Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

Treatment of malignant airway obstruction with Y-shape sigma stent loaded with I125 seeds installed via rigid bronchoscopy.

PURPOSE: To summarize and analyze the safety and efficacy of a Y-shape Sigma stent loaded with I125 in patients with inoperable malignant main airway obstruction. METHODS: This study was approved by the Institutional Ethics Committee, and a written informed consent was obtained from each participant. A Y-shape Sigma stent loaded with I125 was placed under vision from rigid bronchoscopy. The primary endpoint was alleviation of symptoms and improvement of Karnofsky Performance Status (KPS) score, and the secondary endpoint was complications and technical success. RESULTS: From November 2018 through June 2023, total 33 patients with malignant airway obstruction were palliatively treated by installing Y-shape Sigma stents loaded with I125. The airway lumen was immediately restored and the average airway opening significantly increased to 70 ± 9.4% after the procedure from baseline 30.2 ± 10.5% (p < 0.05). Average KPS score was improved from baseline 30.0 ± 10.0 to 70.0 ± 10.0 (p < 0.05) as well as PaO2 from baseline 50.1 ± 15.4 mmHg to 89.3 ± 8.6 mmHg (p < 0.05). The technical success rate of placing the stent in this study was 73%, and adverse events or complications including bleeding, I125 loss, and airway infection occurred during or after the procedure. CONCLUSION: Placement of Y-shape Sigma stents under vision from rigid bronchoscopy in the patients with malignant airway obstruction is feasible and it immediately alleviates dyspnea and significantly improves quality of life.

Predictors, prevalence and prognostic role of pulmonary hypertension in patients with chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: To estimate the predictors, prevalence and prognostic role of pulmonary hypertension (PH) in patients with chronic kidney disease (CKD) using meta-analysis. METHODS: The PubMed, EmBase, and the Cochrane library were systematically searched for eligible studies from inception till May 2024. All of pooled analyses were performed using the random-effects model. RESULTS: Fifty observational studies involving 17,558 CKD patients were selected. The prevalence of PH in CKD patients was 38% (95% confidence interval [CI]: 33%-43%), and the prevalence according to CKD status were 31% (95% CI: 20%-42%) for CKD (I-V), 39% (95% CI: 25%-54%) for end stage kidney disease (ESKD) (predialysis), 42% (95% CI: 35%-50%) for ESKD (hemodialysis), and 26% (95% CI: 19%-34%) for renal transplant. We noted the risk factors for PH in CKD included Black individuals (relative risk [RR]: 1.39; 95% CI: 1.18-1.63; p < 0.001), chronic obstructive pulmonary disease (RR: 1.48; 95% CI: 1.21-1.82; p < 0.001), cardiovascular disease history (RR: 1.62; 95% CI: 1.05-2.51; p = 0.030), longer dialysis (RR: 1.70; 95% CI: 1.18-2.46; p = 0.005), diastolic dysfunction (RR: 1.88; 95% CI: 1.38-2.55; p < 0.001), systolic dysfunction (RR: 3.75; 95% CI: 2.88-4.87; p < 0.001), and grade 5 CKD (RR: 5.64; 95% CI: 3.18-9.98; p < 0.001). Moreover, PH in CKD patients is also associated with poor prognosis, including all-cause mortality, major cardiovascular events, and cardiac death. CONCLUSION: This study systematically identified risk factors for PH in CKD patients, and PH were associated with poor prognosis. Therefore, patients with high prevalence of PH should be identified for treatment.

3,4-dihydroxyacetophenone inhibits hypoxia-associated human pulmonary artery smooth muscle cell proliferation by reducing Ca2+ influx.

