Weak Bimetal Coupling-Assisted MN4 Catalyst for Enhanced Carbon Dioxide Reduction Reaction.

The design of multimetal catalysts holds immense significance for efficient CO2 capture and its conversion into economically valuable chemicals. Herein, heterobimetallic catalysts (MiMo)L were exploited for the CO2 reduction reactions (CO2RR) using relativistic density functional theory (DFT). The octadentate Pacman-like polypyrrolic ligand (H4L) accommodates two metal ions (Mo, W, Nd, and U) inside (Mi) and outside (Mo) its month, rendering a weak bimetal coupling-assisted MN4 catalytically active site. Adsorption reactions have access to energetically stable coordination modes of -OCO, -OOC, and -(OCO)2, where the donor atom(s) are marked in bold. Among all of the species, (UiMoo)L releases the most energy. Along CO2RR, it favors to produce CO. The high-efficiency CO2 reduction is attributed to the size matching of U with the ligand mouth and the effective manipulation of the electron density of both ligand and bimetals. The mechanism in which heterobimetals synergetically capture and reduce CO2 has been postulated. This establishes a reference in elaborating on the complicated heterogeneous catalysis.

Pathological mechanisms of cold and mechanical stress in modulating cancer progression.

Environmental temperature and cellular mechanical force are the inherent factors that participate in various biological processes and regulate cancer progress, which have been hot topics worldwide. They occupy a dominant part in the cancer tissues through different approaches. However, extensive investigation regarding pathological mechanisms in the carcinogenic field. After research, we found cold stress via two means to manipulate tumors: neuroscience and mechanically sensitive ion channels (MICHs) such as TRP families to regulate the physiological and pathological activities. Excessive cold stimulation mediated neuroscience acting on every cancer stage through the hypothalamus-pituitary-adrenocorticoid (HPA) to reach the target organs. Comparatively speaking, mechanical force via Piezo of MICHs controls cancer development. The progression of cancer depends on the internal activation of proto-oncogenes and the external tumorigenic factors; the above two means eventually lead to genetic disorders at the molecular level. This review summarizes the interaction of bidirectional communication between them and the tumor. It covers the main processes from cytoplasm to nucleus related to metastasis cascade and tumor immune escape.

Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation.

Background: Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. Methods: The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. Results: KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. Conclusion: These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.

Limonin ameliorates cisplatin-induced acute liver injury by inhibiting 11ß-hydroxysteroid dehydrogenase type 1.

BACKGROUND: Acute liver injury (ALI) is a common side effect of cisplatin treatment in the clinic and can lead to liver failure if not treated promptly. Previous studies have revealed that Limonin, a critical bioactive substance in citrus fruits, can protect multiple organs from various medical conditions. However, whether Limonin could ameliorate cisplatin-induced ALI remains unclear. METHODS: In vivo and in vitro models were induced by cisplatin in the present study. Non-targeted metabolomics was employed to analyze the metabolic changes in the liver after ALI. In addition, molecular docking was utilized to predict the potential targets of Limonin. RESULTS: Limonin attenuated hepatic histopathological injury by reducing hepatocyte apoptosis, lipid peroxidation, and inflammation in cisplatin-challenged mice. Employing metabolomics, we revealed that Limonin mediated the balance of various disturbed metabolic pathways in the liver after cisplatin-induced ALI. Integrating public data mining, molecular docking studies, and in vitro experiments demonstrated that Limonin suppressed the expression and activity of its direct target, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), in the liver, thus reducing the production of corticosterone (CORT), a key metabolite promoted hepatocyte apoptosis. CONCLUSIONS: Limonin improves the liver metabolic microenvironment by inhibiting 11ß-HSD1 to protect against cisplatin-induced ALI.

Limonin mitigates cisplatin-induced acute kidney injury through metabolic reprogramming.

