Vitamin D-vitamin D receptor alleviates oxidative stress in ischemic acute kidney injury via upregulating glutathione peroxidase 3.

Vitamin D receptor was previously reported to be protective in acute kidney injury (AKI) with the mechanism unclear, while the role of renal localized glutathione peroxidase 3 (GPX3) was not illustrated. The present study aims to investigate the role of GPX3 as well as its correlation with vitamin D-vitamin D receptor (VD-VDR) in ischemia-reperfusion (I/R)-induced renal oxidative stress injury. We showed that the expression of GPX3 and VDR were consistently decreased in renal tissues of I/R-related AKI patients and mice models. VDR agonist paricalcitol could reverse GPX3 expression and inhibit oxidative stress in I/R mice or hypoxia-reoxygenation (H/R) insulted HK-2 cells. VDR deficiency resulted in aggregated oxidative stress and severer renal injury accompanied by further decreased renal GPX3, while tubular-specific VDR overexpression remarkably reduced I/R-induced renal injury with recovered GPX3 in mice. Neither serum selenium nor selenoprotein P was affected by paricalcitol administration nor Vdr modification in vivo. In addition, inhibiting GPX3 abrogated the protective effects of VD-VDR in HK-2 cells, while GPX3 overexpression remarkably attenuated H/R-induced oxidative stress and apoptosis. Mechanistic probing revealed the GPX3 as a VDR transcriptional target. Our present work revealed that loss of renal GPX3 may be a hallmark that promotes renal oxidative stress injury and VD-VDR could protect against I/R-induced renal injury via inhibition of oxidative stress partly by trans-regulating GPX3. In addition, maintenance of renal GPX3 could be a therapeutic strategy for ischemic AKI.

Changes of intestinal barrier in the process of intestinal inflammation induced by Aeromonas hydrophila in snakehead (Channa argus).

Bacterial intestinal inflammation frequently occurs in cultured fish. Nevertheless, research on intestinal barrier dysfunction in the process of intestinal inflammation is deficient. In this study, we explored the changes of intestinal inflammation induced by Aeromonas hydrophila (A. hydrophila) in snakehead and the relationship between intestinal barrier and inflammation. Snakehead [(13.05 ± 2.39) g] were infected via anus with A. hydrophila. Specimens were collected for analysis at 0, 1, 3, 7 and 21 d post-injection. The results showed that with the increase of exposure time, the hindgut underwent stages of normal function, damage, damage deterioration, repair and recovery. Relative to 0 d, the levels of IL-1ß and TNF-α in serum, and the expression of nod1, tlr1, tlr5, nf-κb, tnf-α and il-1ß in intestine were significantly increased, and showed an upward then downward pattern over time. However, the expression of tlr2 and il-10 were markedly decreased, and showed the opposite trend. In addition, with the development of intestinal inflammation, the diversity and richness of species, and the levels of phylum and genus in intestine were obviously altered. The levels of trypsin, LPS, AMS, T-SOD, CAT, GPx, AKP, LZM and C3 in intestine were markedly reduced, and displayed a trend of first decreasing and then rebounding. The ultrastructure observation showed that the microvilli and tight junction structure of intestinal epithelial cells experienced normal function initially, then damage, and finally recovery over time. The expression of claudin-3 and zo-1 in intestine were significantly decreased, and showed a trend of first decreasing and then rebounding. Conversely, the expression of mhc-i, igm, igt and pigr in intestine were markedly increased, and displayed a trend of increasing first and then decreasing. The above results revealed the changes in intestinal barrier during the occurrence and development of intestinal inflammation, which provided a theoretical basis for explaining the relationship between the two.

Battling Salmonella enteritidis infections: integrating proteomics and in vivo assessment of Galla Chinensis tannic acid.

