Tricyclic antidepressants induce liver inflammation by targeting NLRP3 inflammasome activation.

BACKGROUND: Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood. METHODS: We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout (Nlrp3-/-) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3-/- mice. RESULTS: We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events. CONCLUSION: Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. Video Abstract.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Are Effective Predictors of Prognosis in Patients with Acute Mesenteric Arterial Embolism and Thrombosis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be valuable prognostic markers for a variety of pathological conditions including solid tumors, sepsis, and others. However, the prognostic values of the NLR and PLR in patients with acute mesenteric arterial embolism (AMAE) and acute mesenteric arterial thrombosis (AMAT) have not been elucidated. The aim of this study was to determine the predictive value of the NLR and PLR for poor prognosis in patients with AMAE and AMAT. METHODS: A total of 137 patients with AMAE (n = 77) or AMAT (n = 60) were divided into a poor outcome group (cases of intestinal necrosis or death) and a better outcome group (cases without intestinal necrosis who survived successfully), according to prognosis. Neutrophil, platelet, and lymphocyte counts were recorded before pharmacotherapy or surgery. The NLR and PLR were calculated, and logistic regression analysis was performed to test their prognostic values. RESULTS: The cutoff values for NLR and PLR were 11.05 and 156.26, respectively. The PLR was linearly associated with the NLR (R = 0.769, P < 0.001). NLR (odds ratio [OR] = 6.835, 95% confidence interval [CI] = 2.282-20.469, P = 0.001), PLR (OR = 4.871, 95% CI = 1.627-14.587, P = 0.005), and coronary heart disease (OR = 3.388, 95% CI = 1.156-9.929, P = 0.026) were found to be independent prognostic factors for the patients. CONCLUSIONS: NLR ≥ 11.05, PLR ≥ 156.26, and coronary heart disease were shown to be risk factors for poor prognosis in patients with AMAE and AMAT. According to these factors, patients can be divided into 3 prognostic groups: good, NLR < 11.05 with PLR < 156.26; moderate, NLR < 11.05 with PLR ≥ 156.26 or NLR ≥ 11.05 with PLR < 156.26; and poor, NLR ≥ 11.05 with PLR ≥ 156.26.

Endovascular treatment of thoracic aortic pseudoaneurysm due to brucellosis: a rare case report.

BACKGROUND: Arterial damage is a known complication of brucellosis, but the occurrence of a thoracic aortic pseudoaneurysm secondary to brucellosis has not been previously reported. CASE PRESENTATION: A 65-year-old Chinese man presented with a pseudoaneurysm in the descending segment of the thoracic aorta that caused symptoms of chest pain and intermittent fever. He was diagnosed with a thoracic aortic pseudoaneurysm secondary to brucellosis based on a positive brucella serology test (standard-tube agglutination test) and imaging examination (computed tomography angiography). Anti-brucellosis treatment and covered stent graft implantation were attempted to eliminate the brucellosis and pseudoaneurysm, respectively, and were ultimately successful, with no symptoms after 6 months of follow-up. CONCLUSION: Endovascular repair may be effective and safe for treating a thoracic aortic pseudoaneurysm resulting from brucellosis.

Surgical treatment of syphilitic superficial femoral artery aneurysm: a rare case report.

BACKGROUND: Arterial aneurysm is a known complication of syphilis, but the occurrence of femoral artery aneurysm secondary to the syphilitic disease has never been reported. CASE PRESENTATION: The present study described a 60-year-old Chinese male who presented with two aneurysms in the middle and lower segment of the right superficial femoral artery causing the symptoms of pain, coldness and numbness in the right lower limb. This case was diagnosed with syphilitic superficial femoral aneurysm because of positive syphilitic testing and the inflammatory cell infiltration around the adventitial vasa vasorum under the pathological examination. Anti-syphilis treatment, stent graft implantation and open surgery were attempted to eliminate the syphilis and aneurysm, which was ultimately successful, with no symptoms after a follow-up of 3 months. CONCLUSION: Combined open and endovascular repair may be effective and safe for treatment of syphilitic femoral artery aneurysms.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models.

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs' half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. STATEMENT OF SIGNIFICANCE: Treatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Efficacy of Terpenoid in Attenuating Aortic Atherosclerosis in Apolipoprotein-E Deficient Mice: A Meta-Analysis of Animal Studies.