BACKGROUND: Acute kidney injury (AKI) is a known complication of cisplatin administration; currently, there are no effective ways to prevent it. Therefore, it largely limited the use of cisplatin in chemotherapy in the clinic. In this study, we reported that Limonin, a triterpenoid compound extracted from citrus, alleviated cisplatin-induced AKI through metabolic reprogramming in the diseased kidneys. METHODS: Cisplatin was employed to induce AKI in mice. Three groups were set up: Sham, cisplatin + vehicle, and cisplatin + Limonin. Using UHPLC-TOF/MS, we conducted metabolomics to profile the kidneys' endogenous metabolites and metabolic pathways. A network pharmacological method was performed to identify the targets of Limonin on AKI. The human proximal tubular epithelial cell line (HK-2) was applied for in vitro studies. RESULTS: Limonin preserved serum creatinine and blood urea nitrogen levels after cisplatin-induced AKI. Employing metabolomics, we identified 33 endogenous differentially expressed metabolites and 7 significantly disturbed metabolic pathways in the diseased kidneys within three groups. After AKI, Limonin significantly reduced linoleic acid and its downstream product, arachidonic acid, thus exerting a protective effect on the kidney. The network pharmacological method identified CYP3A4 as a key target of Limonin in treating AKI, while CYP3A4 also serve as a mediator of arachidonic acid metabolism. In vitro, Limonin markedly reduced the level of arachidonic acid and HK-2 cell apoptosis triggered by cisplatin, mainly related to the targeted inhibition of CYP3A4-mediated arachidonic acid metabolism. CONCLUSION: Limonin ameliorates cisplatin-induced AKI by inhibiting CYP3A4 activity to regulate arachidonic acid metabolism, ultimately preserving kidney function.

Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis.

Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis.

Mapping global zoonotic niche and interregional transmission risk of monkeypox: a retrospective observational study.

BACKGROUND: Outbreaks of monkeypox have been ongoing in non-endemic countries since May 2022. A thorough assessment of its global zoonotic niche and potential transmission risk is lacking. METHODS: We established an integrated database on global monkeypox virus (MPXV) occurrence during 1958 - 2022. Phylogenetic analysis was performed to examine the evolution of MPXV and effective reproductive number (Rt) was estimated over time to examine the dynamic of MPXV transmissibility. The potential ecological drivers of zoonotic transmission and inter-regional transmission risks of MPXV were examined. RESULTS: As of 24 July 2022, a total of 49 432 human patients with MPXV infections have been reported in 78 countries. Based on 525 whole genome sequences, two main clades of MPXV were formed, of which Congo Basin clade has a higher transmissibility than West African clade before the 2022-monkeypox, estimated by the overall Rt (0.81 vs. 0.56), and the latter significantly increased in the recent decade. Rt of 2022-monkeypox varied from 1.14 to 4.24 among the 15 continuously epidemic countries outside Africa, with the top three as Peru (4.24, 95% CI: 2.89-6.71), Brazil (3.45, 95% CI: 1.62-7.00) and the United States (2.44, 95% CI: 1.62-3.60). The zoonotic niche of MPXV was associated with the distributions of Graphiurus lorraineus and Graphiurus crassicaudatus, the richness of Rodentia, and four ecoclimatic indicators. Besides endemic areas in Africa, more areas of South America, the Caribbean States, and Southeast and South Asia are ecologically suitable for the occurrence of MPXV once the virus has invaded. Most of Western Europe has a high-imported risk of monkeypox from Western Africa, whereas France and the United Kingdom have a potential imported risk of Congo Basin clade MPXV from Central Africa. Eleven of the top 15 countries with a high risk of MPXV importation from the main countries of 2022-monkeypox outbreaks are located at Europe with the highest risk in Italy, Ireland and Poland. CONCLUSIONS: The suitable ecological niche for MPXV is not limited to Africa, and the transmissibility of MPXV was significantly increased during the 2022-monkeypox outbreaks. The imported risk is higher in Europe, both from endemic areas and currently epidemic countries. Future surveillance and targeted intervention programs are needed in its high-risk areas informed by updated prediction.

Microglia are involved in regulating histamine-dependent and non-dependent itch transmissions with distinguished signal pathways.

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

Macrophage promotes fibroblast activation and kidney fibrosis by assembling a vitronectin-enriched microenvironment.