Salmonella infections pose a significant threat to animal and human health. Phytochemicals present a potential alternative treatment. Galla chinensis tannic acid (GCTA), a hydrolyzable polyphenolic compound, inhibits bacterial growth and demonstrates potential as an alternative or supplement to antibiotics to prevent Salmonella infections. However, little is known about the antimicrobial mechanism of GCTA against Salmonella. Here, we revealed 456 differentially expressed proteins upon GCTA treatment, impacting pathways related to DNA replication, repair, genomic stability, cell wall biogenesis, and lipid metabolism using TMT-labeled proteomic analysis. TEM analysis suggested altered bacterial morphology and structure post-treatment. A Salmonella-infected-mouse model indicated that GCTA administration improved inflammatory markers, alleviated intestinal histopathological alterations, and reduced Salmonella enterica serovar Enteritidis (S. Enteritidis) colonization in the liver and spleen of Salmonella-infected mice. The LD50 of GCTA was 4100 mg/kg with an oral single dose, vastly exceeding the therapeutic dose. Thus, GCTA exhibited antibacterial and anti-infective activity against S. Enteritidis. Our results provided insight into the molecular mechanisms of these antibacterial effects, and highlights the potential of GCTA as an alternative to antibiotics.

A novel ultra-low-volume regimen combining 1 L polyethylene glycol and linaclotide versus 2 L polyethylene glycol for colonoscopy cleansing in low-risk individuals: a randomized controlled trial.

BACKGROUND AND AIMS: The single dose of 2 L polyethylene glycol (PEG) has shown high cleaning efficacy and tolerability in low-risk patients. However, the dosage of this regimen is still challenging for many patients. We investigated the efficacy and tolerability of a novel ultra-low-volume regimen using 1 L PEG and linaclotide (1 L PEG+L) versus a single dose of 2 L PEG in low-risk patients. METHODS: In this prospective, randomized, observer-blinded, multicenter study, low-risk adult patients scheduled for colonoscopy were enrolled and randomized (1:1) to receive the 1 L PEG+L regimen or the 2 L PEG regimen. The primary outcome was the effectiveness of bowel cleansing according to the Boston Bowel Preparation Scale. Secondary outcomes included cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate and adenoma detection rate, tolerability, adverse events, and willingness to repeat bowel preparation. The full analysis set (FAS) and per-protocol set (PPS) were used for statistical analyses. RESULTS: A total of 548 patients comprised the FAS, and 522 patients comprised the PPS. Noninferiority on adequate bowel cleansing of 1 L PEG+L vs 2 L PEG was established both in FAS (90.5% vs 91.6%, P = .644) and PPS (90.3% vs 92.4%, P = .390). There were no significant differences regarding the total score and each segment scores of the Boston Bowel Preparation Scale, cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate, and adenoma detection rate (all, P > .05). However, patients in the 1 L PEG+L group reported less nausea (7.7% vs 17.1%, P < .01) and vomiting (4.0% vs 10.9%, P < .01) and had a higher willingness to repeat bowel preparation (95.2% vs 82.2%, P < .01). CONCLUSIONS: The regimen of 1 L PEG+L was not inferior to 2 L PEG on colon cleansing, with better tolerability and higher willingness to repeat the bowel preparation in a low-risk population. (Clinical trial registration number: ChiCTR2100053273.).

The protective role of vitamin C on intestinal damage induced by high-dose glycinin in juvenile Rhynchocypris lagowskii Dybowski.

This study was to evaluate the mitigative effects of vitamin C (VC) on growth inhibition and intestinal damage induced by glycinin in juvenile Rhynchocypris lagowskii Dybowski. 270 healthy juvenile Rhynchocypris lagowskii Dybowski (4.65 ± 0.04 g) were randomly divided into 3 treatments, and fed with control diet, 80 g/kg glycinin diet and 80 g/kg glycinin+200 mg/kg VC diet respectively for 8 weeks. The results showed that glycinin significantly decreased the weight gain rate, specific growth rate, protein efficiency rate, feed efficiency rate and feeding rate of fish compared with the control group (P < 0.05), while VC supplementation improved the growth performance and feed utilization efficiency, and reached a level similar to the control group. Similarly, VC significantly increased the crude protein content of muscle and whole-body, and hepatopancreas and intestinal protease activities of fish fed with glycinin diet (P < 0.05). The distal intestine of fish in glycinin group showed typical damage characteristics, including breakage and atrophy of intestinal mucosal fold, and increased intestinal mucosal permeability. However, fish fed the glycinin + VC diet showed an unimpaired normal intestinal morphology. Usefully, VC supplementation could also restore impaired immune function and antioxidant capacity. VC down-regulated the mRNA levels of pro-inflammatory cytokines TNF-α and IL-1ß, and up-regulated the mRNA levels of anti-inflammatory cytokines IL-10 and TGF-ß in the distal intestine of fish fed with glycinin. Furthermore, glycinin exposure could reduce the mRNA levels of HO-1, CAT and GPx by inhibiting the activation of Nrf2-Keap1 signaling pathway, while VC supplementation reversed this phenomenon and maintained the homeostasis of antioxidant defense system. Concluded, glycinin causes growth inhibition, digestive dysfunction and intestinal damage of Rhynchocypris lagowskii Dybowski, while sufficient VC intake is beneficial for fish to resist the adverse effects of glycinin.

