4-octyl itaconate inhibits high glucose induced renal tubular epithelial cell fibrosis through TGF-ß-ROS pathway.

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and has become the leading cause of end-stage kidney disease, causing serious health damage and a huge economic burden. Tubulointerstitial fibrosis play important role in the development of DKD. Itaconate, a macrophage-specific metabolite, has been reported to have anti-oxidant, anti-inflammatory effects. However, it is unknown whether it perform anti-fibrotic effect in renal tubular epithelial cells. In this current study, we observed that in human renal tubular epithelial cells (HK2), high glucose induced an increase in transforming growth factor ß (TGF-ß) production, and upregulated the expressions of fibronectin and collagen I through the TGF-ß receptor as verified by administration of TGF-ß receptor blocker LY2109761. Treatment with 4-octyl itaconate (4-OI), a derivant of itaconic acid, reduced the TGF-ß production induced by high glucose and inhibited the pro-fibrotic effect of TGF-ß in a dose-dependent manner. In addition, we found that 4-OI exerted its anti-fibrotic effect by inhibiting the excessive production of ROS induced by high glucose and TGF-ß. In summary, 4-OI could ameliorate high glucose-induced pro-fibrotic effect in HK2 cell, and blocking the expression of TGF-ß and reducing the excessive ROS production may be involved in its anti-fibrotic effect.

Effects of micro-nano bubble water addition on maturation degree and microbial community during aerobic composting.

In order to explore the effects of micro-nano bubble water (MNBW) on compost maturation and the microbial community in cow manure and straw during aerobic composting, we conducted composting tests using tap water with 12 mg/L (O12), 15 mg/L (O15), 18 mg/L (O18), and 21 mg/L (O21) dissolved oxygen in MNBW, as well as tap water with 9 mg/L dissolved oxygen as a control (CK). The results showed that O21 increased the maximum compost temperature to 64 °C, which was higher than the other treatments. All treatments met the harmless standards for compost. The seed germination index (GI) was largest under O21 and 15.1% higher than that under CK, and the non-toxic compost degree was higher. Redundancy analysis showed that the temperature, C/N, pH, and GI were important factors that affected the microbial community composition. The temperature, C/N, and pH were significantly positively correlated with Firmicutes and Actinobacteria (p < 0.05). Firmicutes was the dominant phylum in the mesophilic stage (2-6 days) and it accounted for a large proportion under O21, where the strong thermophilic metabolism increased the production of heat and prolonged the high temperature period. The bacterial genus Ammoniibacillus in Firmicutes accounted for a large proportion under O21 and it accelerated the decomposition of substrates. Therefore, the addition of MNBW changed the microbial community to affect the maturation of the compost, and the quality of the compost was higher under O21.

Characterization of aberrant glycosylation associated with osteoarthritis based on integrated glycomics methods.

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis, affecting millions of aging people. Investigation of abnormal glycosylation is essential for the understanding of pathological mechanisms of OA. METHODS: The total protein was isolated from OA (n = 13) and control (n = 11) cartilages. Subsequently, glycosylation alterations of glycoproteins in OA cartilage were investigated by lectin microarrays and intact glycopeptides analysis. Finally, the expression of glycosyltransferases involved in the synthesis of altered glycosylation was assessed by qPCR and GEO database. RESULTS: Our findings revealed that several glycopatterns, such as α-1,3/6 fucosylation and high-mannose type of N-glycans were altered in OA cartilages. Notably, over 27% of identified glycopeptides (109 glycopeptides derived from 47 glycoproteins mainly located in the extracellular region) disappeared or decreased in OA cartilages, which is related to the cartilage matrix degradation. Interestingly, the microheterogeneity of N-glycans on fibronectin and aggrecan core protein was observed in OA cartilage. Our results combined with GEO data indicated that the pro-inflammatory cytokines altered the expression of glycosyltransferases (ALG3, ALG5, MGAT4C, and MGAT5) which may contribute to the alterations in glycosylation. CONCLUSION: Our study revealed the abnormal glycopatterns and heterogeneities of site-specific glycosylation associated with OA. To our knowledge, it is the first time that the heterogeneity of site-specific N-glycans was reported in OA cartilage. The results of gene expression analysis suggested that the expression of glycosyltransferases was impacted by pro-inflammatory cytokines, which may facilitate the degradation of protein and accelerate the process of OA. Our findings provide valuable information for the understanding of molecular mechanisms in the pathogenesis of OA.