The present study aimed to assess the effects of 3,4-dihydroxyacetophenone (DHAP) on human pulmonary artery smooth muscle cells (HPASMCs). HPASMCs were divided into the normoxia group (NG), hypoxia group (HG), and hypoxia and 0.6×10-4 mol/L (HD1), 1.9×10-4 mol/L (HD2) and 6.0×10-4 mol/L (HD3) DHAP treatment groups. Cell cycle was analyzed by flow-cytometrically. HPASMC growth was examined by the proliferating cell nuclear antigen (PCNA) and MTT assays. Intracellular Ca2+ ([Ca2+]i) was measured by laser scanning confocal microscopy. Compared with the NG, the HG showed significantly increased HPASMC proliferation (P<0.05); meanwhile, cells treated with DHAP showed decreased proliferation compared with the HG (P<0.05). Hypoxia enhanced cell cycle progression and DHAP partly restored cell cycle distribution toward the status of NG cells. Furthermore, CDK2 levels were markedly increased in hypoxic cells (P<0.05), while DHAP treatment starkly decreased CDK2 levels in comparison with the HG (P<0.05). Moreover, hypoxia increased intracellular [Ca2+] levels compared with normoxia (P<0.05); meanwhile, DHAP treatment decreased [Ca2+]i compared with the HG (P<0.05). These findings suggested that DHAP inhibits hypoxia-induced proliferation of HPASMCs involving [Ca2+]i reduction. Therefore, DHAP should be considered an ideal candidate for the prevention and/or treatment of hypoxia-associated pulmonary hypertension and pulmonary vascular remodeling.

3,4-dihydroxyacetophenone inhibits hypoxia-associated human pulmonary artery smooth muscle cell proliferation by reducing Ca2+ influx.

The present study aimed to assess the effects of 3,4-dihydroxyacetophenone (DHAP) on human pulmonary artery smooth muscle cells (HPASMCs). HPASMCs were divided into the normoxia group (NG), hypoxia group (HG), and hypoxia and 0.6×10-4 mol/L (HD1), 1.9×10-4 mol/L (HD2) and 6.0×10--4 mol/L (HD3) DHAP treatment groups. Cell cycle was analyzed by flow-cytometrically. HPASMC growth was examined by the proliferating cell nuclear antigen (PCNA) and MTT assays. Intracellular Ca2+ ([Ca2+]i) was measured by laser scanning confocal microscopy. Compared with the NG, the HG showed significantly increased HPASMC proliferation (P<0.05); meanwhile, cells treated with DHAP showed decreased proliferation compared with the HG (P<0.05). Hypoxia enhanced cell cycle progression and DHAP partly restored cell cycle distribution toward the status of NG cells. Furthermore, CDK2 levels were markedly increased in hypoxic cells (P<0.05), while DHAP treatment starkly decreased CDK2 levels in comparison with the HG (P<0.05). Moreover, hypoxia increased intracellular [Ca2+] levels compared with normoxia (P<0.05); meanwhile, DHAP treatment decreased [Ca2+]i compared with the HG (P<0.05). These findings suggested that DHAP inhibits hypoxia-induced proliferation of HPASMCs involving [Ca2+]i reduction. Therefore, DHAP should be considered an ideal candidate for the prevention and/or treatment of hypoxia-associated pulmonary hypertension and pulmonary vascular remodeling.

RELM-ß promotes human pulmonary artery smooth muscle cell proliferation via FAK-stimulated surviving.

Resistin-like molecule-ß (RELM-ß), focal adhesion kinase (FAK), and survivin may be involved in the proliferation of cultured human pulmonary artery smooth muscle cells (HPAMSCs), which is involved in pulmonary hypertension. HPAMSCs were treated with human recombinant RELM-ß (rhRELM-ß). siRNAs against FAK and survivin were transfected into cultured HPASMCs. Expression of FAK and survivin were examined by RT-PCR and western blot. Immunofluorescence was used to localize FAK. Flow cytometry was used to examine cell cycle distribution and cell death. Compared to the control group, all rhRELM-ß-treated groups demonstrated significant increases in the expression of FAK and survivin (P<0.05). rhRELM-ß significantly increased the proportion of HPASMCs in the S phase and decreased the proportion in G0/G1. FAK siRNA down-regulated survivin expression while survivin siRNA did not affect FAK expression. FAK siRNA effectively inhibited FAK and survivin expression in RELM-ß-treated HPASMCs and partially suppressed cell proliferation. RELM-ß promoted HPASMC proliferation and upregulated FAK and survivin expression. In conclusion, results suggested that FAK is upstream of survivin in the signaling pathway mediating cell proliferation. FAK seems to be important in RELM-ß-induced HPASMC proliferation, partially by upregulating survivin expression.