The effects of dietary supplementation of α-lipoic acid on the growth performance, antioxidant capacity, immune response, and disease resistance of northern snakehead, Channa argus.

The study was the first time to explore the positive effects of α-LA on growth performance, antioxidant capability, immunity, and disease resistance of northern snakehead (Channa argus). Five hundred and forty northern snakehead fish (initial body weight: 8.74 ± 0.12 g (mean ± SE)) were randomly allocated into six groups with three replicates each. Six diets supplemented with α-LA at doses of 0 (CON), 300 (LA300), 600 (LA600), 900 (LA900), 1200 (LA1200), and 1500 (LA1500) mg/kg were fed to northern snakehead for 8 weeks. The results demonstrated that, when compared with the control group, optimal dietary α-LA increased the weight gain (WG), protein efficiency ratio (PER), and specific growth rate (SGR) and reduced the feed conversion ratio (FCR) of the fish (P < 0.05). Also, optimal dietary α-LA enhanced the immune-related parameters and antioxidant enzyme parameters levels in the head kidney, spleen, and liver of northern snakehead (P < 0.05). Dietary α-LA upregulated the mRNA expression levels of anti-inflammatory cytokines (il10 and tgfß) and antioxidant related genes (gst, gsh-px, gr and Cu/Zn sod), down-regulated the pro-inflammatory cytokines (il1ß, il8, il12 and tnfα) mRNA levels in the liver, spleen and head kidney of the northern snakehead (P < 0.05). The above results demonstrated that optimal dietary α-LA showed enhancement effects on the growth, antioxidant and anti-inflammatory capability, and immune response of northern snakehead. The survival rates in all α-LA treatments were significantly raised after the challenge with Aeromonas veronii (P < 0.05). Based on the quadratic regression analysis of WG, GSH-Px, LYS, and il1ß, the optimal dietary α-LA levels were estimated to be 737.0, 775.0, 890.0, and 916.7 mg/kg, respectively. Considering the overall responses in growth performance, antioxidant status, immune response, and inflammatory factors, the recommended dose of α-LA in the diet of fish is 737.0-916.7 mg/kg.

Dietary α-lipoic acid alleviates deltamethrin-induced immunosuppression and oxidative stress in northern snakehead (Channa argus) via Nrf2/NF-κB signaling pathway.

The goal of the study was to determine the ameliorative effects of dietary alpha-lipoic acid (α-LA) on deltamethrin (DEL)-induced immunosuppression and oxidative stress in northern snakehead (Channa argus). The northern snakeheads (15.38 ± 0.09 g) were exposed to DEL (0.242 µg/L) and fed with diets supplemented α-LA at 300, 600, and 900 mg/kg. After the 28-day exposure test, we obtained the following results: i) α-LA alleviates DEL-induced liver injury by reversing the increase of the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver cytochrome P450 enzymes (Cytochrome P450 (cyp)1a and cyp1b) expression levels. ii) α-LA can reverse the DEL-induced reduction of serum complement 4 (C4), C3, immunoglobulin M (IgM), and lysozyme (LYS) levels and the increase of liver and intestine nuclear factor kappa B (nf-κb) p65, tumor necrosis factor (tnf)-α, interleukin (il)-1ß, il-8, and il-6 gene expressions, while il-10 expression levels showed the opposite result. iii) α-LA reversed the reduction of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione-S-transferase (GST) and glutathione peroxidase (GSH-Px) levels in the liver and intestine induced by DEL, while malondialdehyde (MDA) showed the opposite result. iv) α-LA reversed the reduction of Cu/Zn sod, nuclear factor erythroid 2-related factor 2 (nrf2), NAD (P)H: quinone oxidoreductase (nqo)1, and heme oxygenase (ho)-1 antioxidant gene expression levels in the liver and intestine induced by DEL. Therefore, our study indicated that optimal α-LA (600 mg/kg) could attenuate DEL-induced toxicity (including liver damage, immunotoxicity, and oxidative stress) in northern snakehead via Nrf2/NF-κB signaling pathway. This is the first research that explores the alleviated effects of α-LA on DEL-induced toxicity damage in fish. This study provides a positive measure to reduce the toxicity damage caused by DEL to aquatic animals, and provides a theoretical basis for exploring the regulation mechanism of α-LA in toxic substances.