Mechanism for combined application of biochar and Bacillus cereus to reduce antibiotic resistance genes in copper contaminated soil and lettuce.

The remediation of agricultural soil contaminated by antibiotic resistance genes (ARGs) is of great significance for protecting food safety and human health. Reducing the availability of copper in soil may control coresistance to ARGs. However, the feasibility of applying nano-biochar and Bacillus cereus to mitigate the spread of ARGs in Cu contaminated soil remains unclear. Therefore, this study investigated the use of biochar with different particle sizes (2 % apple branch biochar and 0.5 % nano-biochar) and 3 g m-2B. cereus in a 60-day pot experiment with growing lettuce. The effects of single and combined application on the abundances of ARGs in Cu-contaminated soil (Cu = 200 mg kg-1) were compared, and the related mechanisms were explored. Studies have shown that the addition of biochar alone is detrimental to mitigating ARGs in soil-lettuce systems. The combined application of 3 g m-2B. cereus and 0.5 % nano-biochar effectively inhibited the proliferation of ARGs in Cu-contaminated soil, and 3 g m-2B. cereus effectively inhibited the proliferation of ARGs in lettuce. Partial least squares-path modeling and network analysis showed that bacterial communities and mobile genetic elements were the key factors that affected the abundances of ARGs in rhizosphere soil, and Cu resistance genes and bioavailable copper (acid extractable state Cu (F1) + reducing state Cu (F2)) had less direct impacts. The bacterial community was the key factor that affected the abundances of ARGs in lettuce. Rhodobacter (Proteobacteria), Corynebacterium (Actinobacteria), and Methylobacterium (Proteobacteria) may have been hosts of ARGs in lettuce plants. B. cereus and nano-biochar affected the abundances of ARGs by improving the soil properties and reducing the soil bioavailability of Cu, as well as directly or indirectly changing the bacterial community composition in soil and lettuce, thereby impeding the transport of ARGs to aboveground plant parts.

Therapeutic potential of puerarin against cerebral diseases: From bench to bedside.

The incidence of cerebral diseases is rapidly increasing worldwide, and they have become an important challenge for modern medicine. Most of the available chemical drugs used in the treatment of cerebral diseases are highly toxic and single-targeted. Therefore, novel drugs from natural resources have attracted much attention for their potential to manage cerebral diseases. Puerarin is a natural isoflavone isolated from the roots of Pueraria species such as P. lobata (Willd.) Ohwi, P. thomsonii, and P. mirifica. Several authors have reported the beneficial effects of puerarin in cerebral ischemic disease, intracerebral hemorrhage, vascular dementia, Alzheimer's disease, Parkinson's disease, depression, anxiety, and traumatic brain injury. This review summarizes the brain pharmacokinetics, brain drug delivery system, clinical use (in cerebral diseases), toxicity, and the adverse clinical reactions of puerarin. We have systematically presented the pharmacological actions and the molecular mechanisms of puerarin in various cerebral diseases to provide a direction for future researches on the therapeutic use of puerarin in cerebral diseases.

Subtalar arthroereisis combined with medial soft tissue reconstruction in treating pediatric flexible flatfoot with accessory navicular.

