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To explore the effects of hydroxyl‐α‐sanshool (HAS) administration on the intestinal health of high‐fat diet‐fed mice, mice were separated into a control (CN) group, a model (MC) group, a HAS (8 mg/kg bw) (HD) group, and a HAS (8 mg/kg bw) + Compound C (10 mg/kg·4 d) (HA) group. After 4 weeks of treatment, the mice were fasted for 12 h prior to sacrifice, and autopsy samples were taken for analysis. HAS improved inflammatory and metabolic imbalances by activating AMPK, as shown by biochemical, microbiota composition, and metabolomics analyses. These findings suggest that HAS can maintain intestinal health through AMPK‐mediated amino acid metabolism. [ABSTRACT FROM AUTHOR]

As a native fruit of China, chestnut rose (Rosa roxburghii Tratt) juice is rich in bioactive ingredients. Oriental fruit moth (OFM), Grapholita molesta (Busck), attacks the fruits and shoots of Rosaceae plants, and its feeding affects the quality and yield of chestnut rose. To investigate the effects of OFM feeding on the quality of chestnut rose juice, the bioactive compounds in chestnut rose juice produced from fruits eaten by OFM were measured. The electronic tongue senses, amino acid profile, and untargeted metabolomics assessments were performed to explore changes in the flavour and metabolites. The results showed that OFM feeding reduced the levels of superoxide dismutase (SOD), tannin, vitamin C, flavonoid, and condensed tannin; increased those of polyphenols, soluble solids, total protein, bitterness, and amounts of bitter amino acids; and decreased the total amino acid and umami amino acid levels. Furthermore, untargeted metabolomics annotated a total of 426 differential metabolites (including 55 bitter metabolites), which were mainly enriched in 14 metabolic pathways, such as flavonoid biosynthesis, tryptophan metabolism, tyrosine metabolism, and diterpenoid biosynthesis. In conclusion, the quality of chestnut rose juice deteriorated under OFM feeding stress, the levels of bitter substances were significantly increased, and the bitter taste was subsequently enhanced. [ABSTRACT FROM AUTHOR]

To explore the mechanism of Rosa roxburghii juice browning, this experiment was based on nontargeted metabolomics to study the effects of browning on the nutrition, flavor, metabolites, and metabolic pathways of R. roxburghii juice before and after storage. The results showed that the total soluble solids, superoxide dismutase (SOD), vitamin C (VC), total phenol, and total flavonoid of R. roxburghii juice decreased significantly before and after storage. The color difference value ∆E, browning index, and flavor and taste of R. roxburghii juice changed significantly (p < 0.05). A total of 541 metabolites were detected before and after browning of R. roxburghii juice by nontargeted metabolomics, including 435 differential metabolites, of which 221 were upregulated, and 214 were downregulated. The differential metabolites were mainly amino acids and peptides, carbohydrates, and carbohydrate conjugates. There were a total of 76 metabolic pathways enriched by differential metabolites, involving mainly galactose metabolism; alanine, aspartate and glutamate metabolism; and pantothenate and CoA biosynthesis. The experimental results showed that after browning of R. roxburghii juice, VC, total phenol, total flavonoid, and SOD activity were seriously lost, and the flavor deteriorated. The contribution of differential metabolites and metabolic pathways to the browning of R. roxburghii juice was sugar metabolism > amino acid metabolism > ascorbate and aldarate metabolism > phenols. [ABSTRACT FROM AUTHOR]

