Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis.

Nonalcoholic steatohepatitis (NASH) is the major cause of liver dysfunction. Animal and population studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) is implicated in fatty liver disease. However, the role of ALDH2 in NASH and the underlying mechanisms remains unclear. To address this issue, ALDH2 knockout (ALDH2-/-) mice and wild-type littermate mice were fed a methionine-and choline-deficient (MCD) diet to induce a NASH model. Fecal, serum, and liver samples were collected and analyzed to investigate the impact of the gut microbiota and bile acids on this process. We found that MCD-fed ALDH2-/- mice exhibited increased serum pro-inflammation cytokines, hepatic inflammation and fat accumulation than their wild-type littermates. MCD-fed ALDH2-/- mice exhibited worsened MCD-induced intestinal inflammation and barrier damage, and gut microbiota disorder. Furthermore, mice receiving microbiota from MCD-fed ALDH2-/- mice had increased severity of NASH compared to those receiving microbiota from MCD-fed wild-type mice. Notably, the intestinal Lactobacillus was significantly reduced in MCD-fed ALDH2-/- mice, and gavage with Lactobacillus cocktail significantly improved MCD-induced NASH. Finally, we found that ALDH2-/- mice had reduced levels of bile salt hydrolase and specific bile acids, especially lithocholic acid (LCA), accompanied by downregulated expression of the intestinal FXR-FGF15 pathway. Supplementation of LCA in ALDH2-/- mice upregulated intestinal FXR-FGF15 pathway and alleviated NASH. In summary, ALDH2 plays a critical role in the development of NASH through modulation of gut microbiota and bile acid. The findings suggest that supplementing with Lactobacillus or LCA could be a promising therapeutic approach for treating NASH exacerbated by ALDH2 deficiency.

[Biological mechanisms of Oxalis corniculata regulating human prostate cancer PC-3 cells: An investigation based on the NF-κB pathway].

OBJECTIVE: To investigate the biological mechanisms underlying the effect of the Chinese herbal medicine Oxalis corniculata on human prostate cancer PC-3 cells. METHODS: Through in vitro experiment, we treated human prostate cancer PC-3 cells with different concentrations of Oxalis corniculata, assessed the viability of the cells by MTT assay, examined their apoptosis by flow cytometry, evaluated their migration and invasiveness by Transwell assay, and determined the expressions of the proteins p65, p-p65, IκBα and p-IκBα in the NF-κB pathway using protein imprinting technology. RESULTS: Compared with the blank control, Oxalis corniculata significantly inhibited the proliferation and induced the apoptosis of the PC-3 cells (P< 0.05), suppressed their migration and invasiveness in a dose-dependent manner (P< 0.05), and upregulated the expression of IκBα and downregulated those of p-p65 and p-IκBα in the NF-κB pathway (P< 0.05). CONCLUSION: Oxalis corniculata can inhibit the proliferation, migration and invasiveness and induce the apoptosis of human prostate cancer PC cells, which may be attributed to its abilities of inhibiting the expressions of p-p65 and p-IκBα and regulating the activity of the NF-κB pathway.

[Action mechanisms of Xiaoluowan (II) in the treatment of epididymitis: A network pharmacology-based study].

OBJECTIVE: To explore the potential action mechanisms of Xiaoluowan (II) (XLW-II) in the treatment of epididymitis through a network pharmacology approach. METHODS: We searched various databases for relevant targets associated with epididymitis and XLW-II and obtained the common targets of epididymitis and XLW-II on the Venny platform. We acquired the protein-protein interactions (PPI) using the STRING data and had them visualized with the Cytoscape software. After topological analysis, we retrieved the key targets, followed by gene ontology (GO) and KEGG pathway enrichment analyses using the DAVID database. RESULTS: A total of 2 38 drug targets, 2 150 disease targets and 85 common targets were identified. The core targets for the treatment of epididymitis with XLW-II identified by PPI network analysis included TNF, IL6, IL1B, MMP9, AKT1, PTGS2 and TP53. GO function analysis revealed the involvement of the common targets in such biological processes as response to hypoxia, regulation of apoptotic processes, inflammatory response, and positive regulation of the MAPK cascade. KEGG pathway analysis suggested that the signaling pathways such as the cancer pathway, PI3K-Akt pathway, protein glycosylation pathway in cancer, Ras pathway and chemokine pathway might be related to the action mechanisms of XLW-II in the treatment of epididymitis. CONCLUSION: The potential targets and signaling pathways of Xiaoluowan (II) in the treatment of epididymitis were identified on the basis of network pharmacology, which has provided a novel insight into its action mechanisms and offered a new direction for further relevant studies.

