The mechanism underlying bone impairment in patients with diabetes mellitus, a metabolic disorder characterized by chronic hyperglycaemia and dysregulation in metabolism, is unclear. Here we show the difference in the metabolomics of bone marrow stromal cells (BMSCs) derived from hyperglycaemic (type 2 diabetes mellitus, T2D) and normoglycaemic mice. One hundred and forty-two metabolites are substantially regulated in BMSCs from T2D mice, with the tricarboxylic acid (TCA) cycle being one of the primary metabolic pathways impaired by hyperglycaemia. Importantly, succinate, an intermediate metabolite in the TCA cycle, is increased by 24-fold in BMSCs from T2D mice. Succinate functions as an extracellular ligand through binding to its specific receptor on osteoclastic lineage cells and stimulates osteoclastogenesis in vitro and in vivo. Strategies targeting the receptor activation inhibit osteoclastogenesis. This study reveals a metabolite-mediated mechanism of osteoclastogenesis modulation that contributes to bone dysregulation in metabolic disorders.

During its life cycle, Zika virus (ZIKV), an arthropod-borne flavivirus that is associated with Guillain-Barré syndrome and causes microencephaly in fetuses and newborn children, encodes a critical and indispensable helicase domain that has 5'-triphosphatase activity and performs ATP hydrolysis to generate energy and thus, sustains unwinding of double-stranded RNA during ZIKV genome replication. Of these processes, ATP hydrolysis represents the most basic event; however, its dynamic mechanisms remain largely unknown, impeding the further understanding of the function of ZIKV helicase and the ongoing anti-ZIKV drug design. In this work, we determined the crystal structure of ZIKV helicase in complex with ADP-AlF-Mn and ADP-Mn separately. The structural analysis indicates that these structures represent the intermediate state and posthydrolysis state, respectively, of the ATP hydrolysis process of ZIKV helicase. These findings, together with our earlier work, which identified the prehydrolysis state of ZIKV helicase, lead to a proposal of the ATP hydrolysis cycle for ZIKV helicase. On this basis, we used site-directed mutagenesis combined with an enzymatic study to identify successfully residues that are critical for the ATPase activity of ZIKV helicase; this will provide new ideas to understand the function for the key enzyme of ZIKV.-Yang, X., Chen, C., Tian, H., Chi, H., Mu, Z., Zhang, T., Yang, K., Zhao, Q., Liu, X., Wang, Z., Ji, X., Yang, H. Mechanism of ATP hydrolysis by the Zika virus helicase.

Background: Osteoarthritis (OA) is the commonest form of inflammatory joint disease. Unfortunately, to date, there is no appropriate treatment for OA. Boswellia serrata was considered as a potent anti-inflammatory, anti-arthritic and analgesic agent that may be a drug for OA. Methods: In this meta-analysis, data from randomized controlled trials were obtained to assess the effects of Boswellia or its extract versus placebo or western medicine in patients with OA. The primary outcomes included visual analogue score (VAS), WOMAC pain, WOMAC stiffness, WOMAC function and lequesne index. Result: Seven trials involving 545 patients were included. Compared with the control group, Boswellia and its extract may relieve the pain [VAS:

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Branched DNA motifs serve as the basic construction elements for all synthetic DNA nanostructures. However, precise control of branching orientation remains a key challenge to further heighten the overall structural order. In this study, we use two strategies to control the branching orientation. The first one is based on immobile Holliday junctions which employ specific nucleotide sequences at the branch points which dictate their orientation. The second strategy is to use angle‐enforcing struts to fix the branching orientation with flexible spacers at the branch points. We have also demonstrated that the branching orientation control can be achieved dynamically, either by canonical Watson–Crick base pairing or non‐canonical nucleobase interactions (e.g., i‐motif and G‐quadruplex). With precise angle control and feedback from the chemical environment, these results will enable novel DNA nanomechanical sensing devices, and precisely‐ordered three‐dimensional architectures.

