Ferroptosis Is Crucial for Cisplatin Induced Sertoli Cell Injury via N6-Methyladenosine Dependent Manner.

PURPOSE: This study aimed to investigate the effect of the N6-methyladenosine (m6A) dependent ferroptosis on cisplatininduced Sertoli cell injury. MATERIALS AND METHODS: A cisplatin exposure mouse model was established by intraperitoneal injection of cisplatin in our study. TM4 cell lines was used for in vitro study. Ferroptosis was detected according to metabolomic analysis and a series of assays, including malondialdehyde, glutathione, and glutathione disulfide concentration detection, 2',7'-dichlorodihydrofluorescein diacetate and BODIPY 581/591 C11 probe detection, and transmission electron microscope imaging. Key ferroptosis-related genes were identified via transcriptomic analysis, western blot and immunohistochemistry. The m6A modification was demonstrated via m6A RNA immunoprecipitation and luciferase reporter assays. Immune cell infiltration was detected by mass cytometry, and verified by flow cytometry and immunofluorescence. RESULTS: Ferroptosis, but not other types of programmed cell death, is a significant phenomenon in cisplatin-induced testis damage and Sertoli cell loss. Ferroptosis induced by cisplatin in Sertoli cell/TM4 cell is GPX4 independent but is regulated by SLC7A11 and ALOX12. Both SLC7A11 and ALOX12 are regulated via m6A dependent manner by METTL3. Furthermore, overexpressed ALOX12-12HETE pathway may result in macrophage polarization and inflammatory response in cisplatin exposure testis. CONCLUSIONS: Cisplatin-induced Sertoli cell injury via ferroptosis and promoted ferroptosis in an m6A dependent manner. m6A modification of both SLC7A11 and ALOX12 mRNA could result in ferroptosis in our in vitro model. Further, overexpressed ALOX12 can cause more production of 12-HETE, which may be responsible for testis inflammation caused by cisplatin.

Early postoperative complications after transverse colostomy closure, a retrospective study.

BACKGROUND: Ostomy is a common surgery usually performed to protect patients from clinical symptoms caused by distal anastomotic leakage after colorectal cancer (CRC) surgery and perforation or to relieve intestinal obstruction. AIM: To analyze the complications after transverse colostomy closure. METHODS: Patients who underwent transverse colostomy closure from Jan 2015 to Jan 2022 were retrospectively enrolled in a single clinical center. The differences between the complication group and the no complication group were compared. Logistic regression analyses were conducted to find independent factors for overall complications or incision infection. RESULTS: A total of 102 patients who underwent transverse colostomy closure were enrolled in the current study. Seventy (68.6%) patients underwent transverse colostomy because of CRC related causes. Postoperative complications occurred in 30 (29.4%) patients and the most frequent complication occurring after transverse colostomy closure was incision infection (46.7%). The complication group had longer hospital stays (P < 0.01). However, no potential risk factors were identified for overall complications and incision infection. CONCLUSION: The most frequent complication occurring after transverse colostomy closure surgery in our center was incision infection. The operation time, interval from transverse colostomy to reversal, and method of anastomosis might have no impact on the postoperative complications. Surgeons should pay more attention to aseptic techniques.

Automatic measurement of lower limb alignment in portable devices based on deep learning for knee osteoarthritis.