BACKGROUND: The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the clinical benefit of terpenoids in humans are scarce. This systematic review and meta-analysis evaluated the effects of terpenoid administration on atherosclerotic lesion area in ApoE -/- mice. METHODS: A comprehensive literature search using PubMed, Embase, and the Cochrane Library databases was performed to identify studies that assessed the effects of terpenoids on atherosclerosis in ApoE -/- mice. The primary outcome was atherosclerotic lesion area, and study quality was estimated using SYRCLE's risk of bias tool. RESULTS: The meta-analysis included 25 studies. Overall, terpenoids significantly reduced atherosclerotic lesion area when compared to vehicle control (P<0.00001; SMD: -0.55; 95% CI: -0.72, -0.39). In terpenoid type and dose subgroup analyses, sesquiterpenoid (P=0.002; SMD -0.93; 95% CI: -1.52, -0.34), diterpenoid (P=0.01; SMD: -0.30; 95% CI: -0.54, -0.06), triterpenoid (P<0.00001; SMD: -0.66; 95% CI: -0.94, -0.39), tetraterpenoid (P<0.0001; SMD: -1.81; 95% CI: -2.70, -0.91), low dose (P=0.0001; SMD: -0.51; 95% CI: -0.76, -0.25), medium dose (P<0.0001; SMD: -0.48; 95% CI: -0.72, -0.24), and high dose (P=0.002; SMD: -1.07; 95% CI: -1.74, -0.40) significantly decreased atherosclerotic lesion area when compared to vehicle control. PROSPERO register number is CRD42019121176. CONCLUSION: Sesquiterpenoid, diterpenoid, triterpenoid, and tetraterpenoid have potential as antiatherosclerotic agents with a wide range of doses. This systematic review provides a reference for research programs aimed at the development of terpenoid-based clinical drugs.

Multifocal osteonecrosis affecting all four limbs in systemic lupus erythematosus: A case report.

Osteonecrosis is a condition that frequently affects patients with systemic lupus erythematosus (SLE). However, reports on severe multifocal osteonecrosis involving more than three anatomical sites in patients with SLE are scarce. The present study describes a case of SLE with multifocal osteonecrosis involving all four limbs. A 22-year-old woman was diagnosed with SLE in 2010 and the disease was controlled by treatment with methylprednisolone and hydroxychloroquine. Approximately 1 year following the diagnosis of SLE, the patient developed pain in the elbows and hips. Magnetic resonance imaging revealed evidence of multifocal osteonecrosis in the bilateral distal segments of the humerus and femoral head, the distal segment of the right femur and the proximal segment of the right tibia. The patient was treated with right total hip arthroplasty and core decompression of the right femur and tibia, followed by continuation of the earlier medical treatment for SLE. The present case highlights the importance of conducting a careful investigation of patients with SLE who present with multiple joint involvement, and the choice of the appropriate treatment according to the presentation.

Neutrophil-to-lymphocyte ratio is effective prognostic indicator for post-amputation patients with critical limb ischemia.

OBJECTIVES: To confirm whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are indicators for the prognosis of post-amputation patients with critical limb ischemia (CLI). Methods: In this retrospective observational study a total 270 post-amputation patients with CLI were included between January 2010 and December 2014 in the First Hospital of Jilin University, Changchun, China. The neutrophil and lymphocyte counts were recorded before amputations. Neutrophil-to-lymphocyte ratio was calculated and NLR ≥8.08 was defined as elevated. Logistic regression analysis was conducted to test the prognostic value. Results: According to the statistical analysis, it was indicated that NLR ≥8.08 (odds ratio [OR]: 26.228, 95% confidence interval [CI]: 5.801-118.583, p less than 0.001), PLR ≥237.14 (OR: 3.464, 95% CI: 1.289-9.308, p=0.014) and coronary heart disease (OR: 2.739, 95% CI: 1.060-7.082, p=0.038) were the independent prognostic indicators for the patients. Conclusion: Neutrophil-to-lymphocyte ratio, PLR, and coronary heart disease are independent prognostic indicators for post-amputation patients with CLI.

[Relationship of Serum D-dimer, Fibrinogen, C Reactive Protein and Interleukin 6 with Thrombus Dissolution Volume in Acute Iliac Femoral Vein Thrombosis Model Rats].