Taurine can improve intestinal function and integrity in juvenile Rhynchocypris lagowskii Dybowski fed high-dose glycinin.

The present study evaluated the protective effect and the regulatory mechanism of taurine on growth inhibition and intestinal damage induced by glycinin in juvenile Rhynchocypris lagowskii Dybowski. The control diets had no glycinin and taurine, the glycinin diets contained only 80 g/kg glycinin, and the glycinin + taurine diets contained 80 g/kg glycinin+10 g/kg taurine. Juvenile Rhynchocypris lagowskii Dybowski (4.65 ± 0.03 g/tail) were respectively fed with these 3 diets for 8 weeks. The results showed that glycinin significantly decreased the final body weight, weight gain rate, specific growth rate, protein efficiency rate, feed efficiency rate and feeding rate of fish compared with the control group (P < 0.05). While taurine supplementation improved the growth performance and feed efficiency, but final body weight, weight gain rate, specific growth rate of the glycinin + taurine group were still significantly lower than the control group (P < 0.05). Compared with the glycinin group, taurine supplementation significantly increased whole-body and muscle crude protein content, and hepatopancreas and intestinal protease activities (P < 0.05). Distal intestinal villous dysplasia and mucosal damage, and increased intestinal mucosal permeability were observed in the glycinin group, while taurine supplementation alleviated these adverse effects. Usefully, taurine supplementation could also partially restore the impaired immune function and antioxidant capacity of fish fed glycinin diets. Compared with the glycinin group, taurine supplementation down-regulated pro-inflammatory cytokines TNF-α and IL-1ß mRNA levels, and up-regulated anti-inflammatory cytokines IL-10 and TGF-ß mRNA levels. Furthermore, taurine partially reversed the reduction of antioxidant genes Nrf2、HO-1, CAT and GPx mRNA levels in distal intestine induced by glycinin. Concluded, 80 g/kg glycinin led to intestinal damage, digestive dysfunction and increased intestinal mucosal permeability in juvenile Rhynchocypris lagowskii Dybowski, and these adverse effects were ultimately manifested in growth inhibition. But taurine supplementation could partially mitigate the negative effects induced by glycinin.

Causes of death following small cell lung cancer diagnosis: a population-based analysis.

PURPOSE: To examine the distribution of causes of death (CODs) in patients with small cell lung cancer (SCLC). METHODS: Patients diagnosed with SCLC were identified from the Surveillance, Epidemiology, and End Results Program database during 2004-2015. Standardized mortality rates (SMRs) were performed for each COD to present changes in risk for a particular COD following SCLC diagnosis. RESULTS: A total of 44,506 patients diagnosed with SCLC were identified in this study, and 42,476 patients died during the follow-up. Of total deaths, 69.5% occurred within the first years after diagnosis, 26% occurred from 1 to 3 years, and 4.5% individuals survived longer than 3 years. In addition, 88.7% of deaths were caused by SCLC, followed by non-cancer causes (7.1%) and other cancers (4.2%). Moreover, non-cancer CODs increased from 6.3 to 30% over time after 3 years of diagnosis. As for non-cancer CODs, cardiovascular diseases, COPD, and septicemia were the most common in SCLC. CONCLUSION: Non-cancer CODs, such as cardiovascular events, COPD and septicemia, contribute to a considerable proportion of deaths among long-term SCLC survivors, supporting the involvement of multidisciplinary care for the follow-up strategy in SCLC.

