Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons.

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.

Ginsenoside Rh2 Ameliorates Neuropathic Pain by inhibition of the miRNA21-TLR8-mitogen-activated protein kinase axis.

Ginsenoside Rh2 is one of the major bioactive ginsenosides in Panax ginseng. Although Rh2 is known to enhance immune cells activity for treatment of cancer, its anti-inflammatory and neuroprotective effects have yet to be determined. In this study, we investigated the effects of Rh2 on spared nerve injury (SNI)-induced neuropathic pain and elucidated the potential mechanisms. We found that various doses of Rh2 intrathecal injection dose-dependently attenuated SNI-induced mechanical allodynia and thermal hyperalgesia. Rh2 also inhibited microglia and astrocyte activation in the spinal cord of a murine SNI model. Rh2 treatment inhibited SNI-induced increase of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. Expression of miRNA-21, an endogenous ligand of Toll like receptor (TLR)8 was also decreased. Rh2 treatment blocked the mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting of phosphorylated extracellular signal-regulated kinase expression. Finally, intrathecal injection of TLR8 agonist VTX-2337 reversed the analgesic effect of Rh2. These results indicated that Rh2 relieved SNI-induced neuropathic pain via inhibiting the miRNA-21-TLR8-MAPK signaling pathway, thus providing a potential application of Rh2 in pain therapy.

Chemerin induces lipolysis through ERK1/2 pathway in intramuscular mature adipocytes of dairy bull calves.

The adipokine Chemerin has been reported to regulate differentiation and metabolism of adipocytes, but the mechanism underlying lipolysis is still largely unknown. The purpose of this study was to explore whether ERK1/2 pathway is involved in regulating Chemerin during bovine intramuscular mature adipocyte lipolysis. Intramuscular mature adipocytes of dairy bull calves were cultured in vitro and were treated with Chemerin or U0126, which is an inhibitor of ERK1/2 pathway. The results showed that TG content in cells was significantly decreased, glycerol and free fatty acid were significantly increased in cell culture media, and the expression of phosphorylated ERK1/2 in cells was increased in Chemerin-treated group, suggested that ERK1/2 pathway was involved in regulation of lipolysis by Chemerin. In addition, the expression of lipolytic-related critical factors ATGL, HSL, LPL, PPARα, UCP3, and CPT1 were upregulated, but the expression of adipogenic key factors, including PPARγ and C/EBPα were downregulated by Chemerin. Interestingly, all the effects of Chemerin on genes expression in intramuscular mature adipocytes or fat tissue were inhibited by U0126, showed that the function of Chemerin to promote adipose decomposition will be significantly weakened if the ERK1/2 pathway is suppressed, and confirmed that ERK1/2 pathway is involved in mediate Chemerin-enhanced lipolysis. In conclusion, the study demonstrated that Chemerin induce intramuscular mature adipocytes lipolysis through activation of the ERK1/2 pathway. Our research at least provide partial mechanisms of Chemerin on lipolysis and deposition of intramuscular fat tissue of dairy bull calves.

An exploration of older Hong Kong residents' willingness to make copayments toward vouchers for community care.

Because of its rapidly aging population, Hong Kong faces great challenges in the provision and financing of long-term care (LTC) and needs to explore sustainable funding mechanisms. However, there is a paucity of research on older people's willingness to pay (WTP) for LTC services in Hong Kong. This study utilizes data collected in Hong Kong in 2011 (N = 536) to investigate older people's receptivity to this financing mode by assessing their co-payments for a community care service voucher scheme and then testing how potential factors affect respondents' amount of co-payment. Results show that respondents' WTP was positively associated with family financial support, financial condition, and positive attitudes toward this novel policy and negatively associated with family caregiving support. Direct and moderating effects of family financial support on WTP were found. The policy-related implications of LTC financing to improve older people's acceptance of co-payment mechanisms, financial condition, and shared responsibility of care are discussed.

Factors associated with older people's long-term care needs: a case study adopting the expanded version of the Anderson Model in China.