OBJECTIVE: To explore the relationship among the serum D- two polymer, fibrinogen, C reactive protein and interleukin 6 and thrombus dissolution volume in acute iliac femoral venous thrombosis model rats. METHODS: A total of 60 rats were randomly divided into 3 groups: deep venous thrombosis group (DVT group), sham operation group and normal control group. In DVT group the single side of the iliofemoral vein incomplete with micro vessel was cliped under chloral hydrate anesthesia; in sham operation group the single side of the iliofemoral vein should be explored without using micro vessel clip under chloral hydrate anesthesia; the and normal control group only experienced chloral hydrate anesthesia. A positive correlation was showed between the 2 time points of D-dimer and the corresponding thrombolytic volume, and the Pearson coefficient was 0.307, and R2 was 0.412 (P<0.05). RESULTS: The D-dimer, fibrinogen, C reactive protein and interleukin-6 levels before and after treatment of 60 rats were shown to be significantly different (P<0.05) between DVT group, sham operation group and normal control group. The D-dimer and fibrinogen level was first rised and then decreased in DVT group, sham operation group. There was a positive correlation between C reactive protein/interleukin-6 and the level of D-dimer /fibrinogen from T1 to T3 time point (P<0.05). There was a negative correlation between C reactive protein/interleukin-6 and the level of D-dimer /fibrinogen from T4 to T6 time point (P<0.05). CONCLUSION: The changes of serum D-dimer, fibrinogen, C reactive protein and interleukin 6 in the acute iliac femoral vein thrombosis model firstly increase and then decrease. These changes can reflect the process of blood coagulation and fibrin dissolution in the course of venous thrombosis of iliac vein.

The effects of RNA interference mediated VEGF gene silencing on biological behavior of renal cell carcinoma and transplanted renal tumor in nude mice.

OBJECTIVE: This study was to explore the effects of RNA interference mediated vascular endothelial growth factor (VEGF) gene silencing on biological behavior of renal cell carcinoma (RCC), transplanted renal tumor and angiogenesis in nude mice. METHODS: The specific siRNA sequence targeting VEGF were designed and synthesized to construct hVEGF-siRNA plasmid which was transfected into RCC 786-O cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the detection of VEGF gene expression and western blot was adopted for the examination of VEGF protein expression. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell growth as well as cell migration and invasion. The transplanted renal tumor models in nude mice were established, and the growth condition of nude mice, and VEGF protein expression in transplanted tumor slices and the microvessel density (MVD) were detected. RESULTS: The expression level of VEGF mRNA in VEGF-siRNA group was significant lower than that in the control group and negative group, suggesting that establishment of plasmid specifically inhibited the expression of VEGF gene The expression level of VEGF protein in VEGF-siRNA group was significant lower than that in the control group and negative group. VEGF gene silencing has the significant inhibition effects on proliferation, migration and invasion of RCC 786-O cells. The tumor weight, VEGF protein positive rate and MVD in VEGF-siRNA group were significant lower than those in negative group and blank group. CONCLUSION: The VEGF gene silencing could inhibit the cell proliferation, migration and invasion of RCC 786-O cells; inhibition of VEGF protein expression could prevent transplanted RCC growth and tumor angiogenesis.

Identification of biomarkers for diagnosis of gastric cancer by bioinformatics.

BACKGROUND: We aimed to discover potential gene biomarkers for gastric cancer (GC) diagnosis. MATERIALS AND METHODS: Genechips of 10 GC tissues and 10 gastric mucosa (GM, para-carcinoma tissue, normal control) tissues were generated using an exon array of Affymetrix containing 30,000 genes. The differentially expressed genes (DEGs) between GC tissues and normal control were identified by the Limma package and analyzed by hierarchical clustering analysis. Gene ontology (GO) and pathway enrichment analyses were performed for investigating the functions of DEGs. Receiver operating characteristics (ROC) analysis was performed to measure the effects of biomarker candidates for diagnosis of GC. RESULTS: Totals of 896 up-regulated and 60 down-regulated DEGs were identified to be differentially expressed between GC samples and normal control. Hierarchical clustering analysis showed that DEGs were highly differentially expressed and most DEGs were up-regulated. The most significantly enriched GO-BP term was revealed to be mitotic cell cycle and the most significantly enriched pathway was cell cycle. The intersection analysis showed that most significant DEGs were cyclin B1 (CCNB1) and cyclin B2 (CCNB2). The sensitivities and specificities of CCNB1 and CCNB2 were both high (p<0.0001). Areas under the ROC curve for CCNB1 and CCNB2 were both greater than 0.9 (p<0.0001). CONCLUSIONS: CCNB1 and CCNB2, which were involved in cell cycle, played significant roles in the progression and development of GC and these genes may be potential biomarkers for diagnosis and prognosis of GC.