Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX’s protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.

The pathogenesis of pulmonary arterial hypertension (PAH) is closely linked to the abnormal proliferation of pulmonary artery smooth muscle cells. Studies have demonstrated that microRNAs play pivotal roles in the progression of pulmonary hypertension. We found that microRNA-637 (miR-637) and microRNA-661 (miR-661) are expressed at low levels in the serum of PAH patients. Moreover, the overexpression of miR-637 or miR-661 inhibited human pulmonary artery smooth muscle cell (HPASMC) proliferation and migration in hypoxic culture. Mechanistically, we overexpressed these two microRNAs in HPASMCs, and the RNA-sequencing (RNA-seq) results demonstrated that TRIM29 mRNA was suppressed, indicating that TRIM29 is a substrate. TRIM29 accumulates in the serum of patients with PAH and promotes cell proliferation and migration by activating AKT/mTOR signalling. In addition, overexpression of miR-637 or miR-661 reversed TRIM29-mediated HPASMC proliferation and migration. This study revealed that miR-637 and miR-661 are able to inhibit the proliferation ability of HPASMCs under hypoxic conditions through targeting TRIM29, suggesting that the microRNA-637/661/TRIM29 axis may act as a target for PAH treatment.

Background: Dexmedetomidine (DEX) reportedly protects against ischemia-reperfusion (I/R) injury and associated damage to the kidneys, but the underlying mechanisms have yet to be established. Methods: Unilateral nephrectomy was performed in Wistar rats, and the remaining kidney was clamped for 1 h prior to reperfusion to establish an experimental model system. These animals were then randomized into Sham, DEX + Sham, DEX + I/R, ATI (Altepamizole, α2-adrenergic receptor inhibitor) + DEX + I/R, and 3-MA (3-methyladenine, autophagy inhibitor) + DEX + I/R groups. Serum renal function biomarkers, acute kidney injury (AKI) histopathological scores, serum inflammatory factors, redox biomarkers, markers of autophagic flux, and autophagosome numbers were assessed. Levels of proteins related to the autophagic pathway, including mTOR and AMPK, were also analyzed. Results: Serum creatinine and urea nitrogen levels in the I/R group were significantly elevated over those in sham control rats, as were AKI scores, serum inflammatory cytokine concentrations (IL-6, IL-1β, and TNF-α), and serum levels of the oxidative stress biomarker malondialdehyde (MDA). All of these parameters were significantly reduced in the DEX + I/R group relative to I/R model rats. I/R group rats also exhibited significant decreases in renal levels of autophagic flux-related biomarkers and autophagosome numbers relative to sham controls, while DEX administration partially restored normal autophagic flux in these rats. Acute I/R also suppress the expression of AMPK in the kidney while increasing mTOR expression, and DEX reversed these effects. The beneficial impact of DEX on I/R-associated AKI was ablated by ATI or 3-MA administration. Conclusions: These analyses provide strong evidence for the ability of DEX to protect against I/R-associated AKI via the α2-AR/AMPK/mTOR pathway-mediated enhancement of autophagic activity.