Background: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis. However, how macrophage regulates fibroblast activation in the fibrotic kidney remains elusive. In this study, we show that macrophages promoted fibroblast activation by assembling a vitronectin (Vtn)-enriched, extracellular microenvironment. Methods: We prepared decellularized kidney tissue scaffold (KTS) from normal and fibrotic kidney after unilateral ischemia-reperfusion injury (UIRI) and carried out an unbiased quantitative proteomics analysis. NRK-49F cells were seeded on macrophage-derived extracellular matrix (ECM) scaffold. Genetic Vtn knockout (Vtn-/-) mice and chronic kidney disease (CKD) model with overexpression of Vtn were used to corroborate a role of Vtn/integrin αvß5/Src in kidney fibrosis. Results: Vtn was identified as one of the most upregulated proteins in the decellularized kidney tissue scaffold from fibrotic kidney by mass spectrometry. Furthermore, Vtn was upregulated in the kidney of mouse models of CKD and primarily expressed and secreted by activated macrophages. Urinary Vtn levels were elevated in CKD patients and inversely correlated with kidney function. Genetic ablation or knockdown of Vtn protected mice from developing kidney fibrosis after injury. Conversely, overexpression of Vtn exacerbated renal fibrotic lesions and aggravated renal insufficiency. We found that macrophage-derived, Vtn-enriched extracellular matrix scaffold promoted fibroblast activation and proliferation. In vitro, Vtn triggered fibroblast activation by stimulating integrin αvß5 and Src kinase signaling. Either blockade of αvß5 with neutralizing antibody or pharmacological inhibition of Src by Saracatinib abolished Vtn-induced fibroblast activation. Moreover, Saracatinib dose-dependently ameliorated Vtn-induced kidney fibrosis in vivo. These results demonstrate that macrophage induces fibroblast activation by assembling a Vtn-enriched extracellular microenvironment, which triggers integrin αvß5 and Src kinase signaling. Conclusion: Our findings uncover a novel mechanism by which macrophages contribute to kidney fibrosis via assembling a Vtn-enriched extracellular niche and suggest that disrupting fibrogenic microenvironment could be a therapeutic strategy for fibrotic CKD.

Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury.

Acute kidney injury (AKI) is a refractory clinical syndrome with limited effective treatments. Amid AKI, activation of the extracellular signal-regulated kinase (ERK) cascade plays a critical role in promoting kidney repair and regeneration. However, a mature ERK agonist in treating kidney disease remains lacking. This study identified limonin, a member of the class of compounds known as furanolactones, as a natural ERK2 activator. Employing a multidisciplinary approach, we systemically dissected how limonin mitigates AKI. Compared to vehicles, pretreatment of limonin significantly preserved kidney functions after ischemic AKI. We revealed that ERK2 is a significant protein linked to the limonin's active binding sites through structural analysis. The molecular docking study showed a high binding affinity between limonin and ERK2, which was confirmed by the cellular thermal shift assay and microscale thermophoresis. Mechanistically, we further validated that limonin promoted tubular cell proliferation and reduced cell apoptosis after AKI by activating ERK signaling pathway in vivo. In vitro and ex vivo, blockade of ERK abolished limonin's capacity of preventing tubular cell death under hypoxia stress. Our results indicated that limonin is a novel ERK2 activator with strong translational potential in preventing or mitigating AKI.

Proteomic landscape of the extracellular matrix in the fibrotic kidney.

The extracellular matrix (ECM) is a complex three-dimensional network of proteins surrounding cells, forming a niche that controls cell adhesion, proliferation, migration and differentiation. The ECM network provides an architectural scaffold for surrounding cells and undergoes dynamic changes in composition and contents during the evolution of chronic kidney disease (CKD). Here, we unveiled the proteomic landscape of the ECM by delineating proteome-wide and ECM-specific alterations in normal and fibrotic kidneys. Decellularized kidney tissue scaffolds were made and subjected to proteomic profiling by liquid chromatography with tandem mass spectrometry. A total of 172 differentially expressed proteins were identified in these scaffolds from mice with CKD. Through bioinformatics analysis and experimental validation, we identified a core set of nine signature proteins, which could play a role in establishing an oxidatively stressed, profibrotic, proinflammatory and antiangiogenetic microenvironment. Among these nine proteins, glutathione peroxidase 3 (GPX3) was the only protein with downregulated expression during CKD. Knockdown of GPX3 in vivo augmented ECM expression and aggravated kidney fibrotic lesions after obstructive injury. Transcriptomic profiling revealed that GPX3 depletion resulted in an altered expression of the genes enriched in hypoxia pathway. Knockdown of GPX3 induced NADPH oxidase 2 expression, promoted kidney generation of reactive oxygen species and activated p38 mitogen-activated protein kinase. Conversely, overexpression of exogenous GPX3 alleviated kidney fibrosis, inhibited NADPH oxidase 2 and p38 mitogen-activated protein kinase. These findings suggest that oxidative stress is a pivotal element of the fibrogenic microenvironment. Thus, our studies represent a comprehensive proteomic characterization of the ECM in the fibrotic kidney and provide novel insights into molecular composition of the fibrogenic microenvironment.

