Molecular mechanism of the metal-independent production of hydroxyl radicals by thiourea dioxide and H2O2.

It is well-known that highly reactive hydroxyl radicals (HO•) can be produced by the classic Fenton system and our recently discovered haloquinone/H2O2 system, but rarely from thiol-derivatives. Here, we found, unexpectedly, that HO• can be generated from H2O2 and thiourea dioxide (TUO2), a widely used and environmentally friendly bleaching agent. A carbon-centered radical and sulfite were detected and identified as the transient intermediates, and urea and sulfate as the final products, with the complementary application of electron spin-trapping, oxygen-18 isotope labeling coupled with HPLC/MS analysis. Density functional theory calculations were conducted to further elucidate the detailed pathways for HO• production. Taken together, we proposed that the molecular mechanism for HO• generation by TUO2/H2O2: TUO2 tautomerizes from sulfinic acid into ketone isomer (TUO2-K) through proton transfer, then a nucleophilic addition of H2O2 on the S atom of TUO2-K, forming a S-hydroperoxide intermediate TUO2-OOH, which dissociates homolytically to produce HO•. Our findings represent the first experimental and computational study on an unprecedented new molecular mechanism of HO• production from simple thiol-derived sulfinic acids, which may have broad chemical, environmental, and biomedical significance for future research on the application of the well-known bleaching agent and its analogs.

Chromosomal-scale genomes of two Rosa species provide insights into genome evolution and ascorbate accumulation.

Rosa roxburghii and Rosa sterilis, two species belonging to the Rosaceae family, are widespread in the southwest of China. These species have gained recognition for their remarkable abundance of ascorbate in their fresh fruits, making them an ideal vitamin C resource. In this study, we generated two high-quality chromosome-scale genome assemblies for R. roxburghii and R. sterilis, with genome sizes of 504 and 981.2 Mb, respectively. Notably, we present a haplotype-resolved, chromosome-scale assembly for diploid R. sterilis. Our results indicated that R. sterilis originated from the hybridization of R. roxburghii and R. longicuspis. Genome analysis revealed the absence of recent whole-genome duplications in both species and identified a series of duplicated genes that possibly contributing to the accumulation of flavonoids. We identified two genes in the ascorbate synthesis pathway, GGP and GalLDH, that show signs of positive selection, along with high expression levels of GDP-d-mannose 3', 5'-epimerase (GME) and GDP-l-galactose phosphorylase (GGP) during fruit development. Furthermore, through co-expression network analysis, we identified key hub genes (MYB5 and bZIP) that likely regulate genes in the ascorbate synthesis pathway, promoting ascorbate biosynthesis. Additionally, we observed the expansion of terpene synthase genes in these two species and tissue expression patterns, suggesting their involvement in terpenoid biosynthesis. Our research provides valuable insights into genome evolution and the molecular basis of the high concentration of ascorbate in these two Rosa species.

TNFAIP3 Derived from Skeletal Stem Cells Alleviated Rat Osteoarthritis by Inhibiting the Necroptosis of Subchondral Osteoblasts.

Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). This study aimed to investigate the potential effects of exogenous skeletal stem cells (SSCs) on the necroptosis of subchondral osteoblasts in OA. Human SSCs and subchondral osteoblasts isolated from human tibia plateaus were used for Western blotting, real-time PCR, RNA sequencing, gene editing, and necroptosis detection assays. In addition, the rat anterior cruciate ligament transection OA model was used to evaluate the effects of SSCs on osteoblast necroptosis in vivo. The micro-CT and pathological data showed that intra-articular injections of SSCs significantly improved the microarchitecture of subchondral trabecular bones in OA rats. Additionally, SSCs inhibited the necroptosis of subchondral osteoblasts in OA rats and necroptotic cell models. The results of bulk RNA sequencing of SSCs stimulated or not by tumor necrosis factor α suggested a correlation of SSCs-derived tumor necrosis factor α-induced protein 3 (TNFAIP3) and cell necroptosis. Furthermore, TNFAIP3-derived from SSCs contributed to the inhibition of the subchondral osteoblast necroptosis in vivo and in vitro. Moreover, the intra-articular injections of TNFAIP3-overexpressing SSCs further improved the subchondral trabecular bone remodeling of OA rats. Thus, we report that TNFAIP3 from SSCs contributed to the suppression of the subchondral osteoblast necroptosis, which suggests that necroptotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.

miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence.

