ratio derived from 3-dimensional echocardiography predicts outcomes in systemic lupus erythematosus-associated pulmonary arterial hypertension patients.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune connective tissue disease (CTD) that is an important cause of devastating pulmonary arterial hypertension (PAH), and persistent progression of PAH can lead to right heart failure, predicting a poor prognosis for SLE patients. Right ventricular-pulmonary arterial (RV-PA) coupling with echocardiography has been demonstrated to be a noninvasive alternative method for evaluating PAH patients' predictive outcomes. Whether the ratio of right ventricular stroke volume (RVSV) to right ventricular end-systolic volume (RVESV) measured by three-dimensional echocardiography (3DE) is a new index of RV-PA coupling has not been discussed as a new predictor for the clinical outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). METHODS: From June 2019 to February 2023, 46 consecutive patients with SLE-PAH were enrolled prospectively, and their clinical data and echocardiographs were studied and analyzed. The control group consisted of 30 healthy subjects matched for age, sex, and body surface area (BSA). The main endpoints of this study were a composite of all-cause mortality and adverse clinical events. Baseline clinical characteristics and echocardiographic assessments were analyzed. RESULTS: During a median of 24 months (IQR 18-31), 16 of 46 SLE-PAH patients (34.7%) experienced endpoint-related events. At baseline, patients who experienced mortality or adverse events had a worse WHO functional class (WHO FC) and lower anti-double-stranded DNA (dsDNA) antibody levels. The right ventricular (RV) systolic dysfunction in SLE-PAH subjects was significantly worse than that in the healthy control group, especially in SLE-PAH patients in the endpoint event group. Compared to controls, patients with SLE-PAH had a lower RVSV/RVESV ratio. In the group comparison, patients who had experienced an endpoint event had a sequentially worse ratio (1.86 (1.65-2.3) versus 1.30 (1.09-1.46) versus 0.64 (0.59-0.67), p < .001). There were statistically significant associations between the RVSV/RVESV ratio to routine RV systolic function and clinical parameters. The RVSV/RVESV ratio was negatively correlated with the WHO FC (r = -0.621, p < .001) and positively correlated with the anti-dsDNA level. The ROC curve showed that the optimal cutoff for RVSV/RVESV < 0.712 determined a higher risk of poor prognosis. Kaplan‒Meier survival curves showed that an RVSV/RVESV ratio >0.712 was associated with more favorable long-term outcomes. CONCLUSIONS: The 3DE-derived SV/ESV ratio as a noninvasive alternative surrogate of RV-PA coupling was an eximious indicator for identifying endpoint events in SLE-PAH patients and can provide a diagnostic basis for clinical intervention.

The radiomics features of the temporal lobe region related to menopause based on MR-T2WI can be used as potential biomarkers for AD.

Menopause may be an important pathogenic factor for Alzheimer's disease (AD). The M1 polarization of microglia and neuroinflammatory responses occur in the early pathogenetic stages of AD. Currently, no effective monitoring markers are available for AD's early pathological manifestations. Radiomics is an automated feature generation method for the extraction of hundreds of quantitative phenotypes (radiomics features) from radiology images. In this study, we retrospectively analyzed the magnetic resonance T2-weighted imaging (MR-T2WI) on the temporal lobe region and clinical data of both premenopausal and postmenopausal women. There were three significant differences were identified for select radiomic features in the temporal lobe between premenopausal and postmenopausal women, i.e. the texture feature Original-glcm-Idn (OI) based on the Original image, the filter-based first-order feature Log-firstorder-Mean (LM), and the texture feature Wavelet-LHH-glrlm-Run Length Nonuniformity (WLR). In humans, these three features were significantly correlated with the timing of menopause. In mice, these features were also different between the sham and ovariectomy (OVX) groups and were significantly associated with neuronal damage, microglial M1 polarization, neuroinflammation, and cognitive decline in the OVX groups. In AD patients, OI was significantly associated with cognitive decline, while LM was associated with anxiety and depression. OI and WLR could distinguish AD from healthy controls. In conclusion, radiomics features based on brain MR-T2WI scans have the potential to serve as biomarkers for AD and noninvasive monitoring of pathological progression in the temporal lobe of the brain in women undergoing menopause.