Role of tRNA derived fragments in renal ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI). tRNA derived fragments (tRFs/tiRNAs) are groups of small noncoding RNAs derived from tRNAs. To date, the role of tRFs/tiRNAs in renal IRI has not been reported. Herein, we aimed to investigate the involvement of tRFs/tiRNAs in the occurrence and development of ischemia-reperfusion-induced AKI. METHODS: Moderate/severe renal IRI mouse models were established by bilateral renal pedicle clamping. The tRF/tiRNA profiles of healthy controls and moderate/severe IRI-stressed kidney tissues were sequenced by Illumina NextSeq 500. Candidate differentially expressed tiRNAs were further verified by RT-qPCR. Biological analysis was also performed. RESULTS: Overall, 152 tRFs/tiRNAs were differentially expressed in the moderate ischemic injury group compared with the normal control group (FC > 2, p < 0.05), of which 47 were upregulated and 105 were downregulated; in the severe ischemic injury group, 285 tRFs/tiRNAs were differentially expressed (FC > 2, p < 0.05), of which 157 were upregulated, and 128 were downregulated. RT-qPCR determination of eight abundantly expressed tiRNAs was consistent with the sequencing results. Gene Ontology analysis for target genes of the tRFs/tiRNAs showed that the most enriched cell components, molecular functions and biological processes were Golgi apparatus, cytoplasmic vesicles, protein binding, cellular protein localization and multicellular organism development. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these target genes were mainly involved in the natural killer cell mediated cytotoxicity pathway, citrate cycle, and regulation of actin cytoskeleton signaling pathway. CONCLUSION: Our results indicated that tRFs/tiRNAs were involved in renal IRI. These tRFs/tiRNAs may be effective partly via regulation of renal immunity, inflammation and metabolism processes. Candidate genes, including tiRNA-Gly-GCC-003, tiRNA-Lys-CTT-003, and tiRNA-His-GTG-002, might be potential biomarkers and therapeutic targets of ischemia-reperfusion injury-induced acute kidney injury.

Dietary α-lipoic acid can alleviate the bioaccumulation, oxidative stress, cell apoptosis, and inflammation induced by lead (Pb) in Channa argus.

This study aims to evaluate the effects of dietary α-lipoic acid (α-LA) on bioaccumulation, oxidative stress, apoptosis, and inflammation in Channa argus after 28 d of lead (Pb) exposure. A total of 300 fish were divided into five groups: the first group was the control group and the other four groups were exposed to waterborne Pb (800 ppb) and fed α-LA diets supplemented with 0, 300, 600, and 900 mg/kg. The results demonstrated that dietary α-LA effectively reduced the Pb accumulation in the liver, kidney, gill, intestine, and muscle of C. argus after exposure to Pb. Meanwhile, dietary α-LA reversed alterations in the biochemical parameters (Alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), blood urea nitrogen (BUN), cortisol (COR), and creatinine (CRE)) and immunity parameters (myeloperoxidase (MPO), complement 3 (C3), lysozyme (LYS), complement 4 (C4), C-reactive protein (CRP), and immunoglobulin M (IgM)) in the serum of fish caused by Pb. Pb-induced reduction of antioxidant enzyme activities (Catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px)) was inhibited by dietary α-LA. And malondialdehyde (MDA) and protein carbonyl (PC) content exhibited an opposite trend. Meanwhile, dietary supplemented with α-LA was found to relieve Pb-induced oxidative stress by downregulating Keap1 mRNA expression levels and upregulating the expression levels of CAT, nuclear factor erythroid 2-related factor 2 (Nrf2), GSH-Px, and Cu/Zn SOD. Furthermore, α-LA supplementation reversed Pb-induced upregulation of pro-inflammatory genes (interleukin (IL)-6, IL-1ß, tumor necrosis factor α (TNF-α), and nuclear factor kappa B (NF-κB)), Pro-apoptotic genes (Bcl-2-associated X (Bax), caspase (Cas)-3, and tumor protein p53 (p53)) and Hsp70, and downregulation of anti-inflammatory genes (IL-10, inhibitor of κBα (IκBα), and transforming growth factor ß (TGF-ß)) and anti-apoptosis gene (B-cell lymphoma-2 (Bcl-2)). Overall, dietary α-LA supplementation could enhance the innate immunity and antioxidant capacity of fish, attenuating the Pb accumulation, and cell apoptosis after being exposed to Pb. Furthermore, dietary α-LA could relieve Pb-induced inflammatory response and oxidative stress of fish via regulating NF-κB and Nrf2 signaling, respectively.

