Peroxisome proliferator activated receptor-α (PPAR-α) is significantly expressed in various tissues such as the liver, kidney, myocardium, and skeletal muscle, which plays a central role in the development of various diseases by regulating key physiological processes such as energy homeostasis, redox balance, inflammatory response, and ferroptosis. As an important metabolic and excretory organ of the body, renal dysfunction can lead to water and electrolyte imbalance, toxin accumulation, and multiple system complications. The causes of kidney injury are complex and diverse, including acute injury factors (such as ischemia/reperfusion, nephrotoxic drugs, septic shock, and immune glomerulopathy), as well as chronic progressive causes [such as metabolic disease-related nephropathy, hypertensive nephropathy (HN)], and risk factors such as alcohol abuse, obesity, and aging. This review briefly describes the structure, function, and activity regulation mechanism of PPAR-α, systematically elucidates the molecular regulatory network of PPAR-α in the pathological process of kidney injury including acute kidney injury (AKI) such as renal ischemia/reperfusion injury (IRI), drug-induced AKI, sepsis-associated acute kidney injury (SA-AKI), glomerulonephritis, chronic kidney disease (CKD) such as diabetic nephropathy (DN), HN, and other kidney injury, and summarizes the mechanisms related to PPAR-α regulation of kidney injury, including regulation of metabolism, antioxidation, anti-inflammation, anti-fibrosis, and anti-ferroptosis. This review also evaluates PPAR-α's medical value as a novel therapeutic target, and aims to provide theoretical basis for the development of kidney protection strategies based on PPAR-α targeted intervention.
Humans ; PPAR alpha/metabolism* ; Acute Kidney Injury/therapy* ; Animals ; Kidney/metabolism*

Objective:To investigate the differences in acute intestinal injury and regulatory mechanisms in mice following carbon ion FLASH radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).Methods:Healthy C57BL/6J mice were randomly divided into three groups: control group, FLASH-RT group (100 Gy/s), and CONV-RT group (0.1 Gy/s), with 9 mice in each group. All mice received carbon ion whole abdominal radiotherapy. DNA double-strand breaks (DSB) and cell proliferation were evaluated by measuring the expression of phosphorylated histone H2AX (γ-H2AX) and nuclear-associated antigen 67 (Ki67) using immunohistochemistry; apoptosis was analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL); transcriptome sequencing was used to analyze the differences in molecular pathways between FLASH-RT and CONV-RT.Results:Compared with the CONV-RT group, the FLASH-RT group showed significantly reduced intestinal γ-H2AX signal at 3 h after radiotherapy ( t=3.80, P<0.01), significantly increased expression of Ki67 at the base of intestinal crypts at 6 h after radiotherapy ( t=4.30, P<0.001), and a significantly decreased number of TUNEL-positive cells at 12 h after radiotherapy ( t=3.08, P<0.01). Transcriptome sequencing analysis showed that FLASH-RT specifically activated the insulin-like growth factor (IGF) pathway, avoiding the excessive activation of CONV-RT-induced nuclear factor-κB and B cell receptor inflammatory pathways as well as the inhibition of energy metabolism. Conclusions:Compared with CONV-RT, carbon ion FLASH-RT can reduce DSB damage, preserve the proliferative activity of intestinal stem cells, activate the IGF pathway, and regulate inflammatory, immune, and metabolic pathways, thereby significantly alleviating acute intestinal epithelial injury. Specifically, the regulation of repair pathways mediated by reduced DSB and the inhibition of inflammatory pathways are potential protective mechanisms for normal tissues.

Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

BACKGROUND:Synovitis is involved in all stages of osteoarthritis and is a key factor contributing to the development of osteoarthritis.Studies have shown that circular RNA(circRNA)plays an important role in the proliferation,apoptosis and extracellular matrix degradation of synovial cells and chondrocytes.OBJECTIVE:To observe the effects of circRNA SEC24A on the interleukin-1β-induced proliferation,apoptosis,and expression of inflammatory factors in human synovial fibroblasts.METHODS:Human synovial fibroblasts were divided into four groups,including control group,interleukin-1β group,empty vector group,and sh-circSEC24A group.Except for the control group,the other three groups were induced with 10 ng/mL interleukin-1β for 24 hours to establish inflammatory cell models;the empty vector group and sh-circSEC24A group were infected with empty vector virus and lentiviral vector knocking down circSEC24A.CCK-8 assay was used to detect cell proliferation.Flow cytometry was used to detect cell apoptosis.ELISA was used to detect the levels of matrix metalloproteinase-9,matrix metalloproteinase-13,interleukin-6,and tumor necrosis factor-α in cell supernatant.Western blot assay was used to detect the relative expression levels of Bax,Bcl-2,matrix metalloproteinase-9,matrix metalloproteinase-13,casepase3,cleaved-casepase3,casepase8,and cleaved-casepase8 proteins in cells.RESULTS AND CONCLUSION:(1)qRT-PCR results showed that compared with the normal group,the expression of circSEC24A in human synovial fibroblasts induced by interleukin 1β was significantly up-regulated.(2)The absorbance value of cells in the sh-circSEC24A group detected by CCK-8 assay was significantly higher than that of interleukin 1β group and empty vector group(P＜0.05).The apoptosis rate of sh-circSEC24A group detected by flow cytometry was significantly lower than that of interleukin 1β group and empty vector group(P＜0.05).(3)The levels of tumor necrosis factor α and interleukin 6 in the supernatant of human synovial fibroblasts in the sh-circSEC24A group detected by ELISA were significantly lower than those in the interleukin 1β group and the empty vector group(P＜0.01,P＜0.001).(4)Western blot assay results showed that compared with the interleukin 1β group and the empty vector group,the expression of the pro-apoptotic factor Bax protein in the sh-circSEC24A group significantly decreased,and the expression of the anti-apoptotic factor Bcl-2 protein increased significantly(P＜0.05);apoptosis and related activating factors cleaved-casepase3 and cleaved-casepase8 protein expressions were both reduced(P＜0.05).(5)ELISA and western blot assay results showed that compared with the interleukin 1β group and the empty vector group,the sh-circSEC24A group had lower levels of matrix metalloproteinase 9 and matrix metalloproteinase 13 protein(P＜0.05).These findings indicated that the expression of circSEC24A was abnormally increased in human synovial fibroblasts induced by interleukin 1β.Knocking down circSEC24A expression could promote the proliferation of human synovial fibroblasts and inhibit apoptosis,inflammatory factor release,and extracellular matrix degradation,suggesting that circSEC24A may be an important intervention target for early osteoarthritis.

This study was aimed atanalyzing the epidemic characteristics of dengue fever in Ruili City atthe China-Myanmar bor-der in late 2023,to provide evidence for local dengue fever prevention and control measures.Adult Aedes mosquitoes were collected from Ruili City with a backpack type mosquito sucking machine in October of 2023.Serum samples frompatients with suspected den-gue were collected in acutephase,in November of 2023.Detection ofdengue virus(DENV)nucleic acids in Aedesmosquitoes and acute phase serum samples from suspected dengue fever patients using reverse transcription-polymerase chain reaction,and nucleic acid positive samples were inoculated into Vero cells for viral culture.After three consecutive blind passage,samples with cytopathic effect(CPE)were collected for be sequencingand analysisof genetic and evolutionary information.Dengue case characteristics were analyzed through descriptive epidemiological methods.Among the 109 cases of dengue fever,the ratio of males to females was 1.27∶1.The youngest patient was 1 year old,the oldest patient was 84 years old,the age group of 20～59 years accounted for 73.39%,and the major-ity of occupations were freelancer(40.37%).A total of 827 female Aedes albopictus and 312 Aedes aegypti were collected,all of which tested negative for DENV nucleic acid.109 serum samples tested positive for DENV nucleic acid,including 49 DENV-1 and 60 DENV-2.Moreover,five DENV-1 and nine DENV-2 samples were obtainedthrough third-generation blind passaging with CPE.The E gene sequences of these five DENV-1 strains were detected,all were found to belong to DENV-1 genotype I,and had same evolu-tionary branch as the 2023 Guangzhou,China(PP563911),the 2019 Myanmar(MW793710),and 2019 Attapeu,Laos(MW559046).The nucleotide and amino acid sequence similarityamong the five DENV-1 genotype was 99.4%-99.9%and 99.8%-100.0%.Compared with the aforementioned epidemic strains,their nucleotide similarities were 99.5%-100.0%,99.4%-99.6%and 99.3%-99.5%,respec-tively,and amino acid similarity was 99.8%-100.0%.Nine DENV-2 E gene sequences were of Asian genotype I and belonged to the same evolutionary branch as the 2018 Myanmar(MW788982),2019 Hangzhou(OP684212)and 2019 Ruili(OQ928150).The nucleotide and amino acid similarities of the nine samples were 99.5%-100.0%and 99.8%-100.0%,respectively.Compared with the aforementioned epidemic strains,their nucleotide similarities were 99.7%-100.0%,99.3%-99.7%and 99.3%-99.7%,respectively,and the amino acid similarity was 99.8%-100%,99.8%-100.0%and 99.4%-99.6%,respectively.Two dengue vectors,Aedes albopictus and Aedes aegypti,were present in Ruili city,and the dengue outbreak was caused primarily by DENV-1 genotype I and DENV-2 Asian genotype I in later 2023.The sources of DENV-1 were probably the same as those of DENV-1 with Guangzhou(2023),and the sources of DENV-2 were probably from Myanmar.Dengue cases were found primarilyin the 20-59 year age group and freelancers,thus suggesting that relevant local departments should strengthen surveillance of dengue imported case and vector.