Background. Diabetes is a major public health concern. In addition, there is some evidence to support curcumin as part of a diabetes treatment program. Methods. Data from randomized controlled trials were obtained to assess the effects of curcumin versus placebo or western medicine in patients with type 2 diabetes mellitus (T2DM). The study’s registration number is CRD42018089528. The primary outcomes included homeostasis model assessment-insulin resistance (HOMA-IR), glycosylated hemoglobin (HbAlc), total cholesterol (TC), and triglyceride (TG). Results. Four trials involving 453 patients were included. The HOMA-IR of curcumin group is lower in Asia (WMD: −2.41, 95% CI: −4.44 to −0.39, P = 0.02 ) and the Middle East subgroups (WMD: −0.60, 95% CI: −0.74 to −0.46, P < 0.00001 ). The HbAlc in the curcumin group is lower than that in the control group (WMD: −0.69; 95% CI: −0.91, −0.48; P < 0.0001 ). The TC and TG levels of the curcumin group are lower in the Asia subgroup (TC: WMD: −23.45, 95% CI: −40.04 to −6.84, P = 0.006 ; TG: WMD: −54.14, 95% CI: −95.71 to −12.57, P = 0.01 ), while in the Middle East the difference was of not statistically significant (TC: WMD: 22.91, 95% CI: −16.94 to 62.75, P = 0.26 ; TG: WMD: −4.56, 95% CI: −19.28 to 10.16, P = 0.54 ). Conclusion. Based on the current evidence, curcumin may assist in improving the insulin resistance, glycemic control, and decreased TG and TC in patients with T2DM.

Edited by Ronald C. Wek REV7, also termed mitotic arrest-deficient 2-like 2 (MAD2L2 or MAD2B), acts as an interaction module in a broad array of cellular pathways, including translesion DNA synthesis, cell cycle control, and nonhomologous end joining. Numerous REV7 binding partners have been identified, including the human small GTPase Ras-associated nuclear protein (RAN), which acts as a potential upstream regulator of REV7. Notably, the Shigella invasin IpaB hijacks REV7 to disrupt cell cycle control to prevent intestinal epithelial cell renewal and facilitate bacterial colonization. However, the structural details of the REV7-RAN and REV7-IpaB interactions are mostly unknown. Here, using fusion protein and rigid maltose-binding protein tagging strategies, we determined the crystal structures of these two complexes at 2.00-2.35 Å resolutions. The structures revealed that both RAN and IpaB fragments bind the "safety belt" region of REV7, inducing rearrangement of the C-terminal ␤-sheet region of REV7, conserved among REV7-related complexes. Of note, the REV7-binding motifs of RAN and IpaB each displayed some unique interactions with REV7 despite sharing consensus residues. Structural alignments revealed that REV7 has an adaptor region within the safety belt region that can rearrange secondary structures to fit a variety of different ligands. Our structural and biochemical results further indicated that REV7 preferentially binds GTP-bound RAN, implying that a GTP/GDP-bound transition of RAN may serve as the molecular switch that controls REV7's activity. These results provide insights into the regulatory mechanism of REV7 in cell cycle control, which may help with the development of small-molecule inhibitors that target REV7 activity.

BackgroundDietary polyphenol treatment of non-alcoholic fatty liver disease (NAFLD) is a novel direction, and the existing clinical studies have little effective evidence for its therapeutic effect, and some studies have inconsistent results. The effectiveness of dietary polyphenols in the treatment of NAFLD is still controversial. The aim of this study was to evaluate the therapeutic efficacy of oral dietary polyphenols in patients with NAFLD.MethodsThe literature (both Chinese and English) published before 30 April 2022 in PubMed, Cochrane, Medline, CNKI, and other databases on the treatment of NAFLD with dietary polyphenols was searched. Manual screening, quality assessment, and data extraction of search results were conducted strictly according to the inclusion and exclusion criteria. RevMan 5.3 software was used to perform the meta-analysis.ResultsThe RCTs included in this study involved dietary supplementation with eight polyphenols (curcumin, resveratrol, naringenin, anthocyanin, hesperidin, catechin, silymarin, and genistein) and 2,173 participants. This systematic review and meta-analysis found that 1) curcumin may decrease body mass index (BMI), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Triglycerides (TG) total cholesterol (TC), and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) compared to placebo; and curcumin does not increase the occurrence of adverse events. 2) Although the meta-analysis results of all randomized controlled trials (RCTs) did not reveal significant positive changes, individual RCTs showed meaningful results. 3) Naringenin significantly decreased the percentage of NAFLD grade, TG, TC, and low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) but had no significant effect on AST and ALT, and it is a safe supplementation. 4) Only one team presents a protocol about anthocyanin (from Cornus mas L. fruit extract) in the treatment of NAFLD. 5) Hesperidin may decrease BMI, AST, ALT, TG, TC, HOMA-IR, and so on. 6) Catechin may decrease BMI, HOMA-IR, and TG level, and it was well tolerated by the patients. 7) Silymarin was effective in improving ALT and AST and reducing hepatic fat accumulation and liver stiffness in NAFLD patients.ConclusionBased on current evidence, curcumin can reduce BMI, TG, TC, liver enzymes, and insulin resistance; catechin can reduce BMI, insulin resistance, and TG effectively; silymarin can reduce liver enzymes. For resveratrol, naringenin, anthocyanin, hesperidin, and catechin, more RCTs are needed to further evaluate their efficacy and safety.