Handwashing Sink Contamination and Carbapenem-resistant Klebsiella Infection in the Intensive Care Unit: A Prospective Multicenter Study.

BACKGROUND: Handwashing sinks can become contaminated by carbapenem-resistant Klebsiella (CRK), including carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Klebsiella oxytoca (CRKO), but whether they are major sources of CRK infections remains unknown. METHODS: We performed a prospective multicenter study in 16 intensive care units (ICUs) (9 general and 7 neonatal) at 11 hospitals. All sinks at these locations were sampled to screen CRK. All CRK clinical isolates recovered between 2 weeks before and 3 months after sampling in ICUs with CRK-positive sinks or other participating ICUs at the same hospital were collected. Whole-genome sequencing of all isolates was performed. Isolates of the same sequence type (ST) were assigned to clones by calling single-nucleotide polymorphisms. RESULTS: Among 158 sinks sampled, 6 CRKP and 6 CRKO were recovered from 12 sinks in 7 ICUs, corresponding to a 7.6% CRK contamination rate. Twenty-eight clinical isolates were collected, and all were CRKP. The 34 CRKP isolates belonged to 7 STs, including ST789 (n = 14, all had blaNDM-5); ST11 (n = 12, 5 belonged to KL64 and 7 to KL47, all had blaKPC-2); ST709 (n = 4, all had blaNDM-5); and ST16, ST20, ST1027, and ST2407 (n = 1 each). One particular ST789 clone caused an outbreak and contaminated a sink. ST11_KL47 sink isolates were likely the source of a cluster of clinical isolates. Two ST11_KL64 isolates belonged to a common clone but were from 2 hospitals. CONCLUSIONS: Contaminated sinks were not the major source of CRK in our local settings. ST789 blaNDM-5-carrying CRKP might represent an emerging lineage causing neonatal infections.

Cervical dilation balloon combined with intravenous drip of oxytocin for induction of term labor: a multicenter clinical trial.

OBJECTIVE: This study aimed to investigate the effectiveness and safety of a method combining double-balloon catheter for cervical ripening and intravenous drip of oxytocin on the induction of term labor, providing the reference for clinical safety. METHODS: A total of 120 pregnant women with a gestation between 37+0 and  41+6 weeks, indications of labor induction, singleton pregnancy with cephalic presentation were enrolled. The patients were divided into the research group receiving cervical dilation balloon combined with intravenous drip of oxytocin and the control group receiving an intravenous drip of oxytocin at a concentration of 0.5% for labor induction (n = 60 for each). The effectiveness and safety of labor induction were evaluated by the rates of successful cervical ripening promotion and labor induction, as well as the vaginal delivery rate, induced labor time, total duration of labor, the total amount of postpartum hemorrhage within 24 h after giving birth, the incidences of postpartum hemorrhage, cervical laceration, puerperal infection and neonatal outcomes. RESULTS: There was no statistical difference in the basal demographic and clinical characteristics, including ages, gestational weeks, delivery times and Bishop scores at admission between two groups. The rate of successful cervical ripening promotion (research vs. control = 90.00% vs. 55.00%), the rate of successful induction (95.00% vs. 40.00%), the vaginal delivery rate (93.33% vs. 63.33%), the induced labor time (15.03 ± 5.40 vs. 30.68 ± 10.82 h), and the total duration of labor (8.12 ± 2.65 vs. 15.01 ± 6.06 h) were significantly different between two groups (all P < 0.05). There was no significant difference in the total amount of postpartum hemorrhage, incidences of postpartum hemorrhage, cervical laceration, puerperal infection as well as the neonatal outcomes, including neonatal weight, neonatal asphyxia and incidence of meconium aspiration syndrome between two groups. CONCLUSIONS: Compared to labor induction of oxytocin, the method combining double-balloon catheter for cervical ripening and intravenous drip of oxytocin for the induction of term labor has a higher vaginal delivery rate, shorter total duration of labor, and does not increase the incidences of postpartum hemorrhage and neonatal infection, which is a more effective and safer method for induction of term labor.