Insulin-like growth factor 2 mRNA-binding protein 3 promotes kidney injury by regulating ß-catenin signaling.

Wnt/ß-catenin is a developmental signaling pathway that plays a crucial role in driving kidney fibrosis after injury. Activation of ß-catenin is presumed to be regulated through the posttranslational protein modification. Little is known about whether ß-catenin is also subjected to regulation at the posttranscriptional mRNA level. Here, we report that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays a pivotal role in regulating ß-catenin. IGF2BP3 was upregulated in renal tubular epithelium of various animal models and patients with chronic kidney disease. IGF2BP3 not only was a direct downstream target of Wnt/ß-catenin but also was obligatory for transducing Wnt signal. In vitro, overexpression of IGF2BP3 in kidney tubular cells induced fibrotic responses, whereas knockdown of endogenous IGF2BP3 prevented the expression of injury and fibrosis markers in tubular cells after Wnt3a stimulation. In vivo, exogenous IGF2BP3 promoted ß-catenin activation and aggravated kidney fibrosis, while knockdown of IGF2BP3 ameliorated renal fibrotic lesions after obstructive injury. RNA immunoprecipitation and mRNA stability assays revealed that IGF2BP3 directly bound to ß-catenin mRNA and stabilized it against degradation. Furthermore, knockdown of IGF2BP3 in tubular cells accelerated ß-catenin mRNA degradation in vitro. These studies demonstrate that IGF2BP3 promotes ß-catenin signaling and drives kidney fibrosis, which may be mediated through stabilizing ß-catenin mRNA. Our findings uncover a previously underappreciated dimension of the complex regulation of Wnt/ß-catenin signaling and suggest a potential target for therapeutic intervention of fibrotic kidney diseases.

Ethanol Extract of Glycyrrhiza uralensis Fisch: Antidiarrheal Activity in Mice and Contraction Effect in Isolated Rabbit Jejunum.

OBJECTIVE: To evaluate the antidiarrheal effect of ethanol extract of Glycyrrhiza uralensis Fisch root (GFR) in vivo and jejunal contraction in vitro. METHODS: In vivo, 50 mice were divided into negative control, positive control (verapamil), low-, medium- and high-dose GFR (250, 500, 1,000 mg/kg) groups by a random number table, 10 mice in each group. The antidiarrheal activity was evaluated in castor oil-induced diarrhea mice model by evacuation index (EI). In vitro, the effects of GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) on the spontaneous contraction of isolated smooth muscle of rabbit jejunum and contraction of pretreated by Acetylcholine (ACh, 10 µmol/L) and KCl (60 mmol/L) were observed for 200 s. In addition, CaCl2 was accumulated to further study its mechanism after pretreating jejunal smooth muscle with GFR (1 and 3 g/L) or verapamil (0.03 and 0.1 µmol/L) in a Ca2+-free-high-K+ solution containing ethylene diamine tetraacetic acid (EDTA). RESULTS: GFR (500 and 1,000 mg/kg) significantly reduced EI in castor oil-induced diarrhea model mice (P<0.01). Meanwhile, GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) inhibited the spontaneous contraction of rabbit jejunum (P<0.05 or P<0.01). Contraction of jejunums samples pretreated by ACh and KCl with 50% effective concentration (EC50) values was 1.05 (0.71-1.24), 0.34 (0.29-0.41) and 0.15 (0.11-0.20) g/L, respectively. In addition, GFR moved the concentration-effect curve of CaCl2 down to the right, showing a similar effect to verapamil. CONCLUSIONS: GFR can effectively against diarrhea and inhibit intestinal contraction, and these antidiarrheal effects may be based on blocking L-type Ca2+ channels and muscarinic receptors.