Interplay between edaphic and climatic factors unravels plant and microbial diversity along an altitudinal gradient.

Altitude influences biodiversity and physiochemical soil attributes in terrestrial ecosystems. It is of immense importance to know the patterns of how interactions among climatic and edaphic factors influence plant and microbial diversity in various ecosystems, particularly along the gradients. We hypothesize that altitudinal variation determines the distribution of plant and microbial species as well as their interactions. To test the hypothesis, different sites with variable altitudes were selected. Analyses of edaphic factors revealed significant (p < 0.001) effects of the altitude. Soil ammonium and nitrate were strongly affected by it contrary to potassium (K), soil organic matter and carbon. The response patterns of individual taxonomic groups differed across the altitudinal gradient. Plant species and soil fungal diversity increased with increasing altitude, while soil archaeal and bacterial diversity decreased with increasing altitude. Plant species richness showed significant positive and negative interactions with edaphic and climatic factors. Fungal species richness was also significantly influenced by the soil ammonium, nitrate, available phosphorus, available potassium, electrical conductivity, and the pH of the soil, but showed non-significant interactions with other edaphic factors. Similarly, soil variables had limited impact on soil bacterial and archaeal species richness along the altitude gradient. Proteobacteria, Ascomycota, and Thaumarchaeota dominate soil bacterial, fungal, and archaeal communities, with relative abundance of 27.4%, 70.56%, and 81.55%, respectively. Additionally, Cynodon dactylon is most abundant plant species, comprising 22.33% of the recorded plant taxa in various study sites. RDA revealed that these communities influenced by certain edaphic and climatic factors, e.g., Actinobacteria strongly respond to MAT, EC, and C/N ratio, Ascomycota and Basidiomycota show strong associations with EC and MAP, respectively. Thaumarcheota are linked to pH, and OM, while Cyperus rotundus are sensitive to AI and EC. In conclusion, the observed variations in microbial as well as plant species richness and changes in soil properties at different elevations provide valuable insights into the factors determining ecosystem stability and multifunctionality in different regions.

Exposures to drinking water disinfection byproducts and kidney function in Chinese women.

BACKGROUND: Disinfection byproducts (DBPs), the ubiquitous contaminants in drinking water, have been shown to impair renal function in experimental studies. However, epidemiological evidence is sparse. OBJECTIVE: To investigate exposures to DBPs in associations with renal function among women. METHODS: A total of 920 women from December 2018 to January 2020 were abstracted from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort study in Wuhan, China. Urine samples were gathered at baseline recruitment and analyzed for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. Serum uric acid (UA), creatinine, and estimated glomerular filtration rate (eGFR) were measured as indicators of renal function. Multivariate linear regression and restricted cubic spline (RCS) models were conducted to assess urinary DCAA and TCAA concentrations in associations with renal function indicators. Stratified analyses by age and body mass index (BMI) were also performed. RESULTS: We found null evidence of urinary TCAA in associations with renal function indicators. However, elevated urinary DCAA tertiles were related to decreased eGFR (ß = -1.78%, 95% CI: 3.21%, -0.36%, comparing the upper vs. lower tertile; P for trend = 0.01). This inverse association still existed when urinary DCAA concentration was treated as a continuous variable, and the dose-response relationship was linear based on the RCS model (P for overall association = 0.002 and P for non-linear associations = 0.44). In the stratified analyses, we found an association of urinary DCAA concentration with decreased UA level among women <30 years but an association with increased UA level among women ≥30 years (P for interaction = 0.04). CONCLUSION: Urinary DCAA but not TCAA was associated with impaired renal function among women undergoing assisted reproductive technology.

M2 tumor-associated macrophages and CXCL2 induce lipid remodeling in hepatocellular carcinoma cell lines.