BACKGROUND: For knee osteoarthritis patients, analyzing alignment of lower limbs is essential for therapy, which is currently measured from standing long-leg radiographs of anteroposterior X-ray (LLR) manually. To address the time wasting, poor reproducibility and inconvenience of use caused by existing methods, we present an automated measurement model in portable devices for assessing knee alignment from LLRs. METHOD: We created a model and trained it with 837 conforming LLRs, and tested it using 204 LLRs without duplicates in a portable device. Both manual and model measurements were conducted independently, then we recorded knee alignment parameters such as Hip knee ankle angle (HKA), Joint line convergence angle (JCLA), Anatomical mechanical angle (AMA), mechanical Lateral distal femoral angle (mLDFA), mechanical Medial proximal tibial angle (mMPTA), and the time required. We evaluated the model's performance compared with manual results in various metrics. RESULT: In both the validation and test sets, the average mean radial errors were 2.778 and 2.447 (P<0.05). The test results for native knee joints showed that 92.22%, 79.38%, 87.94%, 79.82%, and 80.16% of the joints reached angle deviation<1° for HKA, JCLA, AMA, mLDFA, and mMPTA. Additionally, for joints with prostheses, 90.14%, 93.66%, 86.62%, 83.80%, and 85.92% of the joints reached that. The Chi-square test did not reveal any significant differences between the manual and model measurements in subgroups (P>0.05). Furthermore, the Bland-Altman 95% limits of agreement were less than ± 2° for HKA, JCLA, AMA, and mLDFA, and slightly more than ± 2 degrees for mMPTA. CONCLUSION: The automatic measurement tool can assess the alignment of lower limbs in portable devices for knee osteoarthritis patients. The results are reliable, reproducible, and time-saving.

[Recording and identification of depolarization-activated current in intercalated cells].

The depolarization-activated current of intercalated cells in the distal nephron was detected for the first time, and the type of ion channel mediating the current was identified based on electrophysiological and pharmacological properties. The whole-cell current of distal nephron in kidney of C57BL/6J mice was recorded by Axon MultiClamp 700B patch-clamp system, and the effects of several K+ channel inhibitors on the depolarization-activated current in intercalated cells were observed. In addition, the immunofluorescence technique was used to investigate the localization of the channel in intercalated cells. The results showed that when K+ concentration of the bath solution was equal to intracellular fluid (140 mmol/L K+), the depolarization-activated current could be recorded in intercalated cells, but this current was not observed in the principal cells. The depolarization-activated current detected in the intercalated cells could be blocked by Kv4.1 inhibitors. The immunofluorescence experiment showed that the fluorescence of Kv4.1 protein was only present in intercalated cells and not observed in principal cells. Kv4.1 protein immunofluorescence was observed in the luminal and basolateral membrane of intercalated cells, but the fluorescence intensity of luminal membrane was higher than that of basolateral membrane. We conclude that the depolarization-activated current detected in intercalated cells is mediated by Kv4.1 and this channel is mainly expressed in the luminal membrane of intercalated cells.

Dichroa febrifuga Lour.: A review of its botany, traditional use, phytochemistry, pharmacological activities, toxicology, and progress in reducing toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Dichroa febrifuga Lour., a toxic but extensively used traditional Chinese medicine with a remarkable effect, is commonly called "Changshan" in China. It has been used to treat malaria and many other parasitic diseases. AIM OF THE REVIEW: The study aims to provide a current overview of the progress in the research on traditional use, phytochemistry, pharmacological activities, toxicology, and methods of toxicity reduction of D. febrifuga. Additionally, further research directions and development prospects for the plant were put forward. MATERIALS AND METHODS: The article uses "Dichroa febrifuga Lour." "D. febrifuga" as the keyword and all relevant information on D. febrifuga was collected from electronic searches (Elsevier, PubMed, ACS, CNKI, Google Scholar, and Baidu Scholar), doctoral and master's dissertations and classic books about Chinese herbs. RESULTS: 30 chemical compounds, including alkaloids, terpenoids, flavonoids and other kinds, were isolated and identified from D. febrifuga. Modern pharmacological studies have shown that these components have a variety of pharmacological activities, including anti-malarial activities, anti-inflammatory activities, anti-tumor activities, anti-parasitic activities and anti-oomycete activities. Meanwhile, alkaloids, as the material basis of its efficacy, are also the source of its toxicity. It can cause multiple organ damage, including liver, kidney and heart, and cause adverse reactions such as nausea and vomiting, abdominal pain and diarrhea. In the current study, the toxicity can be reduced by modifying the structure of the compound, processing and changing the dosage forms. CONCLUSIONS: There are few studies on the chemical constituents of D. febrifuga, so the components and their structure characterization contained in it can become the focus of future research. In view of the toxicity of D. febrifuga, there are many methods to reduce it, but the safety and rationality of these methods need further study.