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

The anti-cancer drug candidate CBL0137 induced necroptosis via forming left-handed Z-DNA and its binding protein ZBP1 in liver cells.

CBL0137, a promising small molecular anti-cancer drug candidate, has been found to effectively induce apoptosis via activating p53 and suppressing nuclear factor-kappa B (NF-κB). However, it is still not clear whether CBL0137 can induce necroptosis in liver cancer; and if so, what is the underlying molecular mechanism. Here we found that CBL0137 could significantly induce left-handed double helix structure Z-DNA formation in HepG2 cells as shown by Z-DNA specific antibody assay, which was further confirmed by observing the expression of Z-DNA binding protein 1 (ZBP1) and adenosine deaminase acting on RNA 1 (ADAR1). Interestingly, we found that caspase inhibition significantly promoted CBL0137-induced necroptosis, which was further supported with the increase of the late apoptosis and necrosis assessed by the flow cytometry. Furthermore, we found that CBL0137 can also induce the expression of the three necroptosis-related proteins: receptor interacting serine/threonine kinase 1 (RIPK1), receptor interacting serine/threonine kinase 3 (RIPK3), and mixed lineage kinase domain-like (MLKL). Taken together, it was assumed that CBL0137-indued necroptosis in liver cells was due to induction of Z-DNA and ZBP1, which activated RIPK1/RIPK3/MLKL pathway. This represents the first report on the induction of the Z-DNA-mediated necroptosis by CBL0137 in the liver cancer cells, which should provide new perspectives for CBL0137 treatment of liver cancer.

Losartan alleviates renal fibrosis by inhibiting the biomechanical stress-induced epithelial-mesenchymal transition of renal epithelial cells.

Angiotensin receptor blockers (ARBs) have been reported to be beneficial of renal fibrosis, but the molecular and cellular mechanisms are still unclear. In this study, we investigated the effectiveness and relevant mechanism of ARBs in alleviating renal fibrosis, especially by focusing on biomechanical stress-induced epithelial to mesenchymal transition (EMT) of renal epithelial cells. Unilateral ureteral obstruction (UUO) renal fibrosis model was established in mice by ligating the left ureter, and then randomly received losartan at a low dose (1 mg/kg) or a regular dose (3 mg/kg) for 2 weeks. Compared to the control, histological analysis showed that losartan treatment at either a low dose or a regular dose effectively attenuated renal fibrosis in the UUO model. To further understand the mechanism, we ex vivo loaded primary human renal epithelial cells to 50 mmHg hydrostatic pressure. Western blot and immunostaining analyses indicated that the loading to 50 mmHg hydrostatic pressure for 24 h significantly upregulated vimentin, ß-catenin and α-SMA, but downregulated E-cadherin in renal epithelial cells, suggesting the EMT. The addition of 10 or 100 nM losartan in medium effectively attenuated the EMT of renal epithelial cells induced by 50 mmHg hydrostatic pressure loading. Our in vivo and ex vivo experimental data suggest that losartan treatment, even at a low dose can effectively alleviate renal fibrosis in mouse UUO model, at least partly by inhibiting the biomechanical stress-induced EMT of renal epithelial cells. A low dose of ARBs may repurpose for renal fibrosis treatment.

Mediating effect of subclinical inflammation on the process of morning hypertension leading to atrial fibrillation in community-based older adults.

BACKGROUND: The impacts and mechanisms of morning hypertension (MHT) on the risk of new-onset atrial fibrillation (AF) in the elderly have not been clarified. We aimed to investigate an association between MHT and new-onset AF and explore a mediating effect of subclinical inflammation on this association. METHODS: From 2008 to 2010, 1789 older adults aged ≥60 years were recruited in Shandong area, China. Morning blood pressure (BP) was assessed using 24-hour ambulatory BP monitoring. MHT was defined as BP ≥ 135/85 mm Hg during the period from wake time to 0900 a.m. Subclinical inflammation was assessed by hypersensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and galectin-3. New-onset AF was rated during the follow-up period. RESULTS: Over an average 129.0 [standard deviation (SD): 21.58] months of follow-up, the hazard ratio of new-onset AF in MHT patients was 1.39 (95% confidence interval: 1.01 to 1.91) compared with non-MHT participants (Padjusted = 0.027). The risk of new-onset AF was 1.17-fold with one-SD increment of morning systolic BP. Subclinical inflammation was significantly associated with new-onset AF. The hazard ratios of new-onset AF were 2.29, 2.04, 2.08, 2.08, 2.03, and 3.25 for one-SD increment in hsCRP, TNF-α, SII, NLR, PLR, and galectin-3, respectively (Padjusted < 0.001). The analysis showed that hsCRP, TNF-α, SII, NLR, PLR, and galectin-3 separately mediated the process of MHT inducing new-onset AF (Padjusted < 0.05). CONCLUSIONS: MHT is associated with an increased risk of new-onset AF. The subclinical inflammation might play a mediating role in this association.

