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ETHNOPHARMACOLOGICAL RELEVANCE: The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored. AIM OF THE STUDY: To elucidate the specific mechanism by which AS-IV moderates DKD progression. MATERIALS AND METHODS: A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods. RESULTS: AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells. CONCLUSIONS: AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies.
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Nefropatías Diabéticas , Células Epiteliales , Ferroptosis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Proteómica , Saponinas , Triterpenos , Animales , Humanos , Masculino , Ratones , Línea Celular , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Ferroptosis/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Metabolismo de los Lípidos/efectos de los fármacos , Lipidómica , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacologíaRESUMEN
PURPOSE: Anastomotic leakage is a serious complication of colorectal cancer surgery, prolonging hospital stays and impacting patient prognosis. Preventive colostomy is required in patients at risk of anastomotic fistulas. However, it remains unclear whether the commonly used loop colostomy(LC) or loop ileostomy(LI) can reduce the complications of colorectal surgery. This study aims to compare perioperative morbidities associated with LC and LI following anterior rectal cancer resection, including LC and LI reversal. METHODS: In this meta-analysis, the Embase, Web of Science, Scopus, PubMed, and Cochrane Library databases were searched for prospective cohort studies, retrospective cohort studies, and randomized controlled trials (RCTs) on perioperative morbidity during stoma development and reversal up to July 2023, The meta-analysis included 10 trials with 2036 individuals (2 RCTs and 8 cohorts). RESULTS: No significant differences in morbidity, mortality, or stoma-related issues were found between the LI and LC groups after anterior resection surgery. However, patients in the LC group exhibited higher rates of stoma prolapse (RR: 0.39; 95%CI: 0.19-0.82; P = 0.01), retraction (RR: 0.45; 95%CI: 0.29-0.71; P < 0.01), surgical site infection (RR: 0.52; 95%CI: 0.27-1.00; P = 0.05) and incisional hernias (RR: 0.53; 95%CI: 0.32-0.89; P = 0.02) after stoma closure compared to those in the LI group. Conversely, the LI group showed higher rates of dehydration or electrolyte imbalances(RR: 2.98; 95%CI: 1.51-5.89; P < 0.01), high-output(RR: 6.17; 95%CI: 1.24-30.64; P = 0.03), and renal insufficiency post-surgery(RR: 2.51; 95%CI: 1.01-6.27; P = 0.05). CONCLUSION: Our study strongly recommends a preventive LI for anterior resection due to rectal cancer. However, ileostomy is more likely to result in dehydration, renal insufficiency, and intestinal obstruction. More multicenter RCTs are needed to corroborate this.
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Colostomía , Ileostomía , Complicaciones Posoperatorias , Neoplasias del Recto , Humanos , Neoplasias del Recto/cirugía , Ileostomía/efectos adversos , Colostomía/efectos adversos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Masculino , Fuga Anastomótica/etiología , Fuga Anastomótica/prevención & control , Femenino , Persona de Mediana EdadRESUMEN
Background: Meta-analyses have demonstrated that indocyanine green (ICG) can effectively prevent anastomotic leakage (AL) after colorectal surgery. However, recent evidence from large randomized controlled trial (RCT) has suggested that ICG fluorescence angiography does not reduce the incidence of AL in colorectal surgery. This study was conducted to evaluate the value of ICG for the prevention of AL following colorectal surgery. Methods: Up to September 16, 2021, PubMed, Embase, China National Knowledge Infrastructure, Web of Science, Scopus, Cochrane Library, and VIP databases were searched for RCTs and propensity-score matched (PSM) studies evaluating the use of ICG for prevention of AL after colorectal surgery. Mean differences (MDs) or odds ratios (ORs) and 95% confidence intervals (CI) were calculated. Results: Twenty studies (5 RCTs and 15 PSM studies) with a total of 5,125 patients were included. ICG did not reduce the reoperation rate (OR, 0.71; 95% CI, 0.38, 1.30), conversion rates (OR, 1.34; 95% CI, 0.65, 2.78), or mortality (OR, 0.50; 95% CI, 0.13, 1.85), but ICG did reduce the incidence of AL (OR, 0.46; 95% CI, 0.36, 0.59) and symptomatic AL (OR, 0.48; 95% CI, 0.33, 0.71), and reduced the length of hospital stay (MD,-1.21; 95% CI,-2.06,-0.35) and intraoperative blood loss (MD,-9.13; 95% CI,-17.52,-0.74). In addition, ICG use did not increase the incidence of total postoperative complications (OR, 0.93; 95% CI, 0.64, 1.35), postoperative ileus (OR, 1.26; 95% CI, 0.53, 2.97), wound infection (OR, 0.76; 95% CI, 0.44, 1.32), urinary tract infection (OR, 0.87; 95% CI, 0.30, 2.59), pulmonary infection (OR, 0.23; 95% CI, 0.04, 1.45), urinary retention (OR, 1.08; 95% CI, 0.23, 5.04), anastomotic bleeding (OR, 1.53; 95% CI, 0.27, 8.60), anastomotic stricture (OR, 0.74; 95% CI, 0.24, 2.29), or operative time (MD,-9.64; 95% CI,-20.28, 1.01). Conclusions: ICG can effectively reduce the incidence of AL, without prolonging the operation time or increasing postoperative complications in colorectal surgery. Systematic Review Registration: www.crd.york.ac.uk/prospero/#recordDetails, identifier: CRD42021279064.