Prognostic value of systemic immune-inflammation index in patients with hepatitis B virus-related acute-on-chronic liver failure / 中华传染病杂志

Objective:To investigate the prognostic value of systemic immune-inflammation index (SII) in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).Methods:The clinical data, including age, gender, complications, laboratory examination results post-admission, SII, model for end-stage liver disease (MELD) score, MELD-Na score, Child-Turcotte Pugh (CTP) score of HBV-ACLF patients treated in Huashan Hospital, Fudan University from January 2016 to August 2021 were retrospectively analyzed. The patients were divided into survival group and death group according to the outcome at 90 days of follow-up.Paired sample t test, Mann-Whitney U test and chi-square test were used for statistical analysis.Pearson correlation was used to analyze the correlation between SII and the prognosis prediction model of HBV-ACLF. The area under the curve (AUC) was used to analyze the clinical efficacies of SII, MELD score, MELD-Na score and CTP score in predicting the prognosis of HBV-ACLF patients, and the optimal cut-off value of SII for predicting the prognosis of HBV-ACLF was calculated. Kaplan-Meier method was used for survival analysis. Results:A total of 140 patients with HBV-ACLF were included. There were 88 patients in the survival group, including 65 males and 23 females, with the age of (47.69±11.96) years. There were 52 cases in the death group, including 40 males and 12 females, with the age of (52.73±12.22) years. The age, aspartate aminotransferase, total bilirubin, serum creatinine, international normalized ratio, neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, SII, MELD score, MELD-Na score, CTP score and the incidence of infection in the death group were all significantly higher than those in the survival group, and albumin, lymphocyte count, platelet count, prognostic nutritional index in the death group were all significantly lower than those in the survival group, and the differences were all statistically significant ( t=-2.39, Z=-2.84, t=-4.81, Z=-2.15, Z=-4.91, Z=-3.47, Z=-3.36, Z=-3.83, Z=-4.69, Z=-4.56, Z=-6.31, χ2=24.96, t=3.06, t=3.03, Z=-7.57 and t=4.12, respectively, all P<0.05). Pearson correlation analysis showed that SII was positively correlated with CTP score ( r=0.272 7, P=0.001), MELD score ( r=0.365 8, P<0.001) and MELD-Na score ( r=0.381 1, P<0.001). The AUC of SII was the largest of 0.80, and 0.76 for MELD score, 0.74 for MELD-Na score and 0.73 for CTP score. The optimal cut-off value of SII was 447.49. Kaplan-Meier analysis showed that the 90 days survival rate of patients with SII≥447.49(38.60%(22/57)) was lower than that of SII<447.49 group (79.52%(66/83)), and the difference between the two groups was significant ( χ2=23.80, P<0.001). Conclusions:SII can be used to assess the severity and prognosis of HBV-ACLF patients. SII ≥447.49 indicates poor prognosis.

Ethanol Extract of Glycyrrhiza uralensis Fisch: Antidiarrheal Activity in Mice and Contraction Effect in Isolated Rabbit Jejunum / 中国结合医学杂志

OBJECTIVE@#To evaluate the antidiarrheal effect of ethanol extract of Glycyrrhiza uralensis Fisch root (GFR) in vivo and jejunal contraction in vitro.@*METHODS@#In vivo, 50 mice were divided into negative control, positive control (verapamil), low-, medium- and high-dose GFR (250, 500, 1,000 mg/kg) groups by a random number table, 10 mice in each group. The antidiarrheal activity was evaluated in castor oil-induced diarrhea mice model by evacuation index (EI). In vitro, the effects of GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) on the spontaneous contraction of isolated smooth muscle of rabbit jejunum and contraction of pretreated by Acetylcholine (ACh, 10 µmol/L) and KCl (60 mmol/L) were observed for 200 s. In addition, CaCl2 was accumulated to further study its mechanism after pretreating jejunal smooth muscle with GFR (1 and 3 g/L) or verapamil (0.03 and 0.1 µmol/L) in a Ca2+-free-high-K+ solution containing ethylene diamine tetraacetic acid (EDTA).@*RESULTS@#GFR (500 and 1,000 mg/kg) significantly reduced EI in castor oil-induced diarrhea model mice (P<0.01). Meanwhile, GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) inhibited the spontaneous contraction of rabbit jejunum (P<0.05 or P<0.01). Contraction of jejunums samples pretreated by ACh and KCl with 50% effective concentration (EC50) values was 1.05 (0.71-1.24), 0.34 (0.29-0.41) and 0.15 (0.11-0.20) g/L, respectively. In addition, GFR moved the concentration-effect curve of CaCl2 down to the right, showing a similar effect to verapamil.@*CONCLUSIONS@#GFR can effectively against diarrhea and inhibit intestinal contraction, and these antidiarrheal effects may be based on blocking L-type Ca2+ channels and muscarinic receptors.