BACKGROUND: Alongside changes in society and the economy, the family's function of taking care of older people is weakening and the formal care mode is becoming more accepted. Older Chinese people are facing diverse choices of long-term care (LTC) modes. Acknowledging this situation, to optimize older people's arrangements for LTC services and improve quality of later life, this study sets out to explore and make theoretical sense of older people's LTC needs and to identify the factors influencing their LTC needs. METHODS: Questionnaire data were collected from 1090 participants in four Chinese cities in 2014. A conceptual framework was established based on the Anderson Model (i.e., predisposing factors, enabling factors, and need factors), and further strengthened by adding several psychosocial factors (i.e. intergenerational relationships, unmet care service needs, and self-image). Multinomial logistic regression was adopted to explore the influencing factors of LTC needs. Participants choosing home-and-community-based care were regarded as the reference group. RESULTS: After controlling for predisposing, enabling, and need factors, those with better self-image (OR = 1.027, p = 0.021) and fewer unmet care service needs (OR = 0.936, p = 0.009) were identified as being more likely to choose family care; those with less close intergenerational relationships (OR = 0.676, p = 0.019), fewer unmet care service needs (OR = 0.912, p = 0.027), and better self-image (OR = 1.044, p = 0.026) were more likely to choose institutional care. Gender- and age-related differences in the determinants of LTC needs were observed. CONCLUSIONS: The findings of this study suggest that professionals and service providers should pay more attention to the important role of psychosocial factors in affecting older people's LTC needs and be more sensitive to gender- and age-related differences. Effective efforts to improve intergenerational relationships, to further develop care services for older people, and to foster a more positive image of aging should be emphasized.

Thrombin Stimulated Platelet-Derived Exosomes Inhibit Platelet-Derived Growth Factor Receptor-Beta Expression in Vascular Smooth Muscle Cells.

BACKGROUND/AIMS: It is difficult to predict acute thrombotic cardiovascular events in the clinic. Few studies have reported the presence of plasma exosomes containing microRNAs (miRNAs) in cardiovascular events. Therefore, we aimed to investigate the levels of miR-223, miR-339 and miR-21 in plasma exosomes before thrombosis in mouse models of carotid tandem stenosis, as well as the mechanisms underlying the origin and function of these exosomal miRNAs. METHODS: Plasma samples were collected from the carotid tandem stenosis and sham control groups of our successfully developed atherothrombosis mouse models before thrombosis. Platelets from healthy volunteers and mice were purified to obtain thrombin stimulated platelet-derived exosomes. Exosomes were isolated via differential ultracentrifugation, and western blotting and transmission electron microscopy were used for their identification. The total RNA was extracted, and quantitative real-time PCR was performed to determine the expression levels of miR-223, miR-339 and miR-21. DAVID Tools were used to analyze the pathways that were enriched among the miRNA target genes. Immuno-fluorescence staining was performed to identify the protein expression levels of platelet-derived exosome target genes in vascular smooth muscle cells (SMCs) in vitro and in vivo. RESULTS: The levels of miR-223, miR-339 and miR-21, which are associated with platelet activation, were elevated in pooled mouse plasma exosomes before thrombosis and enriched in thrombin-stimulated platelet-derived exosomes in vitro. Platelet-derived growth factor receptor-beta (PDGFRß) was a target of these miRNAs, and PDGFRß expression in vascular smooth muscle cells (SMCs) was inhibited following incubation with platelet-derived exosomes. Platelet-derived exosomes could also inhibit PDGF-stimulated SMC proliferation. Furthermore, a decrease in PDGFRß expression was observed in vascular SMCs around thrombotic areas in vivo. CONCLUSIONS: Our data indicate that activated platelet-derived exosomes containing miR-223, miR-339 and miR-21 could be transferred into SMCs and inhibit PDGFRß expression; these exosomal miRNAs may be a biomarker for predicting atherothrombosis.

The adipokine Chemerin induces lipolysis and adipogenesis in bovine intramuscular adipocytes.