Primary hepatocellular carcinoma (HCC) is one of the most common malignant tumors, but its pathogenesis remains incompletely elucidated. Recently, many studies indicated that lipid remodeling plays an important role in the occurrence and development of HCC. Furthermore, lipids have been proven to be indispensable mediators in promoting communication between tumor cells and extracellular matrix in the tumor microenvironment. Thus, this study aims to comprehensively investigate the process of lipid remodeling during HCC metastasis based on the LC-electrospray ionization-MS (LC-ESI-MS) combined with multiple reaction monitoring technology. M2 tumor-associated macrophages and the recombinant human protein CXCL2 were used to simulate the tumor microenvironment. After co-incubating SMMC7721 and MHCC97-H cell lines with M2 tumor-associated macrophages or the recombinant human protein CXCL2 for 48 h, LC-ESI-MS was used to quantify the levels of two major classes of lipid molecules, namely, glycerophospholipids and sphingolipids. Our results suggest that lipid remodeling in the tumor microenvironment may promote the migration and invasion of HCC cell lines.

Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14, a novel N-methyl-d-aspartate receptor antagonist, in rats by liquid chromatography-tandem mass spectrometry.

To circumvent the limitations of current antidepressants, WJ-14, a novel N-methyl-d-aspartate receptor antagonist, was synthesized and demonstrated to have remarkable efficiency in the treatment of depression. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14 in rats, a rapid and sensitive liquid chromatography-tandem mass spectrometry-based analytical method was developed and validated for the separation and detection of WJ-14 in both plasma and tissue samples. After oral administration, WJ-14 was rapidly absorbed into the blood with time to reach the maximum plasma concentration (Tmax ) within 0.28 h and quickly eliminated with clearance (Cl) exceeding 6.80 L/h/kg and elimination half-life (t1/2 ) within 2.69 h. No obvious accumulation was found with mean residencetime (MRT) within 4.10 h. Tissue distribution revealed that WJ-14 was extensively distributed in the main tissues of rats, and massive amounts of WJ-14 were distributed in the liver. Extensive distribution and quick elimination led to extremely low absolute bioavailability of WJ-14 (1.91% of 8.33 mg/kg and 3.30% of 24.99 mg/kg). WJ-14 was detected in the brain only 0.083 h after oral administration, which is crucial for a rapid-onset antidepressant candidate. In addition, WJ-14 likely exhibited a non-linear pharmacokinetic process at dosages of 8.33 and 24.99 mg/kg. The findings may provide valuable information for subsequent studies on WJ-14.

Associations of exposure to disinfection by-products with blood coagulation parameters among women: Results from the Tongji reproductive and environmental (TREE) study.

BACKGROUND: Experimental studies have shown that disinfection byproducts (DBPs) induce coagulotoxicity, but human evidence is scarce. OBJECTIVE: This study aimed to explore the relationships of DBP exposures with blood coagulation parameters. METHODS: Among 858 women from the Tongji Reproductive and Environmental (TREE) study, urinary dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were detected as internal biomarkers of DBP exposures. We measured activated partial thromboplastin time (APTT), fibrinogen (Fbg), international normalized ratio (INR), prothrombin time (PT), and thrombin time (TT) as blood coagulation parameters. Multivariable linear regression models were utilized to estimate the relationships between urinary DCAA and TCAA and blood coagulation parameters. The effect modifications by demographic and lifestyle characteristics were further explored. RESULTS: Elevated tertiles of urinary DCAA concentrations were associated with increased PT and INR (11.29%, 95% CI: 1.66%, 20.92% and 0.99%, 95% CI: 0.08%, 1.90% for the third vs. first tertile, respectively; both P for trends < 0.05). Stratification analysis showed that the positive associations were only observed among younger (< 30 years), leaner (body mass index < 24.0 kg/m2), and non-passive smoking women. Moreover, elevated tertiles of urinary TCAA concentrations in positive associations with PT and INR were observed among younger women (17.89%, 95% CI: 2.50%, 33.29% and 1.82%, 95% CI: 0.34%, 3.30% for the third vs. first tertile, respectively; both P for trends < 0.05) but not among older women (both P for interactions < 0.05). CONCLUSION: Higher levels of urinary DCAA and TCAA are associated with prolonged clotting time among women.