[Impact of land use pattern on water quality under different riparian buffer zone scales in Gaya River Basin, Northeast China]. / 不同河岸缓冲区尺度下土地利用方式对嘎呀河流域水质的影响.

River water quality is influenced by land use and landscape distribution patterns. Quantifying the relationship between land use, landscape pattern and water quality factor at different riparian buffer zone scales is of great significance for rational land use planning and water quality improvement. Based on water quality data from 91 sites in May 2021 in the Gaya River Basin, we analyzed the spatial characteristics of land use types and landscape patterns at the riparian buffer zone scales. With redundancy analysis (RDA) and generalized additive models (GAM), we examined the effects of land use and landscape patterns on river water quality. The results showed that water quality was primarily impacted by total nitrogen (TN). Farmland was the dominant land use type at riparian buffer zone of 50, 100 and 500 m. The sampling sites were classified into farmland dominant group and farmland other group. Forest was dominant at riparian buffer zone of 1000, 1500, 2000 m, and the sampling sites were classified into forest dominant group and forest other group. 100 m riparian buffer zone was the strongest scale in the Gaya River, and 1000 m was the second. Land use types in the forest dominant group were closely related with electrical conductivity, dissolved oxygen, phosphate, permanganate index and ammonium (NH4+-N) of water. NH4+-N was positively correlated with proportion of forest and farmland area. Phosphate was significantly affected by Shannon diversity index (SHDI). SHDI and largest patch index (LPI) was the key landscape indices affecting permanganate index. TN was significantly impacted by area proportion of forest, grassland and LPI in farmland dominant group, showing decreasing trend with the area proportion of forest increasing from 8% to 40%. Total suspended solids in farmland other group were significantly correlated with proportion of farmland area, while negatively correlated with proportion of forest area. Water quality in the Gaya River was mainly affected by proportion of forest area, followed by proportion of farmland area. The combined effects of LPI, SHDI and other land use types played an important role in affecting water quality.

Klotho-derived peptide KP1 ameliorates SARS-CoV-2-associated acute kidney injury.

Introduction: The severe cases of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), often present with acute kidney injury (AKI). Although old age and preexisting medical conditions have been identified as principal risk factors for COVID-19-associated AKI, the molecular basis behind such a connection remains unknown. In this study, we investigated the pathogenic role of Klotho deficiency in COVID-19-associated AKI and explored the therapeutic potential of Klotho-derived peptide 1 (KP1). Methods: We assessed the susceptibility of Klotho deficient Kl/Kl mice to developing AKI after expression of SARS-CoV-2 N protein. The role of KP1 in ameliorating tubular injury was investigated by using cultured proximal tubular cells (HK-2) in vitro and mouse model of ischemia-reperfusion injury (IRI) in vivo. Results: Renal Klotho expression was markedly downregulated in various chronic kidney disease (CKD) models and in aged mice. Compared to wild-type counterparts, mutant KL/KL mice were susceptible to overexpression of SARS-CoV-2 N protein and developed kidney lesions resembling AKI. In vitro, expression of N protein alone induced HK-2 cells to express markers of tubular injury, cellular senescence, apoptosis and epithelial-mesenchymal transition, whereas both KP1 and Klotho abolished these lesions. Furthermore, KP1 mitigated kidney dysfunction, alleviated tubular injury and inhibited apoptosis in AKI model induced by IRI and N protein. Conclusion: These findings suggest that Klotho deficiency is a key determinant of developing COVID-19-associated AKI. As such, KP1, a small peptide recapitulating Klotho function, could be an effective therapeutic for alleviating AKI in COVID-19 patients.