Study on the Interaction Behaviors Identification of Construction Workers Based on ST-GCN and YOLO.

The construction industry is accident-prone, and unsafe behaviors of construction workers have been identified as a leading cause of accidents. One important countermeasure to prevent accidents is monitoring and managing those unsafe behaviors. The most popular way of detecting and identifying workers' unsafe behaviors is the computer vision-based intelligent monitoring system. However, most of the existing research or products focused only on the workers' behaviors (i.e., motions) recognition, limited studies considered the interaction between man-machine, man-material or man-environments. Those interactions are very important for judging whether the workers' behaviors are safe or not, from the standpoint of safety management. This study aims to develop a new method of identifying construction workers' unsafe behaviors, i.e., unsafe interaction between man-machine/material, based on ST-GCN (Spatial Temporal Graph Convolutional Networks) and YOLO (You Only Look Once), which could provide more direct and valuable information for safety management. In this study, two trained YOLO-based models were, respectively, used to detect safety signs in the workplace, and objects that interacted with workers. Then, an ST-GCN model was trained to detect and identify workers' behaviors. Lastly, a decision algorithm was developed considering interactions between man-machine/material, based on YOLO and ST-GCN results. Results show good performance of the developed method, compared to only using ST-GCN, the accuracy was significantly improved from 51.79% to 85.71%, 61.61% to 99.11%, and 58.04% to 100.00%, respectively, in the identification of the following three kinds of behaviors, throwing (throwing hammer, throwing bottle), operating (turning on switch, putting bottle), and crossing (crossing railing and crossing obstacle). The findings of the study have some practical implications for safety management, especially workers' behavior monitoring and management.

Two Ferulic Acid Derivatives Inhibit Neuroinflammatory Response in Human HMC3 Microglial Cells via NF-κB Signaling Pathway.

Various physiological and pathological changes are related to the occurrence and development of neurodegenerative diseases. Neuroinflammation is a major trigger and exacerbation of neurodegenerative diseases. One of the main symptoms of neuritis is the activation of microglia. Thus, to alleviate the occurrence of neuroinflammatory diseases, an important method is to inhibit the abnormal activation of microglia. This research evaluated the inhibitory effect of trans-ferulic acid (TJZ-1) and methyl ferulate (TJZ-2), isolated from Zanthoxylum armatum, on neuroinflammation, by establishing the human HMC3 microglial cell neuroinflammation model induced by lipopolysaccharide (LPS). The results showed both compounds significantly inhibited the production and expression of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) contents, and increased the level of anti-inflammatory factor ß-endorphin (ß-EP). Furthermore, TJZ-1 and TJZ-2 can inhibit LPS-induced activation of nuclear factor kappa B (NF-κB). It was found that of two ferulic acid derivatives, both had anti-neuroinflammatory effects by inhibiting the NF-κB signaling pathway and regulating the release of inflammatory mediators, such as NO, TNF-α, IL-1ß, and ß-EP. This is the first report that demonstrates that TJZ-1 and TJZ-2 had inhibitory effects on LPS-induced neuroinflammation in human HMC3 microglial cells, which indicates that two ferulic acid derivates from Z. armatum could be used as potential anti-neuroinflammatory agents.

Angiotensin receptor blocker alleviates liver fibrosis by altering the mechanotransduction properties of hepatic stellate cells.

