ObjectiveTo investigate the therapeutic effects and mechanism of Shenqi Dihuang decoction （SQDHD） on diabetic kidney disease （DKD）， with a focus on its impact on arachidonic acid-related ferroptosis. MethodsSixty C57BL/6 mice were allocated into a normal group （n=10） and a modeling group （n=50）， with 43 mice successfully modeled. The successfully modeled mice were further allocated into model， low-， medium-， and high-dose （4.68， 9.36， and 18.72 g·kg^-1， respectively） SQDHD， and dapagliflozin （0.13 mg·kg^-1） groups. The drug treatment groups were administrated with corresponding agents by gavage， and the normal and model groups were administrated with equal volumes of normal saline by gavage. An electronic balance and a glucometer were used to monitor the body weight and fasting blood glucose level from the tail tip， respectively. Serum creatinine （Scr） and blood urea nitrogen （BUN） levels were measured by enzyme-linked immunosorbent assay （ELISA）. Histopathological changes in the renal tissue were assessed by hematoxylin-eosin staining， Masson staining， and periodic acid-Schiff （PAS） staining. The fluorescence intensity of reactive oxygen species （ROS） in frozen sections was observed by an inverted fluorescence microscope to evaluate the levels of ferrous ions （Fe²⁺） and lipid peroxidation in the renal tissue. Immunofluorescence staining of glutathione peroxidase 4 （GPX4） and acyl-CoA synthetase long-chain family member 4 （ACSL4） in the renal tissue was performed to detect their localization and expression. Western blot was employed to assess the expression levels of key ferroptosis proteins such as GPX4 and cystine/glutamate antiporter （xCT）， as well as the arachidonic acid metabolic pathway-related proteins， including ACSL4， lysophosphatidylcholine acyltransferase 3 （LPCAT3）， and arachidonate 15-lipoxygenase （ALOX15）. Real-time PCR was employed to measure the mRNA levels of key ferroptosis proteins， including solute carrier family 7 member 11 （SLC7A11） and GPX4， as well as arachidonic acid metabolism-related factors （ACSL4， LPCAT3， and ALOX15） in the renal tissue. ResultsCompared with the normal group， DKD model mice exhibited a decrease in body weight （P<0.01）， increases in levels of blood glucose （P<0.01）， 24-hour urinary protein， Scr， and BUN （P<0.01）， along with severe pathological changes， such as mesangial cell proliferation， basement membrane thickening， tubular atrophy， and interstitial inflammatory cell infiltration. In addition， the modeling elevated the levels of Fe²⁺， MDA， LPO， and ROS （P<0.01）， lowered the GPX4 and xCT levels （P<0.01）， raised the ACSL4， LPCAT3， and ALOX15 levels （P<0.01）， down-regulated the mRNA levels of GPX4 and SLC7A11 （P<0.01）， and up-regulated the mRNA levels of ACSL4， LPCAT3， and ALOX15 （P<0.01） in the renal tissue. Compared with the model group， low-， medium-， and high-dose SQDHD groups and the dapagliflozin group showed an increase in body weight （P<0.01）， decreases in levels of blood glucose （P<0.01）， 24-hour urinary protein， and Scr （P<0.01）， alleviated pathological changes in glomeruli and tubules， and reduced degree of glomerular and tubular fibrosis. The high-dose SQDHD group and the dapagliflozin group showed reductions in Fe²⁺， MDA， LPO， and ROS levels （P<0.01）. The medium- and high-dose SQDHD groups and the dapagliflozin group exhibited increased levels of GPX4 and xCT （P<0.01）， decreased levels of ACSL4， LPCAT3， and ALOX15 （P<0.05， P<0.01）， and down-regulated mRNA levels of ACSL4， LPCAT3， and ALOX15 （P<0.01）. ConclusionSQDHD ameliorates DKD by inhibiting ferroptosis potentially by reducing iron ion levels， inhibiting lipid peroxidation， up-regulating GPX4 expression， and down-regulating ACSL4 expression. This study provides new insights and a theoretical basis for the treatment of DKD with traditional Chinese medicine and identifies potential targets for developing novel therapeutics for DKD.