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We previously discovered that traumatic brain injury (TBI) induces significant perturbations in long noncoding RNA (lncRNA) levels in the mouse cerebral cortex, and lncRNA-AK046375 is one of the most significantly changed lncRNAs after TBI. lncRNA-AK046375 overexpression and knockdown models were successfully constructed both in vitro and in vivo. In cultured primary cortical neurons and astrocytes, lncRNA-AK046375 sequestered miR-491-5p, thereby enhancing the expression of metallothionein-2 (MT2), which ameliorated oxidative-induced cell injury. In addition, upregulated lncRNA-AK046375 promoted the recovery of motor, learning, and memory functions after TBI in C57BL/6 mice, and the underlying mechanism may be related to ameliorated apoptosis, inhibited oxidative stress, reduced brain edema, and relieved loss of tight junction proteins at the blood-brain barrier in the mouse brain. Therefore, we conclude that lncRNA-AK046375 enhances MT2 expression by sequestering miR-491-5p, ultimately strengthening antioxidant activity, which ameliorates neurological deficits post-TBI.
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Lesiones Traumáticas del Encéfalo/metabolismo , Encéfalo/metabolismo , Metalotioneína/genética , MicroARNs/genética , Estrés Oxidativo/genética , ARN Largo no Codificante/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/patología , Células Cultivadas , Peróxido de Hidrógeno/toxicidad , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores , Estrés Oxidativo/efectos de los fármacos , ARN Largo no Codificante/genética , Activación TranscripcionalRESUMEN
MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.
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BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI. METHODS: The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies. RESULTS: JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133 ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were prevented by SR144528, a selective CB2 antagonist. CONCLUSIONS: This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction.
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Cannabinoides/farmacología , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Transducción de Señal/fisiología , Sustancia Blanca/metabolismo , eIF-2 Quinasa/biosíntesis , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Agonistas de Receptores de Cannabinoides/uso terapéutico , Cannabinoides/uso terapéutico , Células Cultivadas , Modelos Animales de Enfermedad , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Ratas , Ratas Sprague-Dawley , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/lesiones , eIF-2 Quinasa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Traumatic brain injury (TBI) can induce persistent fluctuation in the gut microbiota makeup and abundance. The present study is aimed at determining whether fecal microbiota transplantation (FMT) can rescue microbiota changes and ameliorate neurological deficits after TBI in rats. METHODS: A controlled cortical impact (CCI) model was used to simulate TBI in male Sprague-Dawley rats, and FMT was performed for 7 consecutive days. 16S ribosomal RNA (rRNA) sequencing of fecal samples was performed to analyze the effects of FMT on gut microbiota. Modified neurological severity score and Morris water maze were used to evaluate neurobehavioral functions. Metabolomics was used to screen differential metabolites from the rat serum and ipsilateral brains. The oxidative stress indices were measured in the brain. RESULTS: TBI induced significance changes in the gut microbiome, including the alpha- and beta-bacterial diversity, as well as the microbiome composition at 8 days after TBI. On the other hand, FMT could rescue these changes and relieve neurological deficits after TBI. Metabolomics results showed that the level of trimethylamine (TMA) in feces and the level of trimethylamine N-oxide (TMAO) in the ipsilateral brain and serum was increased after TBI, while FMT decreased TMA levels in the feces, and TMAO levels in the ipsilateral brain and serum. Antioxidant enzyme methionine sulfoxide reductase A (MsrA) in the ipsilateral hippocampus was decreased after TBI but increased after FMT. In addition, FMT elevated SOD and CAT activities and GSH/GSSG ratio and diminished ROS, GSSG, and MDA levels in the ipsilateral hippocampus after TBI. CONCLUSIONS: FMT can restore gut microbiota dysbiosis and relieve neurological deficits possibly through the TMA-TMAO-MsrA signaling pathway after TBI.
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Lesiones Traumáticas del Encéfalo/microbiología , Lesiones Traumáticas del Encéfalo/terapia , Encéfalo/patología , Disbiosis/complicaciones , Disbiosis/microbiología , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Animales , Lesiones Traumáticas del Encéfalo/sangre , Disbiosis/sangre , Hipocampo/patología , Masculino , Metaboloma , Metilaminas/metabolismo , Estrés Oxidativo , Oxidorreductasas/metabolismo , Proteómica , Ratas Sprague-DawleyRESUMEN
This study aimed to evaluate the influence of a waiting interval of ≥ 8 weeks between the end of preoperative neoadjuvant chemoradiotherapy (nCRT) and surgery on the outcomes of patients with locally advanced rectal cancer. We conducted a comprehensive literature review of retrospective and prospective studies from PubMed, Embase, and Cochrane Library databases to investigate the length of the preoperative nCRT-surgery waiting interval and outcomes in patients with locally advanced rectal cancer. The primary outcome measure was pathologic complete response (pCR) rate. Secondary outcome measures included overall survival, disease-free survival, operative time, and the incidence of local recurrence, postoperative complications, anastomotic leakage, and sphincter-preserving surgery. Standardized mean differences and risk ratios were calculated. Thirteen studies involving 19,652 patients were included. The meta-analysis demonstrated that pCR was significantly increased in patients with locally advanced rectal cancer and a waiting interval of ≥ 8 weeks between preoperative nCRT and surgery compared to a waiting interval of < 8 weeks, or a waiting interval of > 8 weeks compared to ≤ 8 weeks (risk ratio = 1.25; 95% confidence interval, 1.16-1.35; P < .0001). There were no significant differences in overall survival, disease-free survival, operative time, or incidence of local recurrence, postoperative complications, or sphincter-preserving surgery. This study revealed that performing surgery after a waiting interval of ≥ 8 weeks after the end of preoperative nCRT is safe and efficacious for patients with locally advanced rectal cancer, significantly improving pCR without increasing operative time or incidence of postoperative complications, compared to a waiting interval of ≤ 8 weeks.