To clarify the role of glucocerebrosidase (GBA) and Ceramide (Cer) in rheumatoid arthritis (RA). GBA-expressing lentivirus were constructed and injected into collagen-induced arthritis (CIA) mice, and compared with CIA mice injected with empty vector. The severity of arthritis and inflammatory mediators were evaluated. Fibroblast-like synoviocytes (FLS) from RA patients were transfected with GBA-expressing lentivirus, or pretreated with C6-Cer. The migration and invasion of FLS, the production of inflammatory cytokines, and the relevant signaling pathways were assessed. In CIA mice, GBA markedly improved arthritis compared to that in the CIA mice, with increased content of proteoglycan and integral cartilage surfaces and tidemarks. The circulating inflammatory mediators, including interleukin (IL)-1β, IL-6, IL-18, and matrix metalloproteinase (MMP)-1, were significantly reduced in CIA mice with GBA overexpression compared to those in CIA mice. GBA and C6-Cer treatment inhibited migration and invasion of FLS, and suppressed production of inflammatory cytokines and activation of the MAPK pathways. GBA/Cer exhibited a protective role in CIA mice and RA FLS. These results highlight the potential of targeting GBA/Cer as a therapeutic strategy in RA and warrant further investigation. [ABSTRACT FROM AUTHOR]

To explore the hydroxy-alpha-sanshool (HAS) effects on the intestinal metabolites of insulin-resistant mice, the blank group (BG), model group (MG), and HAS dose group (DG) were designed. The insulin resistance (IR) model was induced through streptozotocin (STZ) combined with a high-fat and high-sugar diet. Based on the availability of the model, the HAS dose was given by gavage for 28 days. The determination of cecum and key serum indexes was made, including the contents of insulin (INS), triglycerides (TG), total cholesterol (TC), glycosylated serum protein (GSP), and glycosylated hemoglobin (GHb). The changes in gut microbiota and metabolites in cecal contents were detected by 16S rRNA gene amplicon sequencing and UPLC/HRMS technology, respectively. The results that the levels of GSP, GHb, TG, and TC were significantly increased; this was not the case for INS; or for the changes in the gut microbiota and metabolites in MG. However, the intervention of HAS effectively reversed these changes, for instance, it decreased levels of GSP, GHb, TG, TC, and alterations of metabolite composition for linoleic acid and tyrosine metabolism and recovered trends of declining species diversity and richness of the gut microbiota in MG. It was indicated that HAS alleviated IR by regulating the gut microbiota and metabolites and affecting lipid and amino acid metabolism pathways. [ABSTRACT FROM AUTHOR]

Background: Heart rate variability (HRV), reflecting circadian rhythm of heart rate, is reported to be associated with clinical outcomes in stage 5 chronic kidney disease (CKD5) patients. Whether CKD related factors combined with HRV can improve the predictive ability for their death remains uncertain. Here we evaluated the prognosis value of nomogram model based on HRV and clinical risk factors for all-cause mortality in CKD5 patients. Methods: CKD5 patients were enrolled from multicenter between 2011 and 2019 in China. HRV parameters based on 24-h Holter and clinical risk factors associated with all-cause mortality were analyzed by multivariate Cox regression. The relationships between HRV and all-cause mortality were displayed by restricted cubic spline graphs. The predictive ability of nomogram model based on clinical risk factors and HRV were evaluated for survival rate. Results: CKD5 patients included survival subgroup (n = 155) and all-cause mortality subgroup (n = 45), with the median follow-up time of 48 months. Logarithm of standard deviation of all sinus R-R intervals (lnSDNN) (4.40 ± 0.39 vs. 4.32 ± 0.42; p = 0.007) and logarithm of standard deviation of average NN intervals for each 5 min (lnSDANN) (4.27 ± 0.41 vs. 4.17 ± 0.41; p = 0.008) were significantly higher in survival subgroup than all-cause mortality subgroup. On the basis of multivariate Cox regression analysis, the lnSDNN (HR = 0.35, 95%CI: 0.17–0.73, p = 0.01) and lnSDANN (HR = 0.36, 95% CI: 0.17–0.77, p = 0.01) were associated with all-cause mortality, their relationships were negative linear. Spearman's correlation analysis showed that lnSDNN and lnSDANN were highly correlated, so we chose lnSDNN, sex, age, BMI, diabetic mellitus (DM), β-receptor blocker, blood glucose, phosphorus and ln intact parathyroid hormone (iPTH) levels to build the nomogram model. The area under the curve (AUC) values based on lnSDNN nomogram model for predicting 3-year and 5-year survival rates were 79.44% and 81.27%, respectively. Conclusion: In CKD5 patients decreased SDNN and SDANN measured by HRV were related with their all-cause mortality, meanwhile, SDNN and SDANN were highly correlated. Nomogram model integrated SDNN and clinical risk factors are promising for evaluating their prognosis. [ABSTRACT FROM AUTHOR]