Exploring symptom clusters in Chinese patients with peritoneal dialysis: a network analysis.

BACKGROUND: In recent years, the research on symptom management in peritoneal dialysis (PD) patients has shifted from a single symptom to symptom clusters and network analysis. This study collected and evaluated unpleasant symptoms in PD patients and explored groups of symptoms that may affect PD patients with a view to higher symptom management. METHODS: The symptoms of PD patients were measured using the modified Dialysis Symptom Index. The symptom network and node characteristics were assessed by network analysis, and symptom clusters were explored by factor analysis. RESULTS: In this study of 602 PD patients (mean age 47.8 ± 16.8 years, 47.34% male), most had less than 2 years of dialysis experience. Five symptom clusters were obtained from factor analysis, which were body symptom cluster, gastrointestinal symptom cluster, mood symptom cluster, sexual disorder symptom cluster, and skin-sleep symptom cluster. Itching and decreased interest in sex may be sentinel symptoms, and being tired or lack of energy and feeling anxious are core symptoms in PD patients. CONCLUSIONS: This study emphasizes the importance of recognizing symptom clusters in PD patients for better symptom management. Five clusters were identified, with key symptoms including itching, decreased interest in sex, fatigue, and anxiety. Early intervention focused on these symptom clusters in PD patients holds promise for alleviating the burden of symptoms.

Plant-based diets, genetic predisposition and risk of non-alcoholic fatty liver disease.

BACKGROUND: Diets rich in plant-based foods are associated with lower risks of non-alcoholic fatty liver disease (NAFLD), while the prospective evidence is limited. We aimed to examine longitudinal associations of plant-based diets and genetic susceptibility with NAFLD risk. METHODS: This longitudinal cohort study included 159,222 participants (58.0 ± 8.0 years old, 55.7% female) free of NAFLD in the UK Biobank. We calculated the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI). New-onset NAFLD was the primary outcome. The weighted polygenic risk score was calculated based on risk variants associated with NAFLD. Hazard ratios (HR) and 95% confidential intervals (CI) were estimated by Cox proportional hazards model. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) measured liver fat content in a subsample of 20,692 participants (57.5 ± 7.4 years old, 52.6% female) was the secondary outcome. The associations between plant-based diet indices and MRI-PDFF were evaluated using generalized linear models. RESULTS: During a median follow-up of 9.5 years, 1541 new-onset NAFLD cases were documented. Compared to the lowest quintile, multivariable-adjusted hazard ratios (HRs) of NAFLD in the highest quintile were 0.78 (95% confidential intervals [CI], 0.66-0.93, p-trend =0.02), 0.74 (95% CI, 0.62-0.87, p-trend <0.0001), and 1.24 (95% CI, 1.05-1.46, p-trend = 0.02) for overall PDI, hPDI, and uPDI, respectively. For liver fat content, higher overall PDI and hPDI were associated with lower MRI-PDFF, while higher uPDI was associated with higher liver fat content. We observed a significant interaction between hPDI and PRS (p-interaction =0.03), and the NAFLD risk was lowest among participants with the highest hPDI and low genetic risk. CONCLUSIONS: Higher intake of plant-based diets especially healthful plant-based diets was associated with lower NAFLD risk and liver fat content regardless of genetic susceptibility, whereas an unhealthful plant-based diet was associated with higher NAFLD risk and intrahepatic steatosis. These results suggest that the quality of plant-based foods should be highlighted when adopting a plant-based diet.

Dynamic variation of Paris polyphylla root-associated microbiome assembly with planting years.