FAK mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation by modulating mitochondrial transcription termination factor 1/cyclin D1.

This study aimed to investigate the mechanism of FAK-dependent hypoxia-induced proliferation on human pulmonary artery smooth muscle cells (HPASMCs). Primary HPASMCs were isolated and cultured in vitro under normal and hypoxia conditions to assess cell proliferation with cell counting kit-8. FAK and mitochondrial transcription termination factor 1 (mTERF1) were silenced with siRNA, mRNA, and protein levels of FAK, mTERF1, and cyclin D1 were determined. HPASMC proliferation increased under hypoxia compared to normal conditions. Knocking down FAK or mTERF1 with siRNA led to decreased cell proliferation under both normal and hypoxia conditions. FAK knockdown led to the reduction of both mTERF1 and cyclin D1 expressions under the hypoxia conditions, whereas mTERF1 knockdown led to the downregulation of cyclin D1 expression but not FAK expression under the same condition. However, under normal conditions, knocking down either FAK or mTERF1 had no impact on cyclin D1 expression. These results suggested that FAK may regulate the mTERF1/cyclin D1 signaling pathway to modulate cell proliferation in hypoxia.

Estimating the Economic Impact of Levalbuterol's Potential Transition From the National Reimbursement Drug List for the Treatment of Pediatric Asthma in China: A Budget Impact Analysis.

Background Levalbuterol is a short-acting ß2-agonist (SABA) indicated for treating or preventing asthma exacerbation. It was included in the 2020 Chinese National Reimbursement Drug List (NRDL). This study estimates the economic impact of levalbuterol's status change within and withdrawal from the NRDL in treating pediatric asthma from a publicly funded medical insurance perspective. Methodology A prevalence-based budget impact model was developed. The analysis compared a world with a levalbuterol scenario to a world without levalbuterol. Epidemiological data were obtained from the existing literature. Cost data were estimated based on the drug dosage in clinical trials, real-world settings, and expert opinions. Scenario analysis considered the same length of stay (LOS) in the two groups. One-way sensitivity analyses were carried out to show the impact of varying individual parameters. Results In the base-case analysis, compared to the world without scenario, the preservation of levalbuterol resulted in cost savings of ¥82.8 million in China over three years. In the scenario analysis, savings decreased to ¥76.1 million over three years. Sensitivity analysis showed that, for the most part, the results were robust to changes in input parameter values. Conclusions Using levalbuterol may lead to substantial cost savings for Chinese society.

Effect of I-125 Seed Implantation on Lung Cancer and Its Environmental Impact.

ABSTRACT: This paper compares the efficacy and adverse effects of iodine-125 ( 125 I) seed implantation and external beam radiotherapy (EBRT) in the treatment of lung cancer as well as impact of the 125 I radiation on the environment around the patients. A total of 40 patients who were admitted with lung cancer to our hospital from October 2017 to October 2018 were enrolled into this study. The patients were randomly assigned into study groups treated with 125 I seed implantation (20 patients) and a control group treated with EBRT (20 patients). The patients were followed up for 6 mo by CT scanning of the tumor size as well as measuring serum carcinoembryonic antigen (CEA), cytokeratin fragment (CYRA21-1), and neurospecific enolase (NSE) levels. The dose rate of 125 I at various distances and times after implantation was also measured. The local tumor control rate was higher in the study group than in the control group. CEA, NSE and CYFRA21-1 significantly decreased from the pre-treatment baseline in both groups (p < 0.05). Side effects of pneumothorax, hemoptysis, chest pain, and leukopenia occurred in the patients treated with 125 I seed implantation. Radiation of the 125 I isotope, which was correlated with the number of implanted 125 I seeds, decreased rapidly in a time- and distance-dependent manner. A lead apron could significantly block radiation of 125 I. Compared to EBRT, brachytherapy with 125 I seed implantation in the lung cancer had a better therapeutic outcome with fewer complications. A lead apron could protect members of patient's family as well as public from 125 I radiation.