ObjectiveTo investigate the therapeutic effects and mechanism of Shenqi Dihuang decoction （SQDHD） on diabetic kidney disease （DKD）， with a focus on its impact on arachidonic acid-related ferroptosis. MethodsSixty C57BL/6 mice were allocated into a normal group （n=10） and a modeling group （n=50）， with 43 mice successfully modeled. The successfully modeled mice were further allocated into model， low-， medium-， and high-dose （4.68， 9.36， and 18.72 g·kg^-1， respectively） SQDHD， and dapagliflozin （0.13 mg·kg^-1） groups. The drug treatment groups were administrated with corresponding agents by gavage， and the normal and model groups were administrated with equal volumes of normal saline by gavage. An electronic balance and a glucometer were used to monitor the body weight and fasting blood glucose level from the tail tip， respectively. Serum creatinine （Scr） and blood urea nitrogen （BUN） levels were measured by enzyme-linked immunosorbent assay （ELISA）. Histopathological changes in the renal tissue were assessed by hematoxylin-eosin staining， Masson staining， and periodic acid-Schiff （PAS） staining. The fluorescence intensity of reactive oxygen species （ROS） in frozen sections was observed by an inverted fluorescence microscope to evaluate the levels of ferrous ions （Fe²⁺） and lipid peroxidation in the renal tissue. Immunofluorescence staining of glutathione peroxidase 4 （GPX4） and acyl-CoA synthetase long-chain family member 4 （ACSL4） in the renal tissue was performed to detect their localization and expression. Western blot was employed to assess the expression levels of key ferroptosis proteins such as GPX4 and cystine/glutamate antiporter （xCT）， as well as the arachidonic acid metabolic pathway-related proteins， including ACSL4， lysophosphatidylcholine acyltransferase 3 （LPCAT3）， and arachidonate 15-lipoxygenase （ALOX15）. Real-time PCR was employed to measure the mRNA levels of key ferroptosis proteins， including solute carrier family 7 member 11 （SLC7A11） and GPX4， as well as arachidonic acid metabolism-related factors （ACSL4， LPCAT3， and ALOX15） in the renal tissue. ResultsCompared with the normal group， DKD model mice exhibited a decrease in body weight （P<0.01）， increases in levels of blood glucose （P<0.01）， 24-hour urinary protein， Scr， and BUN （P<0.01）， along with severe pathological changes， such as mesangial cell proliferation， basement membrane thickening， tubular atrophy， and interstitial inflammatory cell infiltration. In addition， the modeling elevated the levels of Fe²⁺， MDA， LPO， and ROS （P<0.01）， lowered the GPX4 and xCT levels （P<0.01）， raised the ACSL4， LPCAT3， and ALOX15 levels （P<0.01）， down-regulated the mRNA levels of GPX4 and SLC7A11 （P<0.01）， and up-regulated the mRNA levels of ACSL4， LPCAT3， and ALOX15 （P<0.01） in the renal tissue. Compared with the model group， low-， medium-， and high-dose SQDHD groups and the dapagliflozin group showed an increase in body weight （P<0.01）， decreases in levels of blood glucose （P<0.01）， 24-hour urinary protein， and Scr （P<0.01）， alleviated pathological changes in glomeruli and tubules， and reduced degree of glomerular and tubular fibrosis. The high-dose SQDHD group and the dapagliflozin group showed reductions in Fe²⁺， MDA， LPO， and ROS levels （P<0.01）. The medium- and high-dose SQDHD groups and the dapagliflozin group exhibited increased levels of GPX4 and xCT （P<0.01）， decreased levels of ACSL4， LPCAT3， and ALOX15 （P<0.05， P<0.01）， and down-regulated mRNA levels of ACSL4， LPCAT3， and ALOX15 （P<0.01）. ConclusionSQDHD ameliorates DKD by inhibiting ferroptosis potentially by reducing iron ion levels， inhibiting lipid peroxidation， up-regulating GPX4 expression， and down-regulating ACSL4 expression. This study provides new insights and a theoretical basis for the treatment of DKD with traditional Chinese medicine and identifies potential targets for developing novel therapeutics for DKD.