MAIN CONCLUSION: P. polyphylla selectively enriches beneficial microorganisms to help their growth. Paris polyphylla (P. polyphylla) is an important perennial plant for Chinese traditional medicine. Uncovering the interaction between P. polyphylla and the related microorganisms would help to utilize and cultivate P. polyphylla. However, studies focusing on P. polyphylla and related microbes are scarce, especially on the assembly mechanisms and dynamics of the P. polyphylla microbiome. High-throughput sequencing of the 16S rRNA genes was implemented to investigate the diversity, community assembly process and molecular ecological network of the bacterial communities in three root compartments (bulk soil, rhizosphere, and root endosphere) across three years. Our results demonstrated that the composition and assembly process of the microbial community in different compartments varied greatly and were strongly affected by planting years. Bacterial diversity was reduced from bulk soils to rhizosphere soils to root endosphere and varied over time. Microorganisms benefit to plants was selectively enriched in P. polyphylla roots as was its core microbiome, including Pseudomonas, Rhizobium, Steroidobacter, Sphingobium and Agrobacterium. The network's complexity and the proportion of stochasticity in the community assembly process increased. Besides, nitrogen metabolism, carbon metabolism, phosphonate and phosphinate metabolism genes in bulk soils increased over time. These findings suggest that P. polyphylla exerts a selective effect to enrich the beneficial microorganisms and proves the sequential increasing selection pressure with P. polyphylla growth. Our work adds to the understanding of the dynamic processes of plant-associated microbial community assembly, guides the selection and application timing of P. polyphylla-associated microbial inoculants and is vital for sustainable agriculture.

The effects of probiotics supplementation on glycaemic control among adults with type 2 diabetes mellitus: a systematic review and meta-analysis of randomised clinical trials.

OBJECTIVE: This systematic review and meta-analysis study aimed to evaluate the effectiveness of probiotics supplementation on glycaemic control in patients with type 2 diabetes mellitus (T2DM) based on the data from the randomised clinical trials (RCTs). METHODS: PubMed, Web of Sciences, Embase, and Cochrane Library were searched from the inception to October 2022, and RCTs about probiotics and T2DM were collected. The standardised mean difference (SMD) with 95% confidence interval (CI) was used to estimate the effects of probiotics supplementation on glycaemic control related parameters, e.g. fasting blood glucose (FBG), insulin, haemoglobin A1c (HbA1c), and homeostasis model of assessment of insulin resistance (HOMA-IR). RESULTS: Thirty RCTs including 1,827 T2MD patients were identified. Compared with the placebo group, the probiotics supplementation group had a significant decrease in the parameters of glycaemic control, including FBG (SMD = - 0.331, 95% CI - 0.424 to - 0.238, Peffect < 0.001), insulin (SMD = - 0.185, 95% CI - 0.313 to - 0.056, Peffect = 0.005), HbA1c (SMD = - 0.421, 95% CI - 0.584 to - 0.258, Peffect < 0.001), and HOMA-IR (SMD = - 0.224, 95% CI - 0.342 to - 0.105, Peffect < 0.001). Further subgroup analyses showed that the effect was larger in the subgroups of Caucasians, high baseline body mass index (BMI ≥ 30.0 kg/m2), Bifidobacterium and food-type probiotics (Psubgroup < 0.050). CONCLUSION: This study supported that probiotics supplementation had favourable effects on glycaemic control in T2DM patients. It may be a promising adjuvant therapy for patients with T2DM.