Single-cell RNA combined with bulk RNA analysis to explore oxidative stress and energy metabolism factors and found a new prostate cancer oncogene MXRA8.

BACKGROUND: Prostate cancer is the most common malignancy among men worldwide, and its diagnosis and treatment are challenging due to its heterogeneity. METHODS: Integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, we identified two molecular subtypes of prostate cancer based on dysregulated genes involved in oxidative stress and energy metabolism. We constructed a risk score model (OMR) using common differentially expressed genes, which effectively evaluated prostate cancer prognosis. RESULTS: Our analysis demonstrated a significant correlation between the risk score model and various factors, including tumor immune microenvironment, genomic variations, chemotherapy resistance, and immune response. Notably, patients with low-risk scores exhibited increased sensitivity to chemotherapy and immunotherapy compared to those with high-risk scores, indicating the model's potential to predict patient response to treatment. Additionally, our investigation of MXRA8 in prostate cancer showed significant upregulation of this gene in the disease as confirmed by PCR and immunohistochemistry. Functional assays including CCK-8, transwell, plate cloning, and ROS generation assay demonstrated that depletion of MXRA8 reduced the proliferative, invasive, migratory capabilities of PC-3 cells, as well as their ROS generation capacity. CONCLUSIONS: Our study highlights the potential of oxidative stress and energy metabolism-related genes as prognostic markers and therapeutic targets in prostate cancer. The integration of scRNA-seq and bulk RNA-seq data enables a better understanding of prostate cancer heterogeneity and promotes personalized treatment development. Additionally, we identified a novel oncogene MXRA8 in prostate cancer.

Dietary calcium, phosphorus, and potassium intake associated with erectile dysfunction in the National Health and Nutrition Examination Survey (NHANES) 2001 to 2004.

BACKGROUND: Erectile dysfunction is now a common disorder of sexual function, and its relationship to dietary calcium, phosphorus, and potassium has not been well studied. We set out to determine if dietary intakes of calcium, phosphorus, and potassium are related to erectile dysfunction in U.S. men. METHODS: For this cross-sectional investigation, we used data from NHANES 2001-2004. To investigate the connection of dietary calcium, phosphorus, and potassium intake with erectile dysfunction, we employed multivariate logistic regression, smoothed curve fitting, and subgroup analysis. RESULTS: This cross-sectional study comprised 3,556 eligible male subjects in total, with a weighted mean age of 49.93±18.13 years. After controlling for race and age, the greatest tertile of calcium consumption was found to have a 34% lower risk of erectile dysfunction than the lowest tertile (OR = 0.66; 95% CI = 0.52-0.84; p = 0.0006). The risk of erectile dysfunction was found to be reduced by 33% (OR = 0.67; 95% CI = 0.52-0.87; p = 0.0024) for the highest tertile of phosphorus intake compared to the lowest tertile of phosphorus intake and by 35% (OR = 0.65; 95% CI = 0.50-0.83; p = 0.0006) for the highest tertile of potassium intake compared to the lowest tertile of potassium intake in the fully adjusted model. CONCLUSION: Erectile dysfunction and dietary consumption of calcium, phosphorus, and potassium are inversely associated with the U.S. population. To confirm the accuracy of our findings, additional prospective studies are necessary. Furthermore, it is imperative to do further fundamental research at the molecular level to gain a deeper understanding of the underlying mechanisms.

Selective Separation of U(VI) from Pu(IV) by 2,9-Diamide-1,10-phenanthroline Ligands at High Acidity: Extraction and Coordination Chemistry.