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Objective: To explore the clinical efficacy of Xiaoshuan enteric-coated capsule (XSECC) in treating cerebral infarction and its potential mechanism of action. Methods: Patients with acute ischemic stroke (AIS) of the qi deficiency and blood stasis type were randomly assigned to the control and observation groups. They were evaluated using the National Institutes of Health Stroke Scale (NIHSS), Activities of Daily Living (ADL), Hachinskilnchemic Scale (HIS), Barthel Index (BI), clinical efficacy scores, and TCM syndrome scores on days 0, 14, 30, and 90. Furthermore, VEGF and BDNF levels were measured on days 30 and 90. Finally, we analyzed the changes in each scale score and vascular neurological factor in both groups. Results: After 14 days of treatment, the difference values in NIHSS, ADL, and BI were higher, and TCM syndrome and clinical efficacy scores were increased in the observation group compared with those of the control group (all P < .05). After 30 days, the NIHSS, ADL, HIS, and TCM syndrome scores were decreased compared with those of the control group, while BI and clinical efficacy scores were increased (all P < .05). After 90 days, the difference value in ADL was higher, and TCM syndrome score was increased in the observation group compared with that of the control group (P = .047, P = .005, respectively). The levels of VEGF and BDNF were higher in the observation group than in the control group on days 14, 30, and 90 (all P < .05). VEGF and BDNF levels on day 0 were associated with prognosis of patients with AIS; therefore, they have a predictive value for the prognosis of acute cerebral infarction. Conclusions XSECC therapy can improve clinical outcomes in patients with acute and recurrent cerebral infarctions. Its mechanism of action may be associated with the secretion of VEGF and BDNF.

Objective To explore the efficacy of negative pressure ureteral access sheath combined with disposable flexible ureteroscope(UAS+FRUS)in the treatment of renal calculi of 2-3 cm,so as to provide reference for the treatment.Methods A retrospective analysis was conducted on 130 cases of renal calculi of 2-3 cm treated with surgery in Xiamen Third Hospital during Sep.2021 and Sep.2023,including 68 cases with UAS+FRUS and 62 cases with super-mini percutaneous nephrolithotripsy(SMP).The perioperative indexes and stone-clearance rate(SFR)were compared between the two groups.Results All operations were successful.There were no statistically significant differences in the total SFR and incidence of complications(5.88％vs.9.67％)between the two groups 3 days(88.24％vs.90.32％)and 1 month(91.18％vs.93.55％)after surgery(P＞0.05).For patients with lower calyceal calculi with infundibulopelvic angle(IPA)＜45°,the SFR of the UAS+FRUS group was significantly lower than that of the SMP group(57.14％vs.100％,P＜0.05).The UAS+FRUS group had a longer operation time than the SMP group[(104.94±8.79)minutes vs.(77.98±6.60)minutes,P＜0.001],higher hospitalization costs[(23 112.82±1152.34)yuan vs.(21 975.84±1512.24)yuan,P＜0.001],less postoperative decrease in hemoglobin[(6.71±2.07)g/L vs.(9.81±4.80)g/L,P＜0.001],and shorter postoperative hospitalization time[(3.28±0.51)d vs.(5.58±0.71)d,P＜0.001].The UAS+FRUS group had lower postoperative VAS score at 6,24,and 48 hours than the SMP group[(6.38±0.69)vs.(7.87±0.88);(3.62±0.73)vs.(5.81±0.83)and(3.12±0.33)vs.(3.81±0.60)],with statistical significance(P＜0.05).Conclusion Both surgical methods have a high SFR in the treatment of renal calculi of 2-3 cm.SMP has the advantages of short operation time,low hospitalization costs,and high SFR for lower calyx calculi,while UAS+FURS has the advantages of little bleeding,minimal trauma,and short hospital stay.Surgeons can make reasonable choices based on the patients'condition and willingness,combined with their own surgical experience.