PURPOSE: Accessory navicular is accompanied by the deformity of valgus flexible flatfoot. The surgical treatment includes reconstruction of insertion of posterior tibial tendon following resection of the accessory navicular. However, this treatment could not correct completely the deformity of valgus flexible flatfoot. This study aimed to evaluate the efficacy of subtalar arthroereisis combined with medial soft tissue reconstruction in treating 8-14-year-old flexible flatfoot patients with accessory navicular. METHODS: Clinical data of 35 pediatric flatfoot patients (with 50 feet) with accessory navicular who underwent subtalar arthroereisis and medial soft tissue reconstruction between April 2013 and September 2018 were analyzed retrospectively. Anteroposterior, lateral, and hindfoot alignment radiological images were measured in the weight-bearing position, and visual analog scale (VAS), American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale, and satisfaction degree were evaluated. Also, surgical complications were recorded. RESULTS: The average follow-up time of the patients was 30 ± 9.3 months. None of the patients presented wound complications, and no implant loosening was detected. The AOFAS and VAS scores improved significantly (P < 0.001). Radiological parameters, such as the talar first metatarsal angle and talonavicular coverage angle on anteroposterior foot view, Meary's angle and calcaneal pitch angle on the lateral view, and calcaneus valgus angle on hindfoot alignment view improved significantly (P < 0.001). Postoperative complications were observed in three patients. CONCLUSION: Subtalar arthroereisis combined with medial soft tissue reconstruction significantly alleviated pain and improved the functions in pediatric and adolescent flexible flatfoot patients with accessory navicular; also, the radiological manifestations and functions improved.

Elevation of α-1,3 fucosylation promotes the binding ability of TNFR1 to TNF-α and contributes to osteoarthritic cartilage destruction and apoptosis.

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis and is characterized by the degradation of articular cartilage and inflammation of the synovial membrane. Fucosylation is an important feature of protein N/O-glycosylation and is involved in a variety of pathological processes, including inflammation and cancer. However, whether fucosylation impacts the OA pathological process is unknown. METHODS: Total proteins were extracted from cartilage samples obtained from patients with OA (n = 11) and OA rabbit models at different time points (n = 12). OA-associated abnormal glycopatterns were evaluated by lectin microarrays and lectin blots. The expression of fucosyltransferases involved in the synthesis of α-1,3 fucosylation was assessed by semi-qPCR. The synthesis of α-1,3 fucosylation mediated by FUT10 was interrupted by the transfection of siRNA, and the effect of α-1,3 fucosylation on OA-associated events was assessed. Then, immunoprecipitation and lectin blotting were used to investigate the relationship between the α-1,3 fucosylation level of tumor necrosis factor receptor superfamily member 1A (TNFR1) and OA. Finally, a TNFR1 antibody microarray was fabricated to evaluate the effect of α-1,3 fucosylation on the ability of TNFR1 to bind to tumor necrosis factor-α (TNF-α). RESULTS: Elevated α-1,3 fucosylation was observed in cartilage from OA patients, rabbit models, and chondrocytes induced by TNF-α (fold change> 2, p< 0.01). Our results and the GEO database indicated that the overexpression of FUT10 contributed to this alteration. Silencing the expression of FUT10 impaired the ability of TNFR1 to bind to TNF-α, impeded activation of the NF-κB and P38/JNK-MAPK pathways, and eventually retarded extracellular matrix (ECM) degradation, senescence, and apoptosis in chondrocytes exposed to TNF-α. CONCLUSION: The elevation of α-1,3 fucosylation is not only a characteristic of OA but also impacts the OA pathological process. Our work provides a new positive feedback loop of "inflammation conditions/TNF-α/FUT10/α-1,3 fucosylation of TNFR1/NF-κB and P38/JNK-MAPK pathways/proinflammatory processes" that contributes to ECM degradation and chondrocyte apoptosis.

The Preventive Value of Acupoint Sensitization for Patients with Stable Angina Pectoris: A Randomized, Double-Blind, Positive-Controlled, Multicentre Trial.