During the PUREX process, the separation between U(VI) and Pu(IV) is achieved by reducing Pu(IV) to Pu(III), which is complicated and energy-consuming. To address this issue, we report here the first case of separation of U(VI) from Pu(IV) by o-phenanthroline diamide ligands under high acidity. Two new o-phenanthroline diamide ligands (1,10-phenanthroline-2,9-diyl)bis(indolin-1-ylmethanone) (L1) and (1,10-phenanthroline-2,9-diyl)bis((2-methylindolin-1-yl)methanone) (L2) were synthesized, which can effectively separate U(VI) from Pu(IV) even at 4 mol/L HNO3. The highest separation factor of U(VI) and Pu(IV) can reach over 1000, setting a new record for the separation of U(VI) from Pu(IV) under high acidity. Furthermore, extracted U(VI) can be easily recovered with water or dilute nitric acid, and the extraction performance remains stable even after 150 kGy gamma irradiation, which provides solid experimental support for potential engineering applications. The results of UV-vis titration and single-crystal X-ray diffraction measurements show that the 1:1 complex formed by L1 with U(VI) is more stable than all of the previously reported phenanthroline ligands, which reasonably reveals that the ligand L1 designed in this work has excellent affinity for U(VI). The findings of this work promise to contribute to the facilitation of the PUREX process by avoiding the use of reducing agents. It also provides new clues for designing ligands to achieve efficient separation between U(VI) and Pu(IV) at high acidity.

Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches.

The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/ß-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.

Effect of intraoperative blood loss on postoperative complications and prognosis of patients with colorectal cancer: A meta­analysis.

The purpose of the present study was to evaluate whether the amount of intraoperative blood loss (IBL) affects the complications and prognosis of patients with colorectal cancer (CRC). The PubMed, EMBASE and the Cochrane Library databases were used to search for eligible studies from inception to November 30, 2020. Hazard ratios (HRs) and 95% confidence intervals (Cls) were pooled up. The overall survival (OS) and disease-free survival (DFS) were compared between the larger IBL group and the smaller IBL group. The present study was performed with RevMan 5.3 (The Cochrane Collaboration). A total of seven studies involving 1,540 patients with CRC were included in the present study. The smaller IBL group had a higher rate of OS (HR=1.45, 95% CI=1.17 to 1.8, P=0.0007) and a higher rate of DFS (HR=1.76, 95% CI=1.40 to 2.21, P<0.00001). Furthermore, the larger IBL group had a higher rate of postoperative complications than the smaller IBL group (odds ratio=2.06, 95% CI=1.72 to 2.15, P<0.00001). In conclusion, a smaller IBL was associated with better OS and DFS, and a lower risk of postoperative complications compared with a larger IBL in patients with CRC, suggesting that surgeons should pay more attention during perioperative management and surgical operation to reduce IBL.

Novel Pyrazole Acyl(thio)urea Derivatives Containing a Biphenyl Scaffold as Potential Succinate Dehydrogenase Inhibitors: Design, Synthesis, Fungicidal Activity, and SAR.

As part of a program to discover novel succinate dehydrogenase inhibitor fungicides, a series of new pyrazole acyl(thio)urea compounds containing a diphenyl motif were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS, and single X-ray crystal diffraction analysis. Most of these compounds possessed excellent activity against 10 fungal plant pathogens at 50 µg mL-1, especially against Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Cercospora arachidicola. Interestingly, compounds 3-(difluoromethyl)-1-methyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9b, EC50 = 0.97 ± 0.18 µg mL-1), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50 = 2.63 ± 0.41 µg mL-1), and N-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (9g, EC50 = 1.31 ± 0.15 µg mL-1) exhibited activities against S. sclerotiorum that were better than the commercial fungicide bixafen (EC50 = 9.15 ± 0.05 µg mL-1) and similar to the positive control fluxapyroxad (EC50 = 0.71 ± 0.11 µg mL-1). These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants. Structure-activity relationships (SAR) are discussed by substituent effects/molecular docking, and density functional theory analysis indicated that these compounds are succinate dehydrogenase inhibitors.

Remission of Nonalcoholic Fatty Liver Disease After Radical Surgery in Patients with Colorectal Cancer: A Single-Center Retrospective Study.