PRDX6-mediated pulmonary artery endothelial cell ferroptosis contributes to monocrotaline-induced pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder whose underlying pathogenesis is unknown. Our previous study showed that pulmonary endothelial cell (PAEC) ferroptosis is involved in the progression of PH by releasing High-mobility group box 1 (HMGB1) and activating Toll-like receptor 4/NOD-like receptor family pyrin domain containing 3 (TLR4/NLRP3) inflammasome signalling. The precise mechanisms that regulate ferroptosis in PH are unclear. This study aimed to investigate the effect of peroxiredoxin 6 (PRDX6) on PAEC ferroptosis in PH. METHODS: A rat model of PH was established with monocrotaline (MCT), and the distribution and expression of PRDX6 in the pulmonary artery were examined. Lentiviral vectors carrying PRDX6 (LV-PRDX6) were transfected into PAECs and injected into MCT-induced PH rats. Cell viability, MDA levels, reactive oxygen species (ROS) levels, labile iron pool (LIP) levels and mitochondrial morphology were examined. Ferroptosis-related proteins (NADPH oxidase-4 (NOX4), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1(FTH1)), TLR4, NLRP3 inflammasome markers, HMGB1 and inflammatory cytokines were examined. Pulmonary vascular remodelling and right ventricular structure and function were measured. RESULTS: PRDX6 was expressed in PAECs and was significantly decreased in PH. PRDX6 overexpression significantly inhibited ferroptosis in PAECs under PH conditions in vitro and in vivo, as indicated by increased cell viability, decreased MDA, ROS and LIP levels, inhibited mitochondrial damage, upregulated GPX4 and FTH1 expression, and downregulated NOX4 expression. PRDX6 overexpression attenuated pulmonary vascular remodelling and changes in right ventricle structure and function in MCT-induced PH rats. Moreover, PRDX6 overexpression prevented HMGB1 release by PAECs and decreased TLR4 and NLRP3 inflammasome expression and inflammatory cytokine release in macrophages, while RSL3, a specific activator of ferroptosis, reversed these effects. CONCLUSIONS: Taken together, these findings indicate that PRDX6 regulates PAEC ferroptosis through the release of HMGB1 and activation of the TLR4/NLRP3 inflammasome signalling pathway, providing novel therapeutic targets for the treatment of PH.

Antidiabetic activity of Tartary buckwheat protein-derived peptide AFYRW and its effects on protein glycosylation of pancreas in mice.

Diabetes Mellitus (DM) is one of the most important public health problems, and new antidiabetic drugs with fewer side effects are urgently needed. Here, we measured the antidiabetic effects of an antioxidant peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) from Tartary Buckwheat Albumin (TBA) in a high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mouse model. The data showed that AFYRW suppressed hepatocyte steatosis and triglycerides while ameliorating insulin resistance in mice. Successively, the influence of AFYRW on aberrant protein glycosylation in diabetic mice was further investigated by lectin microarrays. The results suggested AFYRW could restore the expression of GalNAc, GalNAcα1-3Gal and GalNAcα1-3Galß1-3/4Glc recognized by PTL-I, Siaα2-3Galß1-4Glc(NAc)/Glc, Siaα2-3Gal, Siaα2-3 and Siaα2-3GalNAc recognized by MAL-II, terminating in GalNAcα/ß1-3/6Gal recognized by WFA and αGalNAc, αGal, anti-A and B recognized by GSI-I to normal levels in the pancreas of HFD-STZ-induced diabetic mice. This work may provide new targets for the future discovery of potential biomarkers to evaluate the efficacy of food-derived antidiabetic drugs based on precise alterations of glycopatterns in DM.

Targeting Mitochondria-Inflammation Circuit by ß-Hydroxybutyrate Mitigates HFpEF.

RATIONALE: Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction. Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. OBJECTIVE: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model. METHODS AND RESULTS: By combining the age, long-term high-fat diet, and desoxycorticosterone pivalate challenge in a mouse model, we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of IL (interleukin)-1ß/IL-18 and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing ß-hydroxybutyrate level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokine-triggered mitochondrial dysfunction and fibrosis. Moreover, ß-hydroxybutyrate downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of CS (citrate synthase) and inhibition of fatty acid uptake. CONCLUSIONS: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis, which can be ameliorated by promoting ß-hydroxybutyrate abundance.

Characteristics of molecular markers associated with chloroquine resistance in Plasmodium vivax strains from vivax malaria cases in Yunnan Province, China.