Angiotensin receptor blockers have been reported to be beneficial to liver fibrosis, but the relevant molecular and cellular mechanisms remain unclear. We herein investigated whether low-dose angiotensin receptor blocker alleviated liver fibrosis through mechanotransduction regulation. Hydrostatic pressure-induced liver fibrosis model was established in mice by ligating partially the inferior vena cava, and then randomly received a very low dose of losartan (0.5 mg/kg) or placebo treatment for 8 weeks. We found that losartan administration interfered the expression of several mechanotransductive molecules, and effectively alleviated liver fibrosis. Using a commercial device, we further confirmed that ex vivo loading of hepatic stellate cells to 50 mmHg hydrostatic pressure for 24 h significantly upregulated RhoA, ROCK, AT1R, and p-MLC2, which was effectively attenuated by adding 10 nM losartan in medium. Our in vivo and ex vivo experimental data suggest that low-dose angiotensin receptor blockers may alleviate hydrostatic pressure-induced liver fibrosis by altering the mechanotransduction properties of hepatic stellate cells.NEW & NOTEWORTHY Our ex vivo and in vivo experiments clearly indicated that low-dose losartan alleviated liver fibrosis, likely by modulating the mechanotransduction properties of HSCs. Uncovering the biomechanical signaling pathway of ARB treatment on liver fibrosis will be helpful to develop novel molecular targeting therapy for liver diseases.

Prevention of delayed post-polypectomy bleeding by prophylactic clipping after endoscopic colorectal polypectomy: a meta-analysis.

PURPOSE: This meta-analysis aims to investigate the role of prophylactic clipping after endoscopic colorectal polypectomy or endoscopic mucosal resection (EMR) in prevention of delayed bleeding (DB) following polypectomy. METHODS: We searched the PubMed, Embase, and Cochrane Library databases for randomized controlled trials comparing the effect of prophylactic clipping versus no clipping on DB since inception to 22nd April 2022. We then performed a meta-analysis using a random-effects model. RESULTS: We included 8 studies with 5648 patients and 10,436 lesions. Prophylactic clipping did not reduce the overall risk of DB compared with no clipping (1.54% vs 2.05%; Log RR, -0.29; 95% confidence interval [CI], -0.59, 0.01; P = 0.06). In subgroup analyses, clipping significantly reduced DB rate in polyps ≥ 2 cm (Log RR, -0.63; 95% CI, -1.08, -0.18; P = 0.01), in non-pedunculated polyps (Log RR, -0.63; 95% CI, -1.01, -0.24; P = 0.00), and in large (≥ 2 cm) proximal polyps (Log RR, -0.81; 95% CI, -1.56, 0.05; P = 0.04), but not in polyps < 2 cm (Log RR, 0.01; 95% CI, -.40, 0.42; P = 0.95). CONCLUSION: Prophylactic clipping does not prevent post-polypectomy bleeding after all EMR and should not be performed as a routine practice. Although prophylactic clipping may reduce DB rate following resection of large proximal polyps and non-pedunculated polyps, more high-quality studies are needed to determine the effects of factors such as polyp location, polyp morphology, antithrombotic drug use and complete or partial closure on the effectiveness of prophylactic clipping.

Enhanced aerobic granulation for treating low-strength wastewater in an anaerobic-aerobic-anoxic sequencing batch reactor by selecting slow-growing organisms and adding carriers.

The aerobic granular sludge (AGS) process is a promising technology for wastewater treatment. However, a long start-up period for granulation and instability during long-term operation still hinder the application of AGS technology, especially for low-strength wastewater. To solve these two problems, this study tested a novel strategy involving the selection of slow-growing organisms and the addition of carriers in an anaerobic-aerobic-anoxic sequencing batch reactor (AN/O/AX_SBR). Three identical AN/O/AX_SBRs (R_Ctrl, R_CCM, and R_GAC), fed with low-strength wastewater, were operated for 120 days. R_Ctrl had no carriers, R_CCM contained cell culture microcarriers (CCM), and R_GAC contained granular activated carbon (GAC). Mature AGS was achieved within 80 days in all reactors. The carriers could reduce the maturation period of AGS by approximately 10 days (76, 66, and 69 days in R_Ctrl, R_CCM, and R_GAC, respectively) and improve the physical strength of the AGS. AGS showed a strong structure without excessive proliferation of filamentous bacteria, full-grown size (900-1100 µm), and good settleability (SVI5 was 15.4-19.4 mL/g). Microbiological analysis showed that AN/O/AX_SBRs can provide a metabolic selective pressure to select slow-growing organisms such as nitrifying bacteria (norank_f__NS9_marine_group, Ellin6067, and Nitrospira), glycogen and phosphorus accumulating organisms (GAOs: Candidatus_Competibacter and Defluviicoccus; PAOs: Candidatus_Accumulibacter and Flavobacterium). All reactors showed good performance for simultaneous nitrification, endogenous denitrification, and phosphorus removal. The removal efficiencies of total nitrogen and total phosphorous were above 70% and 80%, respectively. The cycle test showed intermediate PAO-GAO metabolism prevailed in the system, and endogenous denitrification was primarily carried out by denitrifying GAOs.