Purpose: The purpose of this study was to investigate the relationship between remission of nonalcoholic fatty liver disease (NAFLD) and radical surgery for colorectal cancer (CRC) patients. Methods: From January 2014 to December 2021, data of patients with concurrent CRC and NAFLD who underwent radical surgery in a single-center hospital were retrospectively collected. NAFLD was defined as a mean computed tomography (CT) liver attenuation value of <40 Hounsfield units (HUs). Comparison of preoperative and 1-year postoperative CT images was performed to evaluate the change of NAFLD. Multivariate logistic regression analysis was performed to identify independent predictive factors for NAFLD remission. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival (DFS) between the remission group and no remission group. Results: In this study, a total of 55 eligible patients were included. The remission group had 33 (60.0%) patients and the no remission group had 22 (40.0%) patients. The mean preoperative weight was 66.1 ± 9.9 kg. The mean preoperative body mass index (BMI) was 25.4 ± 2.5 kg/m2. We found that the average weight was significantly decreased (P < 0.01), average BMI was significantly decreased (P < 0.01), and HU score was significantly increased (P < 0.01). By comparing baseline characteristics between the remission group and no remission group, we found that the remission group exhibited larger tumor sizes (P = 0.036) than the no remission group. In the multivariate logistic regression analysis, we found that weight change was a predictor for NAFLD (odds ratio = 0.764, 95% confidence interval = 0.618-0.944, P = 0.013). We did not find any statistically significant differences in OS (P = 0.182) or DFS (P = 0.248) between the remission group and no remission group. Conclusions: The NAFLD remission rate reached 60.0% for CRC patients 1 year after radical surgery. In addition, we found that weight change was a predictor of NAFLD remission.

Clinical and radiographic outcomes of long monoblock, hydroxyapatite-coated stem in revision hip arthroplasty with extended trochanteric osteotomy: a multicenter study.

BACKGROUND: The distally fixed stem used in revision total hip arthroplasty (rTHA) with extended trochanteric osteotomy (ETO) is subject to periprosthetic fracture, stem subsidence, and stress shielding. The prospective multicentric study aimed to assess the clinical and radiographic outcomes, and complications of using the Corail revision stem in rTHA with ETO. METHODS: Sixty-four patients undergoing rTHA with ETO using the Corail revision stem between 2019 and 2020 were enrolled in the study. We performed a postoperative follow-up of the patient and obtained radiographs and Harris hip scores (HHSs). These results were used to analyze ETO union, Engh scores, bone remodeling, stem stability and hip function. RESULTS: The mean follow-up duration was 34 months (range 23-41). Sixty-two patients who underwent ETOs achieved complete healing at the final follow-up. Fifty-nine hips had bony ingrowth from the osteotomy fragment to the stem without radiolucent lines. The postoperative Engh score was 21.3 ± 3.59 (range 15.5-27.0). Forty-three hips had regeneration in the proximal femur. Two patients had transient thigh pain postoperatively. The postoperative HHS improved from 40.7 ± 16.67 (range 0-67) preoperatively to 82.1 ± 6.83 (range 73-93). CONCLUSION: Corail revision stems are a viable and reliable option in rTHA with ETO. This stem had excellent clinical and radiographic outcomes, resulting in a high rate of ETO union and stem survival. The revision stem enabled restoration of proximal bone stock in femurs with prerevision bone defects, which were prepared for the next revision operation. Level of evidence Level IIb, Prospective self-control study.

Marinimicrococcus flavescens gen. nov., sp. nov., a new member of the family Geminicoccaceae, isolated from a marine sediment of the South China Sea.