A prospective randomized controlled trial comparing the effect and safety of Piranha and VersaCut morcellation devices in transurethral holmium laser enucleation of the prostate.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) is reported to be widely used in the surgical treatment of benign prostatic hyperplasia (BPH), which consists of two procedures: enucleation and morcellation. This study is to examine the efficiency and safety of two different morcellator systems within a cohort of men undergoing HoLEP for BPH. METHODS: A total of 210 consecutive patients undergoing HoLEP and morcellation procedures were enrolled. Individuals were randomly divided into 2 separated groups: the first group (105 patients) was performed with a nephroscope using a mechanical Versacut morcellator and the second (105 patients) was performed with the new morcellation system, nephroscopes and Piranha morcellator. Perioperative characteristics were studied and analyzed. RESULTS: The morcellation time and the morcellation rate was similar when the prostate volume (PV) ≤ 60 mL while the morcellation time was significantly shorter and the morcellation rate was higher in the Piranha group with PV > 60 mL. No significant difference was observed according to the bladder irrigation time, indwelling catheter time, and discharge time. CONCLUSION: Piranha morcellator presents a higher efficiency for the prostate over 60 mL.

Adjunctive Nonconvulsive Electrotherapy for Patients with Depression: a Systematic Review.

The efficacy and safety of adjunctive nonconvulsive electrotherapy (NET) for patients with depression are undetermined. This systematic review was conducted to examine the efficacy and safety of adjunctive NET for patients with depression. Chinese (WanFang and Chinese Journal Net) and English (PubMed, EMBASE, PsycINFO and the Cochrane Library) databases were systematically searched from their inception until Jan 27, 2021 by three independent investigators. One randomized controlled trial (RCT) with 3 treatment arms (n = 108) and two observational studies (single-group, before-after design, n = 31) were included. In the RCT, the antidepressant efficacy of NET on depression was similar to that of electroconvulsive therapy (ECT) (P > 0.05) but with significantly fewer neurocognitive impairments as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (P < 0.05). In two observational studies, the 17-item Hamilton Depression Rating Scale (HAMD-17) scores decreased significantly from baseline to post-NET (all Ps < 0.05), without adverse neurocognitive effects. In the RCT, adverse drug reactions (ADRs) were not separately reported among the 3 treatment arms but a similar rate of discontinuation was reported. The currently available limited evidence from 3 studies suggests that NET as an adjunctive treatment may be a safe, well-tolerated, effective therapy for depression without serious neurocognitive impairments.

Pectin supplement significantly enhanced the anti-PD-1 efficacy in tumor-bearing mice humanized with gut microbiota from patients with colorectal cancer.

Background: Anti-PD-1-based immunotherapy has emerged as a promising therapy for several cancers. However, it only benefits a small subset of colorectal cancer (CRC) patients. Mounting data supports the pivotal role of gut microbiota in shaping immune system. Pectin, a widely consumed soluble fiber, has been reported to ameliorate the imbalance of gut microbiota. Therefore, we aimed to explore the effect and the underlying mechanisms of pectin in improving anti-PD-1 mAb efficacy. Methods: The C57BL/6 mice were treated with a broad-spectrum antibiotic (ATB) cocktail to depleted endogenous gut microbiota and subsequently humanized with feces from healthy controls or newly diagnosed CRC patients. The antitumor efficacies of anti-PD-1 mAb combined with or without pectin were assessed using these mice. Flow cytometry and immunohistochemistry (IHC) were conducted to investigate the tumor immune microenvironment after treatment. The gut microbiota profiles and short-chain fatty acids (SCFAs) levels were determined by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography-mass spectrometry (GC-MS), respectively. The effect of gut microbiota on anti-PD-1 mAb efficacy after pectin supplement was further tested by fecal microbiota transplantation (FMT). Results: The anti-PD-1 mAb efficacy was largely impaired in the mice humanized with feces from newly diagnosed CRC patients compared to those from healthy controls. However, pectin significantly enhanced the anti-PD-1 mAb efficacy in the tumor-bearing mice humanized with CRC patient gut microbiota. Flow cytometry and IHC analysis revealed increased T cell infiltration and activation in the tumor microenvironment of mice treated with anti-PD-1 mAb plus pectin. In vivo depletion of CD8+ T cells diminished the anti-tumor effect of anti-PD-1 mAb combined with pectin. 16S rRNA gene sequencing showed that pectin significantly increased gut microbial diversity and beneficially regulated microbial composition. In addition, we identified unique bacterial modules that were significantly enriched in the anti-PD-1 mAb + pectin group, which composed of butyrate-producing bacteria indicative of good response to immunotherapy. Meanwhile, GC-MS showed that pectin altered the level of SCFA butyrate. Furthermore, butyrate, a main product of dietary fiber in gut microbial fermentation, was found to be sufficient to promote T cells infiltration and thus enhance the efficacy of anti-PD-1 mAb. In addition, FMT demonstrated the effects of pectin were dependent on gut microbiota. Importantly, the beneficial effects of pectin were confirmed in the mice humanized with gut microbiota from patient with resistance to anti-PD-1 mAb. Conclusion: Pectin facilitated the anti-PD-1 mAb efficacy in CRC via regulating the T cell infiltration in the tumor microenvironment, which was potentially mediated by the metabolite butyrate.