The adipokine Chemerin is reported to regulate adipogenesis and glucose homeostasis in vivo and in 3T3-L1 cells. Our team is focused on the role of Chemerin in metabolism and intramuscular adipocyte differentiation because intramuscular fat is the basic material for the formation of marbling in livestock and poultry meat. In this study, bovine intramuscular mature adipocytes were cultured in medium with Chemerin, and the process of lipolysis of mature adipocytes and the adipogenesis of de-differentiated preadipocytes were investigated. The results showed that Chemerin induced significant lipolytic metabolism in intramuscular mature adipocytes, indicated by increased levels of glycerol, FFA, and up-regulated expression of the lipolysis critical factors HSL, LPL, and leptin. Meanwhile, the expressions of adipogenic key factors PPARγ, C/EBPα, and A-FABP were decreased by Chemerin during lipolysis or dedifferentiation in mature adipocytes. The de-differentiated preadipocytes could re-differentiate into mature adipocytes. Intriguingly, the formation of cells' lipid droplets was promoted by Chemerin during preadipocyte differentiation. In addition, mRNA and protein expressions of PPARγ, C/EBPα, and A-FABP were up-regulated by Chemerin during preadipocytes differentiation. These results suggest that Chemerin promotes lipolysis in mature adipocytes and induces adipogenesis during preadipocyte re-differentiation, further indicating a dual role for Chemerin in the deposition of intramuscular fat in ruminant animals.

Who benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-dimensional model for candidate selection.

BACKGROUND: Despite promising overall survival of stage I lung adenocarcinoma (LUAD) patients, 10-25 % of them still went through recurrence after surgery. [1] While it is still disputable whether adjuvant chemotherapy is necessary for stage I patients. [2] IASLC grading system for non-mucinous LUAD shows that minor high-grade patterns are significant indicator of poor prognosis. [3] Other risk factors, such as, pleura invasion, lympho-vascular invasion, STAS, etc. are also related to poor prognosis. [4-6] There still lack evidence whether IASLC grade itself or together with other risk factors can guide the use of adjuvant therapy in stage I patients. In this article, we tried to establish a multi-variable recurrence prediction model for stage I LUAD patients that is able to identify candidates of adjuvant chemotherapy. METHODS: We retrospectively collected patients who underwent lung surgery from 2018.8.1 to 2018.12.31 at our institution and diagnosed with lung adenocarcinoma pT1-2aN0M0 (stage I). Clinical data, manifestation on CT scan, pathologic features, driver gene mutations and follow-up information were collected. Cox proportional hazards regression analyses were performed utilizing the non-adjuvant cohort to predict disease free survival (DFS) and a nomogram was constructed and applied to the total cohort. Kaplan-Meier method was used to compare DFS between groups. Statistical analysis was conducted by R version 3.6.3. FINDINGS: A total of 913 stage I LUAD patients were included in this study. Median follow-up time is 48.1 months.4-year and 5-year DFS are 92.9 % and 89.6 % for the total cohort. 65 patient experienced recurrence or death. 4-year DFS are 97.0 %,94.6 % and 76.2 %, and 5-year DFS are 95.5 %, 90.0 % and 74.1 % in IASLC Grade1, 2 and 3, respectively(p < 0.0001). High-risk patients defined by single risk factors, such as, IASLC grade 3, pleura invasion, STAS, less LN resected could not benefit from adjuvant therapy. A LASSO-COX regression model was built and patients are divided into high-risk and low-risk groups. In the high-risk group, patients underwent adjuvant chemotherapy have longer DFS than those who did not (p = 0.024), while in the low-risk group, patients underwent adjuvant chemotherapy have inferior DFS than those who did not (p < 0.001). INTERPRETATION: IASLC grading is a significant indicator of DFS, however it could not guide adjuvant therapy in our stage I LUAD cohort. Growth patterns and T indicators together with other risk factors could identify high-risk patients that are potential candidate of adjuvant therapy, including some stage IA LUAD patients.

[Band depth analysis and partial least square regression based winter wheat biomass estimation using hyperspectral measurements].