ABSTRACT Objective: The aims of this study were to investigate and compare the clinical features and prognosis of chronic critical illness (CCI)/persistent inflammation immunosuppression and catabolism (PICS). Methods: This is a prospective observational clinical study. During this study period, we collect intensive care unit patients' data from Suzhou Municipal Hospital and Suzhou Ninth People's Hospital. All patients older than 18 years were included, and according to the corresponding exclusion and diagnostic criteria, they were divided into four groups: PICS group, CCI group, CCI and PICS group (CCI + PICS), and neither CCI nor PICS group (NCCI + NPICS) and collected and recorded age, sex, hospital time, hospital diagnosis, Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, C-reactive protein, absolute value lymphocyte count, serum albumin, white blood cell count, absolute value neutrophil count, secondary infection, and 28-day case fatality rate separately. Results: A total of 687 patients were admitted to the intensive care unit during the study period. The hospitalization time less than 14 days were excluded, and 168 patients were eventually included. There are 17 in the PICS group, 71 in the CCI group, 50 in the CCI + PICS group, and 30 in the NCCI + NPICS group. Baseline characteristics showed statistically significant differences in Sequential Organ Failure Assessment, length of hospital stay, and 28-day mortality among four groups. Baseline main indicator and multiple comparisons showed that the CCI + PICS group had longer hospital stay, worse prognosis, and more adverse outcomes. Multivariate analysis showed that final age, C-reactive protein on days 14 and 21, and serum albumin on days 1 and 21 had an impact on the prognosis (P < 0.05). Conclusion: The clinical prognosis of the four groups decreased in order of NCCI + NPICS, CCI, PICS, and CCI + PICS. Our finding of clinically isolated PICS may indicate that PICS acts as an inducement or independent factor to worsen the prognosis of CCI.

Background: Hepatocellular carcinoma is one kind of clinical common malignant tumor with a poor prognosis, and its pathogenesis remains to be clarified urgently. This study was performed to elucidate key genes involving HCC by bioinformatics analysis and experimental evaluation. Methods: We identified common differentially expressed genes (DEGs) based on gene expression profile data of GSE60502 and GSE84402 from the Gene Expression Omnibus (GEO) database. Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, REACTOME pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were used to analyze functions of these genes. The protein-protein interaction (PPI) network was constructed using Cytoscape software based on the STRING database, and Molecular Complex Detection (MCODE) was used to pick out two significant modules. Hub genes, screened by the CytoHubba plug-in, were validated by Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) database. Then, the correlation between hub genes expression and immune cell infiltration was evaluated by Tumor IMmune Estimation Resource (TIMER) database, and the prognostic values were analyzed by Kaplan-Meier plotter. Finally, biological experiments were performed to illustrate the functions of RRM2. Results: Through integrated bioinformatics analysis, we found that the upregulated DEGs were related to cell cycle and cell division, while the downregulated DEGs were associated with various metabolic processes and complement cascade. RRM2, MAD2L1, MELK, NCAPG, and ASPM, selected as hub genes, were all correlated with poor overall prognosis in HCC. The novel RRM2 inhibitor osalmid had anti-tumor activity, including inhibiting proliferation and migration, promoting cell apoptosis, blocking cell cycle, and inducing DNA damage of HCC cells. Conclusion: The critical pathways and hub genes in HCC progression were screened out, and targeting RRM2 contributed to developing new therapeutic strategies for HCC.

Objective: We investigated the roles and mechanisms of IRF2 in sepsis-related acute kidney injury (S-AKI) in a lipopolysaccharide (LPS)-induced HK-2 cell line and caecal ligation and Methods: Quantitative real-time polymerase chain reaction assay was used to detect IRF2 in the serum of S-AKI patients and LPS-induced HK-2 cells. Cell proliferation, death, and apoptosis were analysed by CCK-8, lactate dehydrogenase release, and flow cytometry assays, respectively. The levels of interleukin (IL)-113, IL-18, IL-6, tumour necrosis factor (TNF)-alpha, non-canonical inflammasomes, including caspase-4 and gasdermin-D (GSDMD), and canonical inflammasomes, such as caspase-1, NLR family pyrin domain containing 3 (NLRP3), and apoptosis-associated speck-like protein (ASC) in S-AKI cells or animal models were analysed by enzyme-linked immunosorbent assay or Western blotting. Results: IRF2 was upregulated in the serum of S-AKI patients and LPS-induced HK-2 cells. IRF2 downregulation promoted cell proliferation and inhibited cell death and apoptosis, respectively. IRF2 inhibition reduced the levels of IL-113, IL-18, IL-6, and TNF-alpha in S-AKI cells and animal models. IRF2 knockdown inhibited LPS-treated HK-2 cell pyroptosis by decreasing the expression of caspase-4 and GSDMD, instead of affecting caspase-1, NLRP3, and ASC. An elevated survival rate and alleviated pathological features and scores were observed in the CLP-induced IRF2-/- animal models. IRF2 deficiency also suppressed inflammation and pyroptosis by inhibiting non-canonical inflammasomes as indicated by the decreased expression of caspase-11 and GSDMD. Conclusion: Our findings suggest that IRF2 downregulation protects against S-AKI in vitro and in vivo.