BACKGROUND: Chloroquine (CQ) has been the preferred clinical treatment for vivax malaria in Yunnan Province since 1958, with over 300,000 patients. This study aimed to help make trend predictions regarding variations the in anti-malarial drug susceptibility of Plasmodium vivax distributed in Yunnan Province and effectively implement monitoring measures on the efficacy of anti-malarial drugs for vivax malaria. METHODS: Blood samples collected from patients with mono-P. vivax infections were employed in this study based on the principle of cluster sampling. The whole gene of P. vivax multidrug resistance 1 protein gene (pvmdr1) was amplified by nested-PCR techniques and the PCR amplification produce were sequenced by Sanger bidirectional sequencing. The mutant loci and haplotypes of coding DNA sequence (CDS) were identified by comparison with the reference sequence (NC_009915.1) of the P. vivax Sal I isolate. Parameters such as Ka/Ks ratio were calculated using MEGA 5.04 software. RESULTS: A total of 753 blood samples from patients infected with mono-P. vivax were collected, of which 624 blood samples yielded the full gene sequence (4392 bp) of the pvmdr1 gene, with 283, 140, 119, and 82 sequences from 2014, 2020, 2021 and 2022, respectively. A total of 52 single nucleotide polymorphic (SNP) loci were detected for the 624 CDSs, of which 92.3% (48/52), 34.6% (18/52), 42.3% (22/52), and 36.5% (19/52) SNPs were detected in 2014, 2020, 2021 and 2022, respectively. All of 624 CDSs were defined for a total of 105 mutant haplotypes, with CDSs of 2014, 2020, 2021, and 2022 containing 88, 15, 21, and 13 haplotypes, respectively. Of the 105 haplotypes, the threefold mutant haplotype (Hap_87) was the starting point for stepwise evolution, and the most drastic tenfold mutations were Hap_14 and Hap_78, and the fivefold, sixfold, sevenfold, and eightfold mutations. CONCLUSIONS: In the majority of vivax malaria cases in Yunnan Province, most of them were infected with strains carrying demonstrating highly mutated in pvmdr1 genes. However, the dominant mutation strains types varied from year to year, which warrants further exploration in order to confirm the correlation between with phenotypic changes in P. vivax strains and their susceptibility to anti-malarial drugs such as chloroquine.

Molecular surveillance of chloroquine resistance in Plasmodium vivax isolates from malaria cases in Yunnan Province of China using pvcrt-o gene polymorphisms.

BACKGROUND: The efficacy of chloroquine treatment for vivax malaria has been rarely evaluated due to a lack of an appropriate testing method. The objective of this study was to conduct molecular monitoring of chloroquine resistance in Plasmodium vivax strains from vivax malaria patients in Yunnan Province, focusing on the analysis of polymorphism in the P. vivax chloroquine resistance transporter protein orthologous gene (pvcrt-o). METHODS: In accordance with the principles of a cohort study, blood samples were collected from malaria cases diagnosed with a P. vivax mono-infection in Yunnan Province from 2020 to 2022. Segmental PCR was used to amplify the whole pvcrt-o gene in the blood samples and their products were subsequently sequenced. The sequencing data were arranged to obtain the full coding DNA sequence (CDS) as well as the gene's promoter region sequences. The CDSs were aligned with the reference sequence (XM_001613407.1) of the P. vivax SalI isolate to identify the mutant loci. RESULTS: From a total of 375 blood samples taken from vivax malaria cases, 272 both whole gene CDSs (1272-1275 bp) and promoter DNA sequences (707 bp) of pvcrt-o gene were obtained. Among the whole CDSs, there were 7 single nucleotide polymorphic sites in which c.7 A>G was the minor allele frequency (MAF) site with 4.4% (12/272) detection rate. The mutation detection rate showed a significant decrease from 9.8% (10/102) in 2020 to 1.1% (1/92) in 2021 and 1.3% (1/78) in 2022, indicating statistical significance (χ2 = 11.256, P < 0.05). Among the identified 12 haplotypes, the majority of which were wild type (75.7%; 206/272). These four mutant haplotypes (Hap_3, Hap_5, Hap_9, and Hap_10) were classified as "K10 insertion type" and accounted for 12.1% (33/272). The detection rate of Hap_3 increased from 1.0% (1/102) in 2020 to 13.0% (12/92) in 2021 and 14.1% (11/78) in 2022, indicating statistical significance. A total of 23.8% (65/272) of the samples exhibited 14 bp (bp) deletions in the promoter region, occurring most frequently in the wild type haplotype (Hap_1) samples at a rate of 28.6% (59/206). CONCLUSIONS: In recent years in Yunnan Province, a notable proportion of vivax malaria patients are infected by P. vivax strains with a "K10 insertion" and partial sequence deletions in the promoter region of the pvcrt-o gene, necessitating vigilance.