Gestational psittacosis causes severe pneumonia and miscarriage: A case report and literature review.

Psittacosis is an uncommon zoonotic illness, and gestational psittacosis is even rarer. The clinical signs and symptoms of psittacosis are varied, often overlooked, and swiftly identified by metagenomic next-generation sequencing. We recorded the case of a 41-year-old pregnant woman with psittacosis where the disease was not detected early on, resulting in severe pneumonia and fetal miscarriage. The clinical symptoms, diagnosis, and treatment of psittacosis in pregnancy are the subject of this case study.

[Mechanisms of focal adhesion kinase in the proliferation of human pulmonary artery smooth cells under hypoxia].

OBJECTIVE: To explore the mechanisms of focal adhesion kinase (FAK) in the proliferation of human pulmonary artery smooth muscle cells (HPASMCs) under hypoxia. METHODS: Cultured HPASMCs were passively transfected with FAK oligonucleotides (ODNS) and under normoxia or hypoxia condition. They were divided into four groups: normoxia without fibronectin (FN), normoxia with FN, hypoxia without FN, hypoxia with FN in vitro respectively. Cytoplasmic FAK, Grb2 and paxillin were observed simultaneously by immunoprecipitation and Western blot. In addition, the expressions of cytoplasmic FAK, Grb2 and paxillin were detected by immunocytochemical staining. RESULTS: Immunoprecipitation and Western blot demonstrated that cytoplasmic expressions of FAK, Grb2 and paxillin in HPASMCs increased in hypoxia with FN from 43.4 ± 1.4, 69.7 ± 1.9, 59.3 ± 1.6 to 35.7 ± 1.2, 48.7 ± 1.3, 33.2 ± 1.8 at 1.5 h (all P < 0.05), from 41.3 ± 1.3, 71.3 ± 1.5, 59.4 ± 1.8 to 41.3 ± 1.3, 50.2 ± 1.7, 38.9 ± 1.9 at 24 h respectively (P < 0.01, P < 0.05, P < 0.05). Immunocytochemistry staining showed that the cytoplasmic expressions of FAK, Grb2 and paxillin were enhanced in hypoxia with FN versus normoxia with FN. There were significant differences. CONCLUSION: Hypoxia can induce the activation of cytoplasmic FAK, Grb2 and paxillin so as to regulate the migration, survival and proliferation of HPASMCs.

Role and limitations of the geometric mean method regarding head rotation in salivary gland scintigraphy: a phantom study.

To investigate the possible influence of head rotation on the results of salivary gland scintigraphy, a phantom study was designed to simulate clinical salivary gland scintigraphy. The quantitative accuracy of regional activity counts was compared for two data acquisition methods involving head rotation: (i) an anterior planar projection-only (ANT) method and (ii) a geometric mean (GM) method using both the anterior and posterior planar projections. The roles and limitations of the GM and ANT methods when used at different head rotation angles were examined. Parallel planar projections of a head phantom with four salivary gland simulators, containing 3.7 MBq 99mTc-sodium pertechnetate, at various rotational settings were acquired using a dual-head gamma camera. The difference between the standard activity counts (no phantom rotation) and the activity counts affected by the phantom rotation was calculated and defined as the rotational bias that decreased the accuracy of activity quantification. For small-angle rotation (≤10°), use of the GM method decreased the bias for all salivary gland simulators. In contrast, the bias of large-angle rotation (>10°) between four salivary gland simulators became conspicuous and complex in both methods. This bias may reflect different attenuation effects caused by displacement of the structures. Our data suggest that the GM method can be used when the head rotation angle is small (≤10°); however, when the head rotation angle is >10°, the non-negligible influence of head rotation should be considered during image acquisition.

OPRD1 gene affects disease vulnerability and environmental stress in patients with heroin dependence in Han Chinese.