The major limitation of using existing vegetation indices for crop biomass estimation is that it approaches a saturation level asymptotically for a certain range of biomass. In order to resolve this problem, band depth analysis and partial least square regression (PLSR) were combined to establish winter wheat biomass estimation model in the present study. The models based on the combination of band depth analysis and PLSR were compared with the models based on common vegetation indexes from the point of view of estimation accuracy, subsequently. Band depth analysis was conducted in the visible spectral domain (550-750 nm). Band depth, band depth ratio (BDR), normalized band depth index, and band depth normalized to area were utilized to represent band depth information. Among the calibrated estimation models, the models based on the combination of band depth analysis and PLSR reached higher accuracy than those based on the vegetation indices. Among them, the combination of BDR and PLSR got the highest accuracy (R2 = 0.792, RMSE = 0.164 kg x m(-2)). The results indicated that the combination of band depth analysis and PLSR could well overcome the saturation problem and improve the biomass estimation accuracy when winter wheat biomass is large.

[Relationship and interactions between elevated fasting glucose and hypertension for cardiocerebral vascular disease].

OBJECTIVE: To explore the relationship and interaction of elevated fasting glucose and hypertension on cardiocerebral vascular disease. METHODS: 10 054 males and females were recruited for our cross-sectional study during May 2007 to August 2007. Unconditional logistic regression was used to analysis the relationship between fasting glucose and hypertension on cardiocerebral vascular disease. A product of fasting glucose and hypertension was added to the logistic regression model to evaluate the multiplicative interaction and relative excess risk of interaction (RERI), attributable proportion (AP) of interaction and synergy index (S) was applied to evaluate the additive interaction of the two factors. Bootstrap was used to calculate 95% confidence intervals (CI) of RERI, AP and S. RESULTS: After adjusting age, gender, smoking, drinking, body mass index (BMI) and region, the product of fasting glucose and hypertension was not statistically significant, which means there was no multiplicative interaction between the two. But the additive indexes RERI, AP and S with 95%CI of diabetes and hypertension were 0.64 (0.03, 1.25), 0.27 (0.01, 0.47) and 1.83 (1.02, 5.13) respectively, which means significant additive interaction was shown between the two on cardiovascular disease but not no stroke. And there were no additive interaction between impaired fasting glucose on cardiovascular disease or stroke. CONCLUSIONS: Hypertension was independently related to cardiovascular disease and stroke in Beijing citizens, and diabetes were independently related to stroke. There was additive interaction between diabetes and hypertension on cardiovascular disease.

Phospholipid peroxidation inhibits autophagy via stimulating the delipidation of oxidized LC3-PE.

Phospholipid peroxidation of polyunsaturated fatty acids at the bis-allylic position drives ferroptosis. Here we identify a novel role for phospholipid peroxidation in the inhibition of autophagy. Using in vitro and in vivo models, we report that phospholipid peroxidation induced by glutathione peroxidase-4 inhibition and arachidonate 15-lipoxygenase overexpression leads to overload of peroxidized phospholipids and culminate in inhibition of autophagy. Functional and lipidomics analysis further demonstrated that inhibition of autophagy was associated with an increase of peroxidized phosphatidylethanolamine (PE) conjugated LC3. We further demonstrate that autophagy inhibition occurred due to preferential cleavage of peroxidized LC3-PE by ATG4B to yield delipidated LC3. Mouse models of phospholipid peroxidation and autophagy additionally supported a role for peroxidized PE in autophagy inhibition. Our results agree with the recognized role of endoplasmic reticulum as the primary source for autophagosomal membranes. In summary, our studies demonstrated that phospholipid peroxidation inhibited autophagy via stimulating the ATG4B-mediated delipidation of peroxidized LC3-PE.

[Impact of acute smoking on artery function in healthy chronic smokers].