Rapid start-up and advanced nutrient removal of simultaneous nitrification, endogenous denitrification and phosphorus removal aerobic granular sequence batch reactor for treating low C/N domestic wastewater.

The rapid start-up and advanced nutrient removal of simultaneous nitrification, endogenous denitrification, and phosphorus (P) removal aerobic granular sequence batch reactor (SNEDPR-AGSBR) is a challenge in the treatment of low carbon/nitrogen (C/N) domestic sewage. In this study, the feasibility of the SNEDPR-AGSBR process was examined in an exceedingly single-stage anaerobic/aerobic/anoxic sequencing batch reactor for treating low C/N ratio (3.3-5.0) domestic sewage. The initial results showed that accompanied by the rapid formation of the mature aerobic granular sludge based on the selection for slow-growing organisms, the rapid start-up (38 d) of the SNEDPR-AGSBR process was successfully realized. The formed mature aerobic granules had a dense structure with an average diameter of 667.7 µm and SVI30 of 30.0 mL/g. Two conditions for achieving the competitive balance between phosphorus-accumulating organisms/denitrifying phosphorus-accumulating organisms (PAOs/DPAOs) and glycogen accumulating organisms/denitrifying glycogen accumulating organisms (GAOs/DGAOs) were revealed by the long-term operation results. First, the dissolved oxygen (DO) concentration needed to be decreased to 3.0 mg/L in the aerobic phase, and then, the aerobic and anoxic phase hydraulic retention time (HRT) should be increased to 3.0 h. Notably, high removal efficiencies for NH4+-N (100%), total nitrogen (84.3%), and P (91.8%) of the SNEDPR-AGSBR process were stably obtained with a low C/N ratio of 3.9 domestic sewage. Simultaneous nitrification and endogenous denitrification (SNED) efficiency of 61.6% was achieved during a long-term operation of 142 days. Finally, microbial community analysis confirmed that GAOs (Defluviicoccus)/DGAOs (Candidatus_Competibacter) were responsible for the removal N, and PAOs (Acinetobacter, Candidatus_Accumulibacter, Hypomicrobinm)/DPAOs (Pseudomonas and Dechloromonas) ensured P removal.

Artemisinin derivatives inhibit adipogenic differentiation of 3T3-L1 preadipocytes through upregulation of CHOP.

Artemisinin derivatives could inhibit adipogenic differentiation of 3T3-L1 preadipocytes and prevent obesity in mice. However, the molecular mechanism remains largely unclear. Our research was designed to investigate the specific molecular target of artemisinin derivatives in adipogenic differentiation of 3T3-L1 preadipocytes. Here, we revealed that in response to dihydroartemisinin (DHA) or artesunate (ATS), intracellular lipid was decreased in a concentration dependent manner as shown by BODIPY staining. Quantitative PCR analysis showed that expression of Cebpa, Pparg, Fabp4 and Plin was significantly decreased by DHA treatment in a concentration and time dependent manner. Also, DHA treatment remarkably downregulated expression of CCAAT/enhancer-binding protein α (C/EBPα) and nuclear receptor peroxisome proliferation-activated receptor γ (PPARγ) of adipogenic induced 3T3-L1 cells as assayed by western blotting. RNA-seq analysis identified thousands of differential expression genes (DEGs), among which CHOP expression was significantly improved in DHA treated cells. Upregulation of CHOP was verified by quantitative PCR and western blotting, respectively. Knockdown of CHOP by the specific shRNA revealed that the inhibition of adipogenesis by DHA was strongly blocked, resulting in restored lipid accumulation and expression of adipogenic molecules. In conclusions, the inhibitory effect of DHA on adipogenic differentiation of 3T3-L1 preadipocytes was exerted in a concentration and time dependent manner, which was mediated by expression of CHOP.

Chemical conversion of aged hepatocytes into bipotent liver progenitor cells.