Combined treatment for a rare malignant glomus tumor of the esophagus with pulmonary and liver metastases: a case report and review of literature.

Background: Glomus tumors are typically benign soft tissue tumors that occur at the extremities; malignant and viscerally occurring cases are extremely rare. Case presentation: We report a 49-year old male patient with a malignant esophageal glomus tumor that was complicated by lung and liver metastases. Genetic test results guided the patient's individualized treatment. Consequently, treatment with Anlotinib combined with Tislelizumab achieved significant clinical benefits. Conclusion: Our case report demonstrates that immunotherapy combined with anti-angiogenic therapy in patients with malignant esophageal glomus tumors can achieve significant efficacy and suggests the potential value of next-generation sequencing (NGS) detection in guiding personalized treatments in patients with malignant esophageal glomus tumors.

tRNA-Derived Small RNAs: A Novel Regulatory Small Noncoding RNA in Renal Diseases.

Background: tRNA-derived small RNAs (tsRNAs) are an emerging class of small noncoding RNAs derived from tRNA cleavage. Summary: With the development of high-throughput sequencing, various biological roles of tsRNAs have been gradually revealed, including regulation of mRNA stability, transcription, translation, direct interaction with proteins and as epigenetic factors, etc. Recent studies have shown that tsRNAs are also closely related to renal disease. In clinical acute kidney injury (AKI) patients and preclinical AKI models, the production and differential expression of tsRNAs in renal tissue and plasma were observed. Decreased expression of tsRNAs was also found in urine exosomes from chronic kidney disease patients. Dysregulation of tsRNAs also appears in models of nephrotic syndrome and patients with lupus nephritis. And specific tsRNAs were found in high glucose model in vitro and in serum of diabetic nephropathy patients. In addition, tsRNAs were also differentially expressed in patients with kidney cancer and transplantation. Key Messages: In the present review, we have summarized up-to-date works and reviewed the relationship and possible mechanisms between tsRNAs and kidney diseases.

Acute and 28-Day Repeated-Dose Oral Toxicity of the Herbal Formula Guixiong Yimu San in Mice and Sprague-Dawley Rats.

To evaluate the acute and chronic 28-day repeated-dose oral toxicity of Guixiong Yimu San (GYS) in mice and rats, high-performance liquid chromatography (HPLC) was used to determine the stachydrine hydrochloride in GYS as the quality control. In the acute toxicity trial, the mice were administered orally at a dose rate of 30.0 g GYS/kg body weight (BW) three times a day. The general behavior, side effects, and death rate were noticed for 14 days following treatment. In the subacute toxicity trial, the rats were administered orally at a dose rates of30.0, 15.0, and 7.5 g GYS/kg BW once a day for 28 days. The rats were monitored every day for clinical signs and deaths; changes in body weight and relative organ weights (ROW) were recorded every week, hematological, biochemical, and pathological parameters were also examined at the end of treatment. The results showed that the level of stachydrine hydrochloride in GYS was 2.272 mg/g. In the acute toxicity trial, the maximum-tolerated dose of GYS was more than 90.0 g/kg BW, and no adverse effects or mortalities were noticed during the 14 days in the mice. At the given dose, there were no death or toxicity signs all through the 28-day subacute toxicity trial.The oral administration of GYS at a dose rate of 30.0 g/kg/day BW had no substantial effects on BW, ROW, blood hematology, gross pathology, histopathology, and biochemistry (except glucose), so 30.0 g/kg BW/day was determined as the no-observed-adverse-effect dosage.

NARFL deficiency caused mitochondrial dysfunction in lung cancer cells by HIF-1α-DNMT1 axis.