Objective To explore the impact of antimicrobial volume-based procurement(VBP)and classification management policy on the clinical use of carbapenem antibiotics.Methods Changing trend in defined daily doses(DDDs),procurement cost(Cost),defined daily dose cost(DDDc),and DDDs per 1 000 inhabitants daily(DID)of carbapenem antibiotics in all levels of medical institutions were analyzed by Mann-Kendall trend test.May 1,2020 was taken as the intervention cut-off point of VBP policy,September 2021 was as intervention cut-off point of cla-ssification management list.The impact of VBP and classification management policy on the clinical use of carbape-nem antibiotics were studied by interrupted time series analysis.Results After implementing VBP policy,the DDDs and DID of carbapenem antibiotics increased obviously,but the long-term trend didn't change significantly.Compared with before the implementation of the policy,the cost and DDDc of carbapenem antibiotics decreased im-mediately,the long-term trend of DDDc changed significantly,but the long-term trend of cost didn't change signifi-cantly.The DDDs and Cost of carbapenem antibiotics decreased immediately after the update of classification ma-nagement list,but the long-term downward trend was not significant,and DDDc presented a long-term upward trend.Conclusion VBP policy reduces the DDDc and short-term cost of carbapenem antibiotics,but its long-term impact on DDDs,cost and DID is limited.Classification management has limited impact on the use of carbapenem antibiotics in medical institutions.

BACKGROUND:Synovitis is involved in all stages of osteoarthritis and is a key factor contributing to the development of osteoarthritis.Studies have shown that circular RNA(circRNA)plays an important role in the proliferation,apoptosis and extracellular matrix degradation of synovial cells and chondrocytes.OBJECTIVE:To observe the effects of circRNA SEC24A on the interleukin-1β-induced proliferation,apoptosis,and expression of inflammatory factors in human synovial fibroblasts.METHODS:Human synovial fibroblasts were divided into four groups,including control group,interleukin-1β group,empty vector group,and sh-circSEC24A group.Except for the control group,the other three groups were induced with 10 ng/mL interleukin-1β for 24 hours to establish inflammatory cell models;the empty vector group and sh-circSEC24A group were infected with empty vector virus and lentiviral vector knocking down circSEC24A.CCK-8 assay was used to detect cell proliferation.Flow cytometry was used to detect cell apoptosis.ELISA was used to detect the levels of matrix metalloproteinase-9,matrix metalloproteinase-13,interleukin-6,and tumor necrosis factor-α in cell supernatant.Western blot assay was used to detect the relative expression levels of Bax,Bcl-2,matrix metalloproteinase-9,matrix metalloproteinase-13,casepase3,cleaved-casepase3,casepase8,and cleaved-casepase8 proteins in cells.RESULTS AND CONCLUSION:(1)qRT-PCR results showed that compared with the normal group,the expression of circSEC24A in human synovial fibroblasts induced by interleukin 1β was significantly up-regulated.(2)The absorbance value of cells in the sh-circSEC24A group detected by CCK-8 assay was significantly higher than that of interleukin 1β group and empty vector group(P＜0.05).The apoptosis rate of sh-circSEC24A group detected by flow cytometry was significantly lower than that of interleukin 1β group and empty vector group(P＜0.05).(3)The levels of tumor necrosis factor α and interleukin 6 in the supernatant of human synovial fibroblasts in the sh-circSEC24A group detected by ELISA were significantly lower than those in the interleukin 1β group and the empty vector group(P＜0.01,P＜0.001).(4)Western blot assay results showed that compared with the interleukin 1β group and the empty vector group,the expression of the pro-apoptotic factor Bax protein in the sh-circSEC24A group significantly decreased,and the expression of the anti-apoptotic factor Bcl-2 protein increased significantly(P＜0.05);apoptosis and related activating factors cleaved-casepase3 and cleaved-casepase8 protein expressions were both reduced(P＜0.05).(5)ELISA and western blot assay results showed that compared with the interleukin 1β group and the empty vector group,the sh-circSEC24A group had lower levels of matrix metalloproteinase 9 and matrix metalloproteinase 13 protein(P＜0.05).These findings indicated that the expression of circSEC24A was abnormally increased in human synovial fibroblasts induced by interleukin 1β.Knocking down circSEC24A expression could promote the proliferation of human synovial fibroblasts and inhibit apoptosis,inflammatory factor release,and extracellular matrix degradation,suggesting that circSEC24A may be an important intervention target for early osteoarthritis.