A Gram-stain-negative, catalase-positive and oxidase-positive, nonmotile, aerobic, light yellow, spherical-shaped bacterial strain with no flagella, designated strain YIM 152171T, was isolated from sediment of the South China Sea. Colonies were smooth and convex, light yellow and circular, and 1.0-1.5×1.0-1.5 µm in cell diameter after 7 days of incubation at 28°C on YIM38 media supplemented with sea salt. Colonies could grow at 20-45°C (optimum 28-35°C) and pH 6.0-11.0 (optimum, pH 7.0-9.0), and they could proliferate in the salinity range of 0-6.0 % (w/v) NaCl. The major cellular fatty acids were summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c), C18 : 1 ω7c 11-methyl, C16 : 0, C16 : 1 ω11c, C16 : 1 ω5c, C17 : 1 ω6c and C18 : 1 ω5c. The respiratory quinone was ubiquinone 10, and the polar lipid profile included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol mannoside, one unidentified phospholipid and one unidentified aminolipid. Phylogenetic analyses based on the 16S rRNA gene sequences placed strain YIM 152171T within the order Rhodospirillales in a distinct lineage that also included the genus Geminicoccus. The 16S rRNA gene sequence similarities of YIM 152171T to those of Arboricoccus pini, Geminicoccus roseus and Constrictibacter antarcticus were 92.17, 89.25 and 88.91 %, respectively. The assembled draft genome of strain YIM 152171T had 136 contigs with an N50 value of 134704 nt, a total length of 3 001 346 bp and a G+C content of 70.27 mol%. The phylogenetic, phenotypic and chemotaxonomic data showed that strain YIM 152171T (=MCCC 1K08488T=KCTC 92884T) represents a type of novel species and genus for which we propose the name Marinimicrococcus gen. nov., sp. nov.

Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na+ Channel (ENaC).

BACKGROUND: Kir4.2 and Kir4.1 play a role in regulating membrane transport in the proximal tubule (PT) and in the distal-convoluted-tubule (DCT), respectively. METHODS: We generated kidney-tubule-specific-AT1aR-knockout (Ks-AT1aR-KO) mice to examine whether renal AT1aR regulates Kir4.2 and Kir4.1. RESULTS: Ks-AT1aR-KO mice had a lower systolic blood pressure than Agtr1aflox/flox (control) mice. Ks-AT1aR-KO mice had a lower expression of NHE3 (Na+/H+-exchanger 3) and Kir4.2, a major Kir-channel in PT, than Agtr1aflox/flox mice. Whole-cell recording also demonstrated that the membrane potential in PT of Ks-AT1aR-KO mice was lesser negative than Agtr1aflox/flox mice. The expression of Kir4.1 and Kir5.1, Kir4.1/Kir5.1-mediated K+ currents of DCT and DCT membrane potential in Ks-AT1aR-KO mice, were similar to Agtr1aflox/flox mice. However, angiotensin II perfusion for 7 days hyperpolarized the membrane potential in PT and DCT of the control mice but not in Ks-AT1aR-KO mice, while angiotensin II perfusion did not change the expression of Kir4.1, Kir4.2, and Kir5.1. Deletion of AT1aR did not significantly affect the expression of αENaC (epithelial Na+ channel) and ßENaC but increased cleaved γENaC expression. Patch-clamp experiments demonstrated that deletion of AT1aR increased amiloride-sensitive Na+-currents in the cortical-collecting duct but not in late-DCT. However, tertiapin-Q sensitive renal outer medullary potassium channel currents were similar in both genotypes. CONCLUSIONS: AT1aR determines the baseline membrane potential of PT by controlling Kir4.2 expression/activity but AT1aR is not required for determining the baseline membrane potential of the DCT and Kir4.1/Kir5.1 activity/expression. However, AT1aR is required for angiotensin II-induced hyperpolarization of basolateral membrane of PT and DCT. Deletion of AT1aR had no effect on baseline renal outer medullary potassium channel activity but increased ENaC activity in the CCD.