Exposure to stress not only increases the vulnerability to heroin dependence (HD) but also provokes relapse. The etiology of HD and the role of life stress remain unclear, but prior studies suggested that both genetic and environmental factors are important. Opioid related genes, including OPRM1, OPRD1, OPRK1, and POMC, are obvious candidates for HD. Therefore, this study was conducted to explore whether the genetic polymorphisms of the candidates could affect vulnerability to HD and response to life stress in patients with HD. Ten polymorphisms of the opioid related genes were analyzed in 801 patients and 530 controls. The Life Event Questionnaire was used to assess the perspective and response to life stress in the past year. The genotype distribution and allelic frequency analyses showed that the minor C allele of rs2234918 in OPRD1 is over-represented in the HD group (P = .006 and P = .002, respectively). This finding was further confirmed by logistic regression analysis, showing that C allele carriers have a 1.42 times greater risk for HD compared to T/T homozygotes. A subgroup of 421 patients and 135 controls were eligible for life stress assessment. Patients with HD have a higher occurrence of negative events (No), negative events score (Ns), and average negative event score (Na) than those of controls (all P < .001), but there was no difference regarding positive recent events between the two groups. Gene-stress assessment in the HD group showed that T/T homozygotes of OPRD1 rs2236857 have more severe stress than C allele carriers (Ns, P = .004 and Na, P = .047). Our results indicate that the OPRD1 gene may not only play a role in the pathogenesis of HD but also affect the response to life stress among patients with HD in our Han Chinese population. Patients with the risk genotype may need additional psychosocial intervention for relapse prevention.

Differential effect of the DRD3 genotype on inflammatory cytokine responses during abstinence in amphetamine-dependent women.

Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune-cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1ß) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down-regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1ß levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence.

Focal adhesion kinase antisense oligodeoxynucleotides inhibit human pulmonary artery smooth muscle cells proliferation and promote human pulmonary artery smooth muscle cells apoptosis.

BACKGROUND: Pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in pulmonary vessel structural remodelling. At present, the mechanisms related to proliferation of PASMCs are not clear. Focal adhesion kinase (FAK) is a widely expressed nonreceptor protein tyrosine kinase. Recent research indicates that FAK is implicated in signalling pathways which regulate cytoskeletal organization, adhesion, migration, survival and proliferation of cells. Furthermore, there are no reports about the role of FAK in human pulmonary artery smooth muscle cells (HPASMCs). We investigated whether FAK takes part in the intracellular signalling pathway involved in HPASMCs proliferation and apoptosis, by using antisense oligodeoxynucleotides (ODNs) to selectively suppress the expression of FAK protein. METHODS: Cultured HPASMCs stimulated by fibronectin (40 microg/ml) were passively transfected with ODNs, sense FAK, mismatch sense and antisense-FAK respectively. Expression of FAK, Jun NH2-terminal kinase (JNK), cyclin-dependent kinase 2 (CDK 2) and caspase-3 proteins were detected by immunoprecipitation and Western blots. Cell cycle and cell apoptosis were analysed by flow cytometry. In addition, cytoplasmic FAK expression was detected by immunocytochemical staining. RESULTS: When compared with mismatch sense group, the protein expressions of FAK, JNK and CDK 2 in HPASMCs decreased in antisense-FAK ODNs group and increased in sense-FAK ODNs group significantly. Caspase-3 expression upregulated in HPASMCs when treated with antisense ODNs and downregulated when treated with sense ODNs. When compared with mismatch sense ODNs group, the proportion of cells at G1 phase decreased significantly in sense ODNs group, while the proportion of cells at S phase increased significantly. In contrast, compared with mismatch sense ODNs group, the proportion of cells at G1 phase was increased significantly in antisense-FAK ODNs group. The level of cell apoptosis in antisense-FAK group was higher than in the mismatch sense group and the latter was higher than sense-FAK group. In addition, the sense-FAK ODNs group was strongly stained by immunocytochemistry, whereas the antisense-FAK ODNs group was weakly stained. CONCLUSIONS: The results suggest that FAK relates to the proliferation of HPASMCs. Antisense-FAK ODNs inhibit HPASMCs proliferation and facilitate their apoptosis. It is possible that FAK via JNK, CDK 2 signalling pathways enhances HPASMCs proliferation and via caspase-3 inhibits HPASMCs apoptosis.