[Moxibustion therapy in prevention and treatment of coronavirus disease 2019 (COVID-19): construction and application of non-contact diagnosis and treatment mode].

OBJECTIVE: To establish and promote the non-contact doctor-patient interactive diagnosis and treatment mode based on mobile internet for the treatment of coronavirus disease 2019 (COVID-19) with moxibustion therapy, and to observe the feasibility and effectiveness of the model in the pandemic. METHODS: A total of 43 first-line medical staff and 149 suspected and confirmed cases with COVID-19 [18 cases in medical observation period, 17 cases of mild type (cold dampness and stagnation in the lung), 24 cases of ordinary type (cold-dampness accumulated in the lung) and 90 cases in recovery period (qi deficiency of spleen and lung)] were included. A non-contact doctor-patient interactive diagnosis and treatment platform was established for the treatment of COVID-19 with indirect moxibustion plaster based on mobile internet. By the platform, the patients were instructed to use indirect moxibustion plaster in treatment. For the first-line medical staff and patients in the medical observation period, Zusanli (ST 36), Qihai (CV 6) and Zhongwan (CV 12) were selected. For the mild cases (cold dampness and stagnation in the lung) and the cases of ordinary type (cold-dampness accumulated in the lung), Hegu (LI 4), Taichong (LR 3), Zusanli (ST 36) and Guanyuan (CV 4) were selected. In the recovery period (qi deficiency of spleen and lung), Dazhui (GV 14), Feishu (BL 13), Geshu (BL 17), Zusanli (ST 36) and Kongzui (LU 6) were used. The treatment was given once daily for 40 min each time. The intervention lasted for 10 days. After intervention, the infection rate and the improvement in the symptoms and psychological status of COVID-19 were observed in clinical first-line medical staff and COVID-19 patients. RESULTS: In 10 days of intervention with indirect moxibustion plaster, there was "zero" infection among medical staff. Of 43 first-line physicians and nurses, 33 cases had some physical symptoms and psychological discomforts, mainly as low back pain, poor sleep and anxiety. After treatment, regarding the improvements in the symptoms and psychological discomforts, the effective rate was 78.8% (26/33) and the curative rate was 36.4% (12/33). Regarding the improvements in psychological discomforts, the effective rate was 58.3% (14/24) and the curative rate was 37.5 (9/24). Of 149 patients, 133 cases had the symptoms and psychological discomforts. After treatment, regarding the improvements in the symptoms and psychological discomforts, the effective rate was 81.2% (108/133) and the curative rate was 34.6% (46/133). Regarding the improvements in psychological discomforts, the effective rate was 76.5% (52/68) and the curative rate was 57.4 % (39/68). CONCLUSION: It is feasible to apply the indirect moxibustion plaster technique based on mobile internet to the treatment COVID-19. This mode not only relieves the symptoms such as cough and fatigue, improves psychological state, but also possibly prevents the first-line medical staff from COVID-19.

[Herb-separated moxibustion on dysmenorrhea in ovarian endometriosis: a randomized controlled trial].