Pathogenesis of Airway Mucus Hypersecretion in Chronic Obstructive Pulmonary Disease and Intervention of Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Chronic obstructive pulmonary disease （COPD） is one of the most common chronic diseases of the respiratory system in the clinic. The disease has a long course and is difficult to cure， which seriously threatens human health. Airway mucus hypersecretion （AMH） is an independent risk factor for COPD and has a significant impact on the development and prognosis of the disease. The review finds that the abnormal proliferation of goblet cells and the excessive secretion of mucin are the direct causes of AMH. The pathogenesis of AMH may be closely related to the inhalation of heterogeneous particles， airway inflammation， the imbalance of mucin/water salt ratio， and the regulation of related signaling pathways. Traditional Chinese medicine （TCM） believes that AMH of COPD belongs to the category of lung distension with phlegm-fluid retention syndrome， and the disease is mainly treated from phlegm on the basis of lung distension. This article summarizes the relevant research in the field of TCM in recent years and finds that the single TCM that effectively intervened AMH of COPD is mainly phlegm-resolving TCM， and the main active ingredients of TCM are flavonoids， terpenoids， phenols， and alkaloids. The main TCM compounds are mainly designed to remove heat-phlegm， warmly resolve cold-phlegm， dry dampness to eliminate phlegm， invigorate Qi， promote blood circulation and dispel phlegm， and invigorate lung， spleen， and kidney. Its mechanism of action may be direct inhibition or indirect inhibition of airway epithelial goblet cell metaplasia and mucin expression by inhibiting airway inflammation， regulating aquaporins to correct the imbalance of mucin/water salt ratio， and regulating signaling pathways， so as to reduce mucus oversecretion in COPD. However， there are still some problems. For example， the research mainly focuses on TCM compounds instead of the single TCM or its effective components. The research on the mechanism of action is not thorough enough， and the research results are not interoperable. The clinical transformation rate of basic research is insufficient. This article systematically reviews the research status of AMH in the treatment of COPD with TCM and puts forward some thoughts on the existing problems， so as to provide a reference for clinical rational medication and in-depth research.

Individual-Level Health Care Costs Attributable to Noncommunicable Diseases: A Longitudinal Study Based on the Older Adults in China.

Noncommunicable chronic diseases among the elderly population represent a significant economic burden in China. However, previous disease-related health cost studies lacked representation of older adults and comparability of the burden of multiple chronic diseases. The objective of this study was to determine the fraction of health care costs attributable to the 6 most prevalent chronic diseases and comorbidities in the sample of older adults. This study employed data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), with 3 waves in 2011, 2014, and 2018, and included 18 349 observations in total. Outpatient costs, inpatient costs, and total health care costs were included in this study. Based on a 2-part random effects model, the effect of chronic disease on health service utilization was first explored by constructing a dummy variable for whether or not to utilize health care, followed by estimation of attributable costs in the population with health care utilization. Among the older adults in the sample, hypertension, heart disease, cataracts, arthritis, stroke or Cerebrovascular disease (CVD) and chronic lung disease are the 6 most prevalent chronic conditions. The costs attributable to the 6 chronic diseases mentioned above were 36.00% of outpatient costs, 55.92% of inpatient costs, and 45.05% of total health care costs for older adults. Of these, heart disease, stroke or CVD, and chronic lung disease accounted for 22.11%, 13.24%, and 10.56% of total health care costs, respectively. Moreover, the proportion of health care costs attributable to chronic diseases was higher for older adults who were male, lived in urban areas, and had a lower level of education. The proportion of health care costs attributable to chronic diseases is substantial among older adults in China. Health care costs associated with chronic diseases can be decreased with well-targeted interventions and comprehensive access to health services.

Leveraging diverse cell-death related signature predicts the prognosis and immunotherapy response in renal clear cell carcinoma.

Background: Modulation of programmed cell death in tumor cells alters the tumor microenvironment and the influx of tumor-infiltrating lymphocytes, and the combination of its inducers and immune checkpoint inhibitors plays a synergistic role in enhancing antitumor effects. Methods: We downloaded the data of clear cell renal cell carcinoma samples from The Cancer Genome Atlas and used a machine learning approach to build a new programmed cell death index (PCDI) through 13 programmed cell death-related genes. Based on PCDI, clinical features, tumor immune microenvironment, chemotherapy response and immunotherapy response were systematically analyzed. Results: PCDI consists of eight programmed cell death-related genes (TBX3, BID, TCIRG1, IDUA, KDR, PYCARD, IFNG and LRRK2). PCDI is a reliable predictor of survival in clear cell renal cell carcinoma patients and has been validated in multiple external datasets. We found that the high PCDI group showed higher levels of immune cell infiltration and better response to immunotherapy compared to the low PCDI group, and PCDI can also be used for prognostic prediction in a variety of cancers other than clear cell renal cell carcinoma. In vitro experiments demonstrated that knockdown of IDUA inhibited the proliferation and migration of clear cell renal cell carcinoma. Conclusions: The PCDI identified in this study provides valuable insights into the clinical management of clear cell renal cell carcinoma by accurately evaluating the prognosis of patients with clear cell renal carcinoma and identifying the patient population that would benefit from immunotherapy.