NARFL was reported to be a component of cytosolic iron-sulfur cluster assembly pathway and a causative gene of the diffused pulmonary arteriovenous malformations (dPAVMs). NARFL knockout dramatically impaired mitochondrial integrity in mice, which might promote mitochondrial dysfunction and lead to worse survival rate of lung cancer. However, the underlying molecular mechanism of NARFL deficiency in non-small cell lung cancer (NSCLC) is unknown. Knockdown assay was performed in A549 and H1299 cells. The protein levels of HIF-1α and DNMT1 were measured, and then Complex I activity, mtDNA copy numbers and mRNA levels of mtND genes were determined. Cisplatin resistance and cell proliferation were conducted using CCK8 assay. Cell migration and invasion were detected using wound heal assay and transwell assay. Survival analysis of lung cancer patients and KM plotter database were used for evaluating the potential value of NARFL deficiency. NARFL protein was expressed in two cell lines and knockdown assay significantly reduced its levels. Knockdown NARFL increased the protein levels of HIF-1α and DNMT1, and downregulated the mRNA levels of ND genes, mitochondrial Complex I activity, mtDNA copy number, and ATP levels. The mitochondrial dysfunction caused by NARFL deficiency were ameliorated by siHIF-1α and DNMT1 inhibitor. Knockdown NARFL increased the drug resistance and cell migration, and siHIF-1α reversed this effect. Moreover, NSCLC patients with NARFL deficiency had a poor survival rate using a tissue array and KM plotter database, and it would be a target for cancer prognosis and treatment. NARFL deficiency caused dysregulation of energy metabolism in lung cancer cells via HIF-1α-DNMT1 axis, which promoted drug resistance and cell migration. It provided a potential target for treatment and prognosis of lung cancer.

Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury.

Background: Our previous study showed that vitamin D (VD)-vitamin D receptor (VDR) plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Recently, glucose metabolism reprogramming was reported to be involved in the pathogenesis of AKI. Objective: To investigate the role of VD-VDR in glucose metabolism reprogramming in LPS-induced AKI. Methods: We established a model of LPS-induced AKI in VDR knockout (VDR-KO) mice, renal proximal tubular-specific VDR-overexpressing (VDR-OE) mice and wild-type C57BL/6 mice. In vitro, human proximal tubular epithelial cells (HK-2 cells), VDR knockout and VDR overexpression HK-2 cell lines were used. Results: Paricalcitol (an active vitamin D analog) or VDR-OE reduced lactate concentration, hexokinase activity and PDHA1 phosphorylation (a key step in inhibiting aerobic oxidation) and simultaneously ameliorated renal inflammation, apoptosis and kidney injury in LPS-induced AKI mice, which were more severe in VDR-KO mice. In in vitro experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-PDHA1). Moreover, paricalcitol activated the phosphorylation of AMP-activated protein kinase (AMPK), and an AMPK inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells. Conclusion: VD-VDR alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of PDHA1 phosphorylation via the AMPK pathway.

Vitamin D receptor attenuate ischemia-reperfusion kidney injury via inhibiting ATF4.

Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway-mediated ERS plays an important role in the progression of acute kidney disease (AKI). We have previously reported that Vitamin D receptor (VDR) exert renoprotection in rodent AKI models. However, whether ATF4, as well as ERS, is involved in the protective effect of VDR in ischemia-reperfusion (I/R) induced AKI is unknown. Herein, we showed that VDR agonist paricalcitol and VDR overexpression alleviated I/R-induced renal injury and cells apoptosis with decreased ATF4 and attenuated ERS, while VDR deletion significantly resulted in further increased ATF4, more drastic ERS and renal injury in I/R mice models. In addition, paricalcitol remarkably reduced Tunicamycin (TM) induced ATF4 and ERS with attenuated renal injury, while VDR deletion aggravated the above changes in TM mice models. Moreover, overexpression of ATF4 partially abolished the effect of paricalcitol against TM-induced ERS and apoptosis, while inhibition of ATF4 enhanced the protective effect of paricalcitol. Bioinformatics analysis indicated potential VDR binding sites on ATF4 promotor sequence which were further confirmed by ChIP-qPCR and dual-luciferase reporter gene assay. In conclusion, VDR attenuated I/R-induced AKI by suppressing ERS partly via transcriptional regulation of ATF4.