OBJECTIVES: To explore the effect of acute smoking on vascular endothelial function, arterial stiffness and the possible underlying mechanisms. METHODS: We measured the endothelial function and arterial stiffness in 50 healthy chronic smokers before and after acute smoking with EndoPAT2000. The test was carried out on two separate finger tips. The endothelial function was evaluated by PAT ratio of the finger tip and systemic arterial stiffness was evaluated by augmentation index (AI). Plasma soluble intercellular adhesion molecule-1 (sICAM-1) and tissue plasminogen activator (tPA) before and 20 min after acute smoking were measured with enzyme linked immuno sorbent assay. RESULTS: The PAT ratio was decreased (1.87 ± 0.40 vs. 1.73 ± 0.28, P = 0.004) while AI was significantly increased after acute smoking (2.94% ± 21.77% vs. 7.11% ± 20.65%, P = 0.01). There was no significant changes in sICAM [(306.5 ± 76.1) µg/L vs. (315.7 ± 90.9) µg/L, P = 0.402], but tPA [7.87 (5.41 - 10.08) µg/L vs. 5.77 (3.77 - 9.68) µg/L, P < 0.01] was significantly decreased after smoking. CONCLUSIONS: Smoking could acutely affect endothelia function, arterial stiffness and deteriorate the activity of fibrinolytic system which could lead to coronary thrombosis in smokers.

[Association between marital status and prevalence of peripheral arterial disease among Beijing residents: a cross-sectional study].

OBJECTIVE: To investigate the relationship between marital status and prevalence of peripheral arterial disease (PAD) among Beijing residents. METHODS: From May to August 2007, 10 054 residents were interviewed to collect demographic and biochemistry information. Generalized linear mixed model was used to determine the relationship between marital status and prevalence of PAD in terms of OR and corresponding 95% confidence intervals. RESULTS: After adjusting the traditional risk factors including age, area, lipid, serum glucose, blood pressure, central obesity, smoking, drinking and physical activities for PAD, relationship between marital status and prevalence of PAD was found both at the female and male groups of those with 45 years or older. Compared with married men, OR and 95% confidence interval of PAD for unmarried men were 1.56 (0.39 - 6.35) and 1.61 (0.77 - 3.35) for those with 45 years younger and older respectively, while compared with married women, OR and 95% confidence interval of PAD for unmarried women were 0.75 (0.22 - 2.57) and 1.78 (1.23 - 2.58) for those with 45 years younger and older respectively. Significant differences (all P < 0.01) were found between married and unmarried women of 45 years or older in terms of age, waist circumstances, systolic blood pressure, fasting glucose, total cholesterol, low-density lipoprotein and smoking. CONCLUSIONS: Peripheral arterial disease was related to marital status for women of 45 years or older among Beijing residents. Estrogen level and the distribution of other PAD risk factors might contribute to the observed finding.

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid.

Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

Neuroinflammation in HIV-Related Neuropathic Pain.

In the management of human immunodeficiency virus (HIV) infection around the world, chronic complications are becoming a new problem along with the prolonged life expectancy. Chronic pain is widespread in HIV infected patients and even affects those with a low viral load undergoing long-term treatment with antiviral drugs, negatively influencing the adherence to disease management and quality of life. A large proportion of chronic pain is neuropathic pain, which defined as chronic pain caused by nervous system lesions or diseases, presenting a series of nervous system symptoms including both positive and negative signs. Injury caused by HIV protein, central and peripheral sensitization, and side effects of antiretroviral therapy lead to neuroinflammation, which is regarded as a maladaptive mechanism originally serving to promote regeneration and healing, constituting the main mechanism of HIV-related neuropathic pain. Gp120, as HIV envelope protein, has been found to be the major toxin that induces neuropathic pain. Particularly, the microglia, releasing numerous pro-inflammatory substances (such as TNFα, IL-1ß, and IL-6), not only sensitize the neurons but also are the center part of the crosstalk bridging the astrocytes and oligodendrocytes together forming the central sensitization during HIV infection, which is not discussed detailly in recent reviews. In the meantime, some NRTIs and PIs exacerbate the neuroinflammation response. In this review, we highlight the importance of clarifying the mechanism of HIV-related neuropathic pain, and discuss about the limitation of the related studies as future research directions.

A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis.

Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1ß, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.

Ibudilast Attenuates Folic Acid-Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways.