OBJECTIVE: To observe the clinical therapeutic effect of herb-separated moxibustion on dysmenorrhea in ovarian endometriosis. METHODS: A total of 54 patients with ovarian endometriosis dysmenorrhea were randomized into a herb-separated moxibustion group and a waiting-list group, 27 cases in each one (3 cases dropped off in the herb-separated moxibustion group, 4 cases dropped off in the waiting-list group). Herb-separated moxibustion was applied at hypogastrium and lumbosacral area for 30 min in the herb-separated moxibustion group, once a week for 3 months, and oral ibuprofen sustained-release capsule was given to relieve pain when necessary. Excepting giving ibuprofen sustained-release capsule when necessary, no more intervention was adopted in the waiting-list group. Before and after treatment and in 3 months follow-up, visual analogue scale (VAS) score, days of dysmenorrhea, total dose of oral painkiller were observed. RESULTS: Compared before treatment, the VAS scores after tratment and in follow-up were decreased in the herb-separated moxibustion group (P<0.05), and were less than those in the waiting-list group (P<0.05); the days of dysmenorrhea and the total doses of oral painkiller after tratment and in follow-up were decreased in the herb-separated moxibustion group (P<0.05), and were less than those in the waiting-list group (P<0.05). CONCLUSION: Herb-separated moxibustion can effectively improve dysmenorrhea symptom and shorten dysmenorrhea days in patients with ovarian endometriosis.

[Influence of warming needling technique on gastrointestinal reaction after hyperthermic intrape-ritoneal chemotherapy in patients with postoperation of colon cancer].

OBJECTIVE: To observe the effect of warming needling therapy on gastrointestinal reaction after hyperthermic intraperitoneal chemotherapy (HIPEC) in patients of spleen and stomach deficiency syndrome after colon cancer surgery. METHODS: A total of 120 cases of HIPEC were randomized into observation group and control group, 60 cases in each. The patients of the two groups all received HIPEC. In the observation group, 1 h before HIPEC, warming needling technique was applied to Zusanli (ST36), Sanyinjiao (SP6) and Yinlingquan (SP9) and the even-needing technique of acupuncture was applied to Neiguan (PC6) for 30 min, and then the intravenous injection with Ondansetron was given 30 min before HIPEC. In the control group, The intravenous injection with Ondansetron was given 30 min before HIPEC. In the two groups, the changes in nausea, vomiting, abdominal distention, diarrhea, total bilirubin (TB), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and KPS score, as well as the average hospitalization length of stay were observed. RESULTS: The total effective rates in the treatment of nausea, vomiting, abdominal distention and diarrhea were 91.67%(55/60), 93.33%(56/60), 80.00%(48/60) and 88.33%(53/60) in the observation group and were 78.33%(47/60), 78.33%(47/60), 63.33%(38/60) and 70.00%(42/60) in the control group respectively, and the total effective rate in the treatment of gastrointestinal reaction of HIPEC in the observation group was obviously higher than that in the control group(P<0.05). The KPS score and curative effect in the observation group was obviously higher than those of the control group(P<0.05), and the average hospitalization length of stay in the observation group was obviously reduced as compared with the control group (P<0.05). There were no significant differences in serum TB, ALT and ALP contents between the two groups after treatment (P>0.05). CONCLUSION: The warming needling technique of acupuncture and moxibustion alleviates the gastrointestinal reaction, improves KPS score and reduces the hospitalization length of stay in HIPEC patients after the surgery of colon cancer and differentiated as the spleen and stomach deficiency in traditional Chinese medicine.

Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease.

Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under high-glucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or d-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of d-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, d-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest d-glucarate as a potential therapeutic agent for the amelioration of DKD.

Mimecan, a Hormone Abundantly Expressed in Adipose Tissue, Reduced Food Intake Independently of Leptin Signaling.

Adipokines such as leptin play important roles in the regulation of energy metabolism, particularly in the control of appetite. Here, we describe a hormone, mimecan, which is abundantly expressed in adipose tissue. Mimecan was observed to inhibit food intake and reduce body weight in mice. Intraperitoneal injection of a mimecan-maltose binding protein (-MBP) complex inhibited food intake in C57BL/6J mice, which was attenuated by pretreatment with polyclonal antibody against mimecan. Notably, mimecan-MBP also induced anorexia in A(y)/a and db/db mice. Furthermore, the expression of interleukin (IL)-1ß and IL-6 was up-regulated in the hypothalamus by mimecan-MBP, as well as in N9 microglia cells by recombinant mouse mimecan. Taken together, the results suggest that mimecan is a satiety hormone in adipose tissue, and that mimecan inhibits food intake independently of leptin signaling by inducing IL-1ß and IL-6 expression in the hypothalamus.

China and the global uranium market: prospects for peaceful coexistence.