AIM: In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A-83-01, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated. METHODS: Primary hepatocytes were isolated from aged and young donor rats, respectively. Hepatic histological changes were evaluated. Differences in gene expression in hepatocytes were identified. The in vitro reprogramming plasticity of hepatocytes as evidenced by CLiP conversion and the hepatocyte and cholangiocyte maturation capacity of reprogrammed CLIPs were analyzed. The effect of hepatocyte growth factor (HGF) on cell propagation was also investigated. RESULTS: The histological findings revealed ongoing liver damage with inflammation, fibrosis, senescence, and ductular reaction in aged livers. Microarray analysis showed altered gene expression profiles in hepatocytes from aged donors, especially with regard to metabolic pathways. Aged hepatocytes could be converted into CLiPs (Aged-CLiPs) expressing progenitor cell markers, but with a relatively low proliferative rate compared with young hepatocytes. Aged-CLiPs possessed both hepatocyte and cholangiocyte maturation capacity. HGF facilitated CLiP conversion in aged hepatocytes, which was partly related to the activation of Erk1 and Akt1 signaling. CONCLUSIONS: Aged rat hepatocytes have retained reprogramming plasticity as evidenced by CLiP conversion in culture. HGF promoted proliferation and CLiP conversion in aged hepatocytes. Hepatocytes from aged donors may be used as an alternative cell source to mitigate donor shortage.

MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10.

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-ß1 (TGF-ß1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.

Correction: Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cascade Synthesis from Cyclohexane to ϵ-Caprolactone by Visible-Light-Driven Photocatalysis Combined with Whole-Cell Biological Oxidation.

Cyclohexane was directly oxy-functionalised to ϵ-caprolactone through a cascade reaction sequence combining visible-light-driven photocatalysis with cyclohexanone monooxygenase (CHMO) whole-cell biocatalysis. Two available photocatalysts, Au-doped TiO2 (Au-TiO2 ) and graphitic carbonitride (g-C3 N4 ), were evaluated in the experiment and some optimisations to the cascade reaction were applied. In stepwise mode, the highest degree of conversion from cyclohexanol to ϵ-caprolactone can be up to 41 %, with use of g-C3 N4 . The cascade reaction from cyclohexane to ϵ-caprolactone is achievable under a light intensity of 149 µW cm-2 .

Unusual Two-Step Claisen-type Rearrangement Reaction under Physiological Conditions.

N-aryl hydroxamic acids, which are best known for their metal-chelating properties in chemical and biomedical research, have been found to markedly detoxify carcinogenic halogenated quinones. However, the exact chemical mechanism underlying such detoxication remains unclear. Here, we show that a very fast reaction took place between N-phenylbenzohydroxamic acid (N-PhBHA) and 2,5-dichloro-1,4-benzoquinone (DCBQ), forming an unexpected new carbon-carbon bonding phenyl-quinone product with high yield. In contrast, no reaction was observed with O-benzoyl N-PhBHA. Analogous results were observed for other N-aryl hydroxamic acids and halogenated quinones, which have an ortho-hydrogen adjacent to the reaction site (DCBQ-type). Interestingly, no free radical intermediates could be detected by both ESR spin-trapping and radical-scavenging methods during the reaction process. Taken together, we proposed that nucleophilic substitution followed by an unusual two-step Claisen-type rearrangement reaction was responsible for the formation of a new C-C bonding compound and the detoxication reaction. This represents the first report of an unusually mild and facile two-step Claisen-type rearrangement, which could take place under normal physiological conditions.

Mibefradil Alleviates High-Glucose-induced Cardiac Hypertrophy by Inhibiting PI3K/Akt/mTOR-mediated Autophagy.

Cardiac hypertrophy causes heart failure and is associated with hyperglycemia in patients with diabetes mellitus. Mibefradil, which acts as a T-type calcium channel blocker, exerts beneficial effects in patients with heart failure. In this study, we explored the effects and mechanism of mibefradil on high-glucose-induced cardiac hypertrophy in H9c2 cells. H9c2 cells were incubated in a high-glucose medium and then treated with different concentrations of mibefradil in the presence or absence of the Akt inhibitor MK2206 or mTOR inhibitor rapamycin. Cell size was evaluated through immunofluorescence, and mRNA expression of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain) was assessed by using quantitative real-time polymerase chain reaction. Changes in the expression of p-PI3K, p-Akt, and p-mTOR were evaluated using Western blotting, and autophagosome formation was detected using transmission electron microscopy. Our results indicate that mibefradil reduced the size of H9c2 cells, decreased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain, and decreased the level of autophagic flux. However, MK2206 and rapamycin induced autophagy and reversed the effects of mibefradil on high-glucose-induced H9c2 cells. In conclusion, mibefradil ameliorated high-glucose-induced cardiac hypertrophy by activating the PI3K/Akt/mTOR pathway and inhibiting excessive autophagy. Our study shows that mibefradil can be used therapeutically to ameliorate cardiac hypertrophy in patients with diabetes mellitus.