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro , were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity. [ABSTRACT FROM AUTHOR]

Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients (n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. The CKD5 patients' baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients. [ABSTRACT FROM AUTHOR]

Microwave ablation (MWA) is feasible for severe renal secondary hyperparathyroidism (SHPT) and primary hyperparathyroidism (PHPT) patients ineligible for parathyroidectomy (PTX). Here we compared the clinical manifestations and characteristics of parathyroid glands in these two groups, and summarized the techniques, safety and efficacy of MWA. Baseline clinical characteristics, ablation-related techniques, adverse events/complications, and efficacy were recorded. In SHPT group, malnutrition, cardiovascular/pulmonary complications, and abnormal bone metabolism were severe. SHPT patients had more hyperplastic parathyroid glands. The volume of each gland was smaller, and the time of ablation for a single parathyroid was shorter in the SHPT group, although there were no significant differences compared with patients in the PHPT group. Three patients in both groups had recurrent laryngeal nerve injuries and all recovered, except for one SHPT patient. By the end of follow-up, serum iPTH levels had decreased from 2400.26 ± 844.26 pg/mL to 429.39 ± 407.93 pg/mL (p <.01) in SHPT and from 297.73 ± 295.32 pg/mL to 72.22 ± 36.51 pg/mL in PHPT group (p <.01). Hypocalcemia was more common (p <.001) and serum iPTH levels were prone to rebound in SHPT patients after MWA. MWA can be reserved for those who had high surgical risks because of less invasiveness. Injuries of recurrent laryngeal nerves should be noticed. The health status, perioperative, and intraoperative procedures were more complicated and all parathyroids found by ultrasound should be ablated completely in SHPT patients. [ABSTRACT FROM AUTHOR]

Purpose: Cardiac valve calcification (CVC) is frequently occurred in maintenance hemodialysis (MHD) patients and is associated with cardiovascular and all-cause mortality. This study aimed to evaluate the relationships between risk factors and extent of CVC and further provide the treatment target in MHD patients. Methods: One hundred and forty-five patients who received MHD ≥3 months were enrolled. CVC was assessed by an echocardiographic, semi-quantitative manner called global cardiac calcium scoring system (GCCS), and demographic, clinical, and laboratory parameters including mineral metabolism markers were collected. Results: The average age of the patients was 50 ± 12 years, and 54.5% were men. The mean GCCS was 1.8 ± 2.4; 57.2% of patients had GCCS ≥1. Age, dialysis vintage, serum alkaline phosphatase (ALP), and intact parathyroid hormone levels were positively correlated with CVC, whereas serum albumin levels were negatively related to CVC, based on univariate analysis. With multivariate linear regression analysis, serum ALP was the only bone-derived biomarker that showed significant correlation with CVC. Serum ALP ≥232 U/L was a robust predictor of CVC and was associated with the likelihood of GCCS ≥1 (OR 3.92, 95% CI 1.37–11.2, p = 0.011). The decision tree model was used to identify ALP ≥232 U/L and age ≥60 years as important determinative variables in the prediction of CVC in MHD patients. Conclusion: Serum ALP level is significantly associated with CVC in MHD patients. ALP is suggested to be a promising interventional target for cardiovascular calcification in MHD patients. [ABSTRACT FROM AUTHOR]

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity., (© The Author(s) (2022). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)