Folic acid (FA)-induced renal tubule damage, which is characterized by extensive inflammation, is a common model of acute kidney injury (AKI). Pyroptosis, a pro-inflammatory form of cell death due to the activation of inflammatory caspases, is involved in AKI progression. Ibudilast, a TLR4 antagonist, has been used in the clinic to exert an anti-inflammatory effect on asthma. However, researchers have not explored whether ibudilast exerts a protective effect on AKI by inhibiting inflammation. In the present study, ibudilast reversed FA-induced AKI in mice, as indicated by the reduced serum creatinine and urea nitrogen levels, and improved renal pathology, as well as the downregulation of kidney injury marker-1. In addition, ibudilast significantly increased the production of the anti-inflammatory factor IL-10 while suppressing the secretion of the pro-inflammatory cytokine TNF-α and macrophage infiltration. Moreover, in the injured kidney, ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL1-ß, IL-18, and GSDMD cleavage), and decreased the number of TUNEL-positive cells. Further mechanistic studies showed that ibudilast administration inhibited the FA-induced upregulation of TLR4, blocked NF-κB nuclear translocation, and reduced the phosphorylation of NF-κB and IκBα, p38, ERK, and JNK. Thus, this study substantiates the protective effect of ibudilast on FA-induced AKI in mice and suggests that protection might be achieved by reducing pyroptosis and inflammation, likely through the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways.

Prognostic Value of Inflammatory Biomarkers in Patients With Stage I Lung Adenocarcinoma Treated With Surgical Dissection.

OBJECTIVE: Inflammation plays a crucial role in tumorigenesis and progression. Our purpose was to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII), and develop a nomogram to predict the cancer-specific survival (CSS) and disease-free survival (DFS) of stage I lung adenocarcinoma patients. METHODS: 1431 patients undergoing surgical resection with pathologically confirmed stage I lung adenocarcinoma were reviewed. The optimal cut-off values for NLR, SII, and SIRI were defined by the receiver operating characteristic (ROC) curve. Cox proportional hazards regression analyses were performed to recognize factors significantly correlated with CSS and DFS to construct the nomogram. The value of adjuvant chemotherapy on model-defined high-risk and low-risk patients was further explored. RESULTS: The cohort had a median follow-up time of 63 months. Multivariate analysis revealed that higher NLR (≥2.606), higher SIRI (≥0.705), higher SII (≥580.671), later T stage, histological pattern with solid or micropapillary components and radiologic features with solid nodules were significantly associated with worse CSS and DFS. The concordance index (C-index) of the nomogram established by all these factors was higher than that of the TNM staging system both in CSS (validation set 0.778 vs 0.652) and DFS (validation set 0.758 vs 0.695). Furthermore, the value of the established nomogram on risk stratification in stage I lung adenocarcinoma patients was validated. CONCLUSIONS: Higher NLR, SII and SIRI pretreatment were associated with worse survival outcomes. A practical nomogram based on these three inflammatory biomarkers may help clinicians to precisely stratify stage I lung adenocarcinoma patients into high- and low-risk and implement individualized treatment.

[The smoking status of patients with acute coronary syndrome and effect of simple intervention on smoking cessation.].

OBJECTIVE: To evaluate the abstinence rate and relapse rate of smoker with ACS after discharged from hospital, to evaluate the effect of simple smoking cessation interventions. METHODS: 150 smokers with ACS were collected and was divided into simple intervention group (n = 87) and control group (n = 63), respectively, followed up for 6 months. 2 months, 6 months abstinence rate, relapse rate were compared between two groups, logistic regression model was used to analyzed the relevant factors for relapse. RESULTS: The smoking rate in patients with ACS was 31.14%, 6-month continuous abstinence rate and 6-month relapse rate was 64.6%, 36.4%, respectively. 6-month continuous abstinence rate and relapse rate between simple quit-smoking intervention group and control group showed no difference. Nicotine dependence score more than 4 points can be used as predictor of relapse. CONCLUSIONS: The smoking rate and the abstinence rate of smoker with ACS is higher than the general population, simple quit-smoking intervention do not increase the success rate of quit-smoking, indicated the need to strengthen the intervention in patients with ACS and smoking.