BACKGROUND: Acupoint sensitization is considered an important factor in the efficacy of acupoint therapy. This study aimed to evaluate the efficacy of acupressure in the prevention of stable angina pectoris using acupoints with different pressure-pain sensitivities. METHODS: A total of 202 patients were enrolled and randomly assigned to a high-sensitivity group (HSG) (n = 109) in which patients received acupressure at the five acupoints with the highest sensitivity to pain and a low-sensitivity group (LSG) (n = 93) in which patients received acupressure at the five acupoints with the lowest sensitivity to pain. The duration of acupressure treatment was 4 weeks, and the patients were evaluated at baseline, week 4, and week 8. The primary outcome was a change in the frequency of angina attacks from baseline. The secondary outcomes included nitroglycerin consumption, the Canadian Cardiovascular Society classification, and the Seattle Angina Questionnaire score. Adverse events such as bleeding and subcutaneous haemorrhage were recorded in both groups. RESULTS: The effect of acupressure compared with baseline on the prevention of angina pectoris in HSG was better than that in LSG at week 4 (incidence rate ratio (IRR): 0.691 and 95% confidence interval (CI): [0.569, 0.839]) and week 8 (IRR: 0.692 and 95% CI: [0.569, 0.839]). No significant difference between groups was found in the frequency of nitroglycerin consumption at week 4 (odds ratio (OR) = 0.863 and 95% CI: [0.147, 5.077]) or week 8 (OR = 1.426 and 95% CI: [0.211, 9.661]). Two themes in the questionnaire showed significantly different changes from baseline between the two groups. Scores on the angina frequency (AF) subscale had changed more from the baseline in the HSG at week 8 than in the LSG (mean difference (MD) = 3.807 and 95% CI: [0.673, 6.942]). Scores on the treatment satisfaction (TS) subscale had also changed more in the HSG than in the LSG at week 4 (MD = 3.651 and 95% CI: [0.327, 7.327]) and week 8 (MD = 4.220 and 95% CI: [0.347, 7.346]). One patient in the LSG reported bruising at the acupoint. No unexpected safety problems arose. CONCLUSIONS: This study showed that acupressure at acupoints with high sensitivity to pain may effectively reduce the frequency of stable angina pectoris episodes. This trial is registered with NCT03975140.

Adenotonsillectomy outcomes regarding bone age and osteocalcin in treatment of obstructive sleep apnea syndrome in children.

BACKGROUND: To investigate the effect of adenotonsillectomy (AT) on bone development, quality of life and polysomnography evaluation in children with obstructive sleep apnea syndrome (OSA). METHODS: Preoperative and postoperative (6 months) physical examination, PSG, bone age (BA) and osteocalcin (OC) evaluation were performed on the selected OSA children (n=92) and the healthy children (n=87). The OSA children were also scored based on the OSA 18-item questionnaire. A two-year follow-up was conducted to evaluate BA and OC changes. RESULTS: After AT, 81 (88.04%) OSA children recovered completely, eight (8.70%) achieved remarkable improvements, and three (3.26%) achieved moderate improvements. In the OSA children, postoperative OSA 18-item score and the scores of the five domains were significantly higher than preoperative ones. Compared with the preoperative, body mass index (BMI), weight for age Z-sores, height for age Z-sores, weight for height Z-sores and BMI Z-score in the OSA group 6 months after the operation were significantly increased, but no significant difference was detected between the OSA and the control group. The changes of BA and chronological age in the OSA group were significantly different from those in the control group. Two years after AT, BA between the two groups was no longer significantly different. Preoperative serum OC in the OSA group was lower than that in the control group, but increased to normal levels 6 months after AT. Correlation analysis showed serum OC levels were negatively correlated with apnea hyponea index, obstructive apnea index, arousal index, and lowest oxygen saturation. CONCLUSIONS: After AT, bone growth and development in children with OSA recovered gradually, and the serum OC levels decreased to the normal level. Therefore, preventive measures and positive treatments should be applied to minimize the negative effects of OSA in children.