Hyperuricemia remission after colorectal cancer surgery for colorectal cancer patients.

The purpose of this study was to investigate whether patients with colorectal cancer (CRC) combined with hyperuricemia remitted 1 year after CRC surgery. CRC patients combined with hyperuricemia who underwent radical surgery were included from a single clinical center from Jan 2016 to Dec 2021. Baseline characteristics was compared between the remission group and the non-remission group. Multivariate logistic regression was used to find the possible predictive factors of hyperuricemia remission. A total of 91 patients were included for data analysis, retrospectively. There were 34 (37.4%) patients in the remission group and 57 (62.6%) patients in the non-remission group. The mean preoperative weight and body mass index (BMI) were 61.2 ± 10.7 (kg) and 24.1 ± 3.3 (kg/m2). 21 (23.1%) patients had a history of drinking. We found that the weight and BMI were not significantly different before and 1 year after CRC surgery (P > 0.05). In contrast, uric acid values were significantly decreased (P < 0.01). Meanwhile, the outcomes showed there were no significant differences in the baseline characteristics between the remission and non-remission groups (P > 0.05). According to multivariate logistic regression, we found that the history of drinking was a predictive factor of hyperuricemia remission (OR = 0.046, 95% CI 0.005-0.475, P = 0.010). CRC patients with hyperuricemia had a 37.4% remission from hyperuricemia 1 year after CRC surgery. Tumor location, tumor stage, and tumor size did not predict the remission of hyperuricemia. Notably, the history of drinking was a predictive factor of hyperuricemia remission.

Discovery of Highly Efficient Novel Antifungal Lead Compounds Targeting Succinate Dehydrogenase: Pyrazole-4-carboxamide Derivatives with an N-Phenyl Substituted Amide Fragment.

Developing environmentally friendly fungicides is crucial to tackle the issue of rising pesticide resistance. In this study, a series of novel pyrazole-4-carboxamide derivatives containing N-phenyl substituted amide fragments were designed and synthesized. The structures of target compounds were confirmed by 1H NMR, 13C NMR, and HRMS, and the crystal structure of the most active compound N-(1-(4-(4-(tert-butyl)benzamido)phenyl)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide (U22) was further determined by X-ray single-crystal diffraction. The bioassay results indicated that the 26 target compounds possessed good in vitro antifungal activity against Sclerotinia sclerotiorum with EC50 values for compounds U12, U13, U15, U16, U18, U22, and U23 being 4.17 ± 0.46, 8.04 ± 0.71, 7.01 ± 0.71, 12.77 ± 1.00, 8.11 ± 0.70, 0.94 ± 0.11, and 9.48 ± 0.83 µg·mL-1, respectively, which were the similar to controls bixafen (6.70 ± 0.47 µg·mL-1), fluxapyroxad (0.71 ± 0.14 µg·mL-1), and pydiflumetofen (0.06 ± 0.01 µg·mL-1). Furthermore, in vivo antifungal activity results against S. sclerotiorum indicated that compounds U12 (80.6%) and U22 (89.9%) possessed excellent preventative efficacy at 200 µg·mL-1, which was the same as the control pydiflumetofen (82.4%). Scanning electron microscopy and transmission electron microscopy studies found that the compound U22 could destroy the hyphal morphology and damage mitochondria, cell membranes, and vacuoles. The results of molecular docking of compound U22 and pydiflumetofen with succinate dehydrogenase (SDH) indicated they interact well with the active site of SDH. This study validated our approach and design strategy to produce compounds with an enhanced biological activity as compared to the parent structure.