Increasing evidence has demonstrated that the secretion of cytokines may be associated with cigarette smoke-induced immunomodulatory effects, but a comprehensive analysis of the cytokine profile for cigarette smoke condensate (CSC) exposure is lacking. The aims of this study were to (1) examine the release of 20 cytokines induced by CSC from 12 brands of cigarettes in macrophages cells (Ana-1) and (2) to investigate the general characteristics of the immunomodulatory effects of CSC. Luminex technology was used to simultaneously determine the levels of 20 cytokines (interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), keratinocyte-derived Chemokine (KC), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), induced protein 10 (IP-10), tumor necrosis factor α (TNF-α), vascular endothelial growth factor (VEGF), monkine inducible by γ interferon (MIG), and fibroblast growth factor (FGF)-basic) in the supernatants from Ana-1 cells treated with the CSC. The results showed that the release of eight cytokines was altered (IL-5, IL-6, IL-12, TNF-α, VEGF, IP-10, MCP-1, and MIP-1α) compared with the control. These cytokines fall into two major subtypes: proinflammatory cytokines, including IL-5, IL-6, IL-12, TNF-α, and VEGF, and chemokines, including IP-10, MCP-1, and MIP-1α. Compared with control, the remaining 12 cytokines were not significantly affected by CSC from the 12 brands of cigarettes. As a general characteristic, CSC exerts potently suppressive immunomodulatory effects on cytokine production of Ana-1 cells. Proinflammatory cytokines and chemokines may account for or contribute to the immunosuppressive properties of CSC.

The present study developed an oral hepatocyte growth factor (HGF) gene therapy strategy for gastric ulcers treatment. An attenuated Salmonella typhimurium that stably expressed high HGF (named as TPH) was constructed, and the antiulcerogenic effect of TPH was evaluated in a rat model of gastric ulcers that created by acetic acid subserosal injection. From day 5 after injection, TPH (1 × 10⁹ cfu), vehicle (TP, 1 × 10⁹ cfu), or sodium bicarbonate (model control) was administered orally every alternate day for three times. Then ulcer size was measured at day 21 after ulcer induction. The ulcer area in TPH-treated group was 10.56 ± 3.30 mm², which was smaller when compared with those in the TP-treated and model control groups (43.47 ± 4.18 and 56.25 ± 6.38 mm², respectively). A higher level of reepithelialization was found in TPH-treated group and the crawling length of gastric epithelial cells was significantly longer than in the other two groups (P < 0.05). The microvessel density in the ulcer granulation tissues of the TPH-treated rats was 39.9 vessels/mm², which was greater than in the TP-treated and model control rats, with a significant statistical difference. These results suggest that TPH treatment significantly accelerates the healing of gastric ulcers via stimulating proliferation of gastric epithelial cells and enhancing angiogenesis on gastric ulcer site.

This study examined the significance of macrophage autophagy in extracellular matrix metalloproteinase inducer (EMMPRIN)-mediated atherosclerosis (AS). Apolipoprotein E-deficient (ApoE-/-) mice were fed a western diet to establish an AS model. EMMPRIN and p62/Sequestosome-1(SQSTM1) expression were evaluated in plaque macrophages from the AS mice using immunofluorescence. The EMMPRIN and p62/SQSTM1 protein expression levels in macrophages increased with the increasing vulnerability of the atherosclerotic plaques. RAW264.7 cells and ApoE-/- mice Bone Marrow-derived macrophages were transfected with different small interfering RNAs (siRNAs) or plasmids, or treated with different drugs in the presence or absence of oxidized low-density lipoprotein (oxLDL). The protein levels of the targets were evaluated using western blotting (WB), and the autophagosomes were observed under a transmission electron microscope (TEM). Over-expressed EMMPRIN dramatically inhibited oxLDL-mediated autophagy. EMMPRIN also negatively regulated autophagy primarily through the nuclear factor-kappa B (NF-κB) signalling pathway. In turn, activated NF-κB up-regulated EMMPRIN expression. Inhibition of EMMPRIN decreased cell apoptosis and the release of inflammatory cytokines via the promotion of macrophage autophagy. Infection with an adenovirus delivering the EMMPRIN-siRNA ameliorated AS, promoted macrophage autophagy in plaques and reduced the serum TNF-α, IL-6, MCP-1 and NF-κB expression levels in the AS mice. Chloroquine (CQ) reversed these effects. This study revealed for the first time that the feedback loop of the "EMMPRIN/NF-κB" pathway plays an important role in atherosclerotic plaques via modulation of autophagy in macrophages, which might provide a potential strategy for the clinical treatment of AS.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a CAG repeat expansion in the region of the ATXN3 gene. The main feature of SCA3 is progressive ataxia, which affects balance, gait, and speech. Urine cells (UCs) of a SCA3 patient were successfully translated to induced pluripotent stem cells (iPSCs) by using the Sendai virus delivery system. ZZUi004-A cell line may