Objective: The study investigated the protective effect of Tanshinone IIA sodium sulfonate (TSS) on lipopolysaccharide (LPS)-induced acute lung injury (ALI), and the underlying mechanisms. Methods: Male C57/black mice were subjected to LPS (10 mg/kg, i.p.) administration to induce acute lung injury. Half an hour before LPS injection, mice were pretreated with TSS (30 mg/kg, i.p.). One hour, six and twelve hours later, mice were sacrificed. Lung edema and inflammatory cell infiltration were observed. Expression of pro-inflammatory factors (TNF alpha, IL-1 beta, IL-6) were measured by RT-PCR and ELISA in lung tissues. Markers of autophagy including LC3 and Beclin-1 expression were determined by RT-PCR and Western blot. Number of autophagosomes was observed by electron microscope. Results: Our results showed that TSS did not ameliorate the LPS-induced lung edema, but significantly reduced pro-inflammatory cell infiltration. LPS increased mRNA and protein expression of inflammatory factors (TNF alpha, IL-1 beta, IL-6) at all observed time. TSS markedly reduced the protein expression of IL-6 but not TNF alpha and IL-1 beta. In addition, LPS increased tissue autophagic levels (expression of Beclin-1, LC3 and number of autophagosomes) and TSS treatment further increased the autophagic levels. Conclusion: TSS exerts certain anti-inflammation and enhancing autophagy effects in LPS-induced ALI.

RATIONALE:Hydrofluoric acid (HF) is a highly corrosive agent and can cause corrosive burns. HF can penetrate deeply into tissues through intact skin and the lipid barrier, leading to painful liquefactive necrosis, and inducing hypocalcemia and hypomagnesemia. In this study, we hypothesize that continuous renal replacement therapy (CRRT) may be beneficial in addressing hemodynamic instability in cases of HF poisoning.PATIENT CONCERNS:A 25-year-old man fell into an electroplating pool containing 10% HF and 50% nitric acid.DIAGNOSES:He had severe cutaneous injuries involving approximately 60% of his total body surface area including the head, face, neck, right upper arm, right hand, trunk, perineum, and both lower limbs and feet. Examination at admission showed the following electrolyte concentrations: ionic calcium 0.192 mmol/L, total calcium 0.72 mmol/L, magnesium 0.4 mmol/L, potassium 5.49 mmol/L, and sodium 136.8 mmol/L.INTERVENTIONS:An initial 20 mL intravenous bolus of 10% calcium gluconate was followed by a continuous infusion at 6 g/h plus continuous intravenous drip 25% magnesium sulfate at 1.5 g/h. Continuous cardiac monitoring was performed in the intensive care unit. Extracorporeal membrane oxygenation (ECMO) was used to improve oxygenation function at 38 hours post exposure. Antibiotic therapy using imipenem/cilastin plus vancomycin was required.OUTCOMES:After treatment for 12 hours, electrolyte concentrations returned to normal. On day 11, the hemodynamic parameters were stable and oxygenation function had improved. On day 26, the patient was weaned off CRRT. One month later, the patient twice received skin grafting, then was discharged from the hospital without pulmonary, cardiac, or neurological complications 3 months later.LESSONS:The present case study demonstrates that CRRT may be an effective and potentially lifesaving therapy after severe exposure to HF. Prolonged hemodialysis is recommended to remove delayed release fluoride ions to avoid delayed systemic injury. When conventional therapy can not improve oxygenation and/or carbon dioxide retention, ECMO should be performed as soon as possible.