China's recent reemergence has resulted in a significant increase in the global demand of commodities and is already having major impacts on the dynamics of global commodity markets. In the case of the global uranium market, we stand at the very beginning of a period of change. However, interesting trends are already emerging. Whereas China has had many policy reversals, and some difficulties in taking control of its procurement strategy in other commodity markets, it is seemingly more successful in managing its uranium procurement strategy. Why? The argument presented here is that a mixture of domestic and international level variables has allowed China more room for maneuver in fulfilling its uranium procurement strategy. On the domestic level, a centralized industry, and, on the international level, a geographically dispersed and uncoordinated market have allowed China to forge ahead with an ambitious civilian nuclear power plan and triple its total uranium imports, all within the span of a few years. Many challenges remain, not the least that of negative public opinion, which has surged since the Fukushima disaster in 2011. Nevertheless, should uranium demand continue to grow, this paper will consider the potential for continued peaceful coexistence among uranium market participants worldwide.

Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.

Transforming growth factor (TGF)-ß has been shown to play a central role in the development of tubulointerstitial fibrosis, which can be corrected via treatment with paclitaxel. The biology of microRNA (miR) can be modulated by paclitaxel. We hypothesized that paclitaxel may attenuate renal fibrosis in a rat model of remnant kidney disease by inhibiting TGF-ß induced-miRs. Rats in groups of 12 were subjected to 5/6 nephrectomy and received low-dose intraperitoneal injection of paclitaxel. Renal functions were assessed at 8 weeks. The TGF-ß signalling cascade and ECM proteins were evaluated by real-time polymerase chain reaction (TRT-PCR) and immunofluorescence microscopy. Animals with remnant kidneys developed hypertension, which was not relieved with paclitaxel treatment. However, paclitaxel treatment resulted in dampening the proteinuric response, reduction in serum BUN, creatinine levels and urine protein : creatinine ratio and normalization of creatinine clearance. These effects were accompanied by the inhibition of Smad2/3 activation, attenuation of renal fibrosis and normalization of integrin-linked kinase (ILK), COL(I)A1, COL(IV)A2 and α-SMA expression. Also, paclitaxel down-regulated the expression of miR-192, miR-217 and miR -377, while miR-15 was up-regulated in the remnant kidney. In vitro, in tubular epithelial cells (NRK-52E), paclitaxel also inhibited TGF-ß1-induced Smad2/3 activation and normalized ILK, COL(I)A1, COL(IV)A2 and α-SMA expression. Furthermore, ChIP analyses indicated that Taxol suppressed Smad3-mediated miR-192 transcriptional activity. Over-expression of miR-192 in NRK-52E mimicked the changes seen in the remnant kidney, while inclusion of miR-192 inhibitor in the culture medium blocked TGF-ß1-induced COL(I)A1 and COL(IV)A2 expression, while ILK and α-SMA were unaffected. These data suggest that low-dose paclitaxel ameliorates renal fibrosis via modulating miR-192 pathobiology and TGF-ß/Smad signalling.

Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons.

BACKGROUND: We have previously described fundamental differences in the biology of stem cells as compared to other dividing cell populations. We reasoned therefore that a differential screen using US Food and Drug Administration (FDA)-approved compounds may identify either selective survival factors or specific toxins and may be useful for the therapeutically-driven manufacturing of cells in vitro and possibly in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In this study we report on optimized methods for feeder-free culture of hESCs and hESC-derived neural stem cells (NSCs) to facilitate automated screening. We show that we are able to measure ATP as an indicator of metabolic activity in an automated screening assay. With this optimized platform we screened a collection of FDA-approved drugs to identify compounds that have differential toxicity to hESCs and their neural derivatives. Nine compounds were identified to be specifically toxic for NSCs to a greater extent than for hESCs. Six of these initial hits were retested and verified by large-scale cell culture to determine dose-responsive NSC toxicity. One of the compounds retested, amiodarone HCL, was further tested for possible effects on postmitotic neurons, a likely target for transplant therapy. Amiodarone HCL was found to be selectively toxic to NSCs but not to differentiated neurons or glial cells. Treated and untreated NSCs and neurons were then interrogated with global gene expression analysis to explore the mechanisms of action of amiodarone HCl. The gene expression analysis suggests that activation of cell-type specific cationic channels may underlie the toxicity of the drug. CONCLUSIONS/SIGNIFICANCE: In conclusion, we have developed a screening strategy that allows us to rapidly identify clinically approved drugs for use in a Chemistry, Manufacture and Control protocol that can be safely used to deplete unwanted contaminating precursor cells from a differentiated cell product. Our results also suggest that such a strategy is rich in the potential of identifying lineage specific reagents and provides additional evidence for the utility of stem cells in screening and discovery paradigms.