Objective To explore the impact of antimicrobial volume-based procurement(VBP)and classification management policy on the clinical use of carbapenem antibiotics.Methods Changing trend in defined daily doses(DDDs),procurement cost(Cost),defined daily dose cost(DDDc),and DDDs per 1 000 inhabitants daily(DID)of carbapenem antibiotics in all levels of medical institutions were analyzed by Mann-Kendall trend test.May 1,2020 was taken as the intervention cut-off point of VBP policy,September 2021 was as intervention cut-off point of cla-ssification management list.The impact of VBP and classification management policy on the clinical use of carbape-nem antibiotics were studied by interrupted time series analysis.Results After implementing VBP policy,the DDDs and DID of carbapenem antibiotics increased obviously,but the long-term trend didn't change significantly.Compared with before the implementation of the policy,the cost and DDDc of carbapenem antibiotics decreased im-mediately,the long-term trend of DDDc changed significantly,but the long-term trend of cost didn't change signifi-cantly.The DDDs and Cost of carbapenem antibiotics decreased immediately after the update of classification ma-nagement list,but the long-term downward trend was not significant,and DDDc presented a long-term upward trend.Conclusion VBP policy reduces the DDDc and short-term cost of carbapenem antibiotics,but its long-term impact on DDDs,cost and DID is limited.Classification management has limited impact on the use of carbapenem antibiotics in medical institutions.

Objective To investigate the effects of inclined axial compressive force and flexion moment on the anterior and posterior shear stiffness of the lumbosacral segment.Methods Six fresh-frozen human cadaveric L5-S1 segments were tested under intact and two progressively impaired structural conditions:intact,a 4-mm bilateral facet joint gap,and anterior discectomy with nucleus pulposus removal plus circumferential release of the inner annular fibers(disc injury).A 300 N axial compressive force was applied either vertically downward or with a 10° or 20° anterior inclination through the disc's shear center.Anterior(0 N to 250 N)and posterior(-50 N to 0 N)shear tests were conducted using a material testing machine.These tests were repeated under a 5 N-m flexion moment.The relative motion between L5 and Si was measured using a three-dimensional motion capture system.Results In the intact state,the inclination of the axial compressive force did not significantly alter anterior or posterior shear stiffness.However,the application of a flexion moment increased anterior shear stiffness by 49.3％.Progressive structural damage resulted in incremental increases in anteroposterior shear translation and corresponding reductions in stiffness.Notably,under combined loading with axial compression and flexion moment,anterior stiffness decreased from 939 N/mm(intact)to 224 N/mm(disc injury),while posterior stiffness decreased from 572 N/mm to 217 N/mm.Within the low-load range,no significant differences in shear stiffness were observed across any structural conditions,regardless of axial force inclination or combined with a flexion moment.Conclusions This study supports the clinical view that retro-inclination of the pelvis serves as a compensatory mechanism to enhance segmental shear stability.However,this compensatory capacity gradually diminishes and ultimately fails as spinal degeneration progresses.

Objective To investigate the effects of inclined axial compressive force and flexion moment on the anterior and posterior shear stiffness of the lumbosacral segment.Methods Six fresh-frozen human cadaveric L5-S1 segments were tested under intact and two progressively impaired structural conditions:intact,a 4-mm bilateral facet joint gap,and anterior discectomy with nucleus pulposus removal plus circumferential release of the inner annular fibers(disc injury).A 300 N axial compressive force was applied either vertically downward or with a 10° or 20° anterior inclination through the disc's shear center.Anterior(0 N to 250 N)and posterior(-50 N to 0 N)shear tests were conducted using a material testing machine.These tests were repeated under a 5 N-m flexion moment.The relative motion between L5 and Si was measured using a three-dimensional motion capture system.Results In the intact state,the inclination of the axial compressive force did not significantly alter anterior or posterior shear stiffness.However,the application of a flexion moment increased anterior shear stiffness by 49.3％.Progressive structural damage resulted in incremental increases in anteroposterior shear translation and corresponding reductions in stiffness.Notably,under combined loading with axial compression and flexion moment,anterior stiffness decreased from 939 N/mm(intact)to 224 N/mm(disc injury),while posterior stiffness decreased from 572 N/mm to 217 N/mm.Within the low-load range,no significant differences in shear stiffness were observed across any structural conditions,regardless of axial force inclination or combined with a flexion moment.Conclusions This study supports the clinical view that retro-inclination of the pelvis serves as a compensatory mechanism to enhance segmental shear stability.However,this compensatory capacity gradually diminishes and ultimately fails as spinal degeneration progresses.