Autophagy Modulates the Migration of Retinal Pericytes Induced by Advanced Glycation End Products.

Retinal pericyte migration occurs in the early stage of diabetic retinopathy (DR), which is one of the important causes of pericyte loss. Autophagy has been found to play essential roles in the regulation of many types of cell migration. In this study, we explored the relationship between autophagy and retinal pericyte migration. In diabetic rats, the retinas became thinner, and the level of autophagy in each cell layer increased. In the primary culture of bovine retinal pericytes, we found that advanced glycation end products (AGEs) increased the migratory cell ability without influencing cell viability, which also increased the phosphorylation of focal adhesion kinase (FAK) and the expression of matrix metalloproteinase (MMP)-2 and decreased the expression of vinculin. AGEs-induced retinal pericyte autophagy and the inhibition of autophagy with chloroquine significantly inhibited cell migration, reversed AGEs-induced FAK phosphorylation, and changed vinculin and MMP-2 protein expression. These results provide a new insight into the migration mechanism of retinal pericytes. The early control of autophagy has a potential effect on regulating pericyte migration, which may contribute to keeping the integrity of retinal vessels in DR.

Incidence rate of schizophrenia after the Tangshan earthquake in China: a 44-year retrospective birth cohort study.

Preliminary evidence indicates that natural disasters are associated with an increased risk for schizophrenia. With few longitudinal studies on earthquakes, this retrospective cohort study examined exposure to the 1976 Tangshan earthquake and the subsequent risk of schizophrenia. Population counts and visits to all nine psychiatric hospitals in Tangshan city were collected. We created three cohort groups by earthquake exposure: infant (August 1972 to July 1976 births), fetal (August 1976 to May 1977 births), and unexposed (June 1977 to May 1981 births). The cumulative incidence of schizophrenia in each cohort was calculated by dividing the number of schizophrenia patients by total births in the corresponding period. Altogether, 6424 schizophrenia patients were identified, with 2786 in the infant group, 663 in the fetal group, and 2975 in the unexposed group. The crude cumulative incidence of schizophrenia in the infant, fetal and unexposed groups were 7.64 (95% confidence interval [CI] = 7.36-7.92), 9.07 (95% CI = 8.38-9.76), and 7.40 (95% CI = 7.13-7.66) per thousand population respectively. Adjusted for mortality, the corresponding figures were 7.73 (95% CI = 7.44-8.01), 9.30 (95% CI = 8.60-10.01) and 7.44 (95% CI = 7.18-7.71) per thousand population respectively. The mortality-adjusted risk ratio (aRR) was 1.25 (95% CI = 1.15-1.36) between fetal and unexposed groups (χ2 = 27.31, P < 0.001). Males exposed as infants did not differ from the unexposed in cumulative schizophrenia incidence. People with fetal exposure to the 1976 earthquake had 25% higher risk of developing schizophrenia compared to unexposed counterparts.

Prevalence, risk factors, and prediction of inappropriate use of non-vitamin K antagonist oral anticoagulants in elderly Chinese patients with atrial fibrillation: A study protocol.

Background: Atrial fibrillation (AF) is an arrhythmia that is prevalent globally, and its incidence grows exponentially with aging. Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed in recent years, and it challenges the supremacy of warfarin for thromboembolism prophylaxis in AF. Nevertheless, there are limited data specifically evaluating the real-life use of NOACs in elderly patients with AF in China. Methods: This is a national, multicenter, non-interventional, cross-sectional study that enrolls patients with AF aged 75 years and above from 31 institutions across China. Data were collected using the Hospital Information System. The primary outcomes include (1) profiles of NOAC use in the elderly; (2) frequency of inappropriate NOAC use based on guidelines and approved labeling recommendations; (3) exploring potential risk factors related to NOACs inappropriate use; and (4) creating a prediction tool for inappropriate NOACs use. Conclusion: The results of this study reveal the prevalence, risk factors, and corresponding prediction tool of inappropriate NOACs use in older patients with AF in China, as well as provide valuable insights into the clinical application of NOACs in high-risk populations in the real-world setting. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05361889.