Two nomograms based on radiomics models using triphasic CT for differentiation of adrenal lipid-poor benign lesions and metastases in a cancer population: an exploratory study.

OBJECTIVES: To investigate the effectiveness of CT-based radiomics nomograms in differentiating adrenal lipid-poor benign lesions and metastases in a cancer population. METHODS: This retrospective study enrolled 178 patients with cancer history from three medical centres categorised as those with adrenal lipid-poor benign lesions or metastases. Patients were divided into training, validation, and external testing cohorts. Radiomics features were extracted from triphasic CT images (unenhanced, arterial, and venous) to establish three single-phase models and one triphasic radiomics model using logistic regression. Unenhanced and triphasic nomograms were established by incorporating significant clinico-radiological factors and radscores. The models were evaluated by the receiver operating characteristic curve, Delong's test, calibration curve, and decision curve. RESULTS: Lesion side, diameter, and enhancement ratio resulted as independent factors and were selected into nomograms. The areas under the curves (AUCs) of unenhanced and triphasic radiomics models in validation (0.878, 0.914, p = 0.381) and external testing cohorts (0.900, 0.893, p = 0.882) were similar and higher than arterial and venous models (validation: 0.842, 0.765; testing: 0.814, 0.806). Unenhanced and triphasic nomograms yielded similar AUCs in validation (0.903, 0.906, p = 0.955) and testing cohorts (0.928, 0.946, p = 0.528). The calibration curves showed good agreement and decision curves indicated satisfactory clinical benefits. CONCLUSION: Unenhanced and triphasic CT-based radiomics nomograms resulted as a useful tool to differentiate adrenal lipid-poor benign lesions from metastases in a cancer population. They exhibited similar predictive efficacies, indicating that enhanced examinations could be avoided in special populations. KEY POINTS: • All four radiomics models and two nomograms using triphasic CT images exhibited favourable performances in three cohorts to characterise the cancer population's adrenal benign lesions and metastases. • Unenhanced and triphasic radiomics models had similar predictive performances, outperforming arterial and venous models. • Unenhanced and triphasic nomograms also exhibited similar efficacies and good clinical benefits, indicating that contrast-enhanced examinations could be avoided when identifying adrenal benign lesions and metastases.

Tartary buckwheat protein-derived peptide AFYRW alleviates H2O2-induced vascular injury via the PI3K/AKT/NF-κB pathway.

Tartary buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) is a natural active peptide that hampers the atherosclerosis process, but the underlying role of AFYRW in angiogenesis remains unknown. Here, we present a system-based study to evaluate the effects of AFYRW on H2O2-induced vascular injury in human umbilical vein endothelial cells (HUVECs). HUVECs were co-incubated with H2O2 for 2 h in the vascular injury model, and AFYRW was added 24 h in advance to investigate the protective mechanism of vascular injury. We identified that AFYRW inhibits oxidative stress, cell migration, cell invasion, and angiogenesis in H2O2-treated HUVECs. In addition, we found H2O2-induced upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), phosphorylation of nuclear factor-κB (NF-κB) p65 and nuclear translocation of NF-κB decreased by AFYRW. Taken together, AFYRW attenuated H2O2-induced vascular injury through the PI3K/AKT/NF-κB pathway. Thereby, AFYRW may serve as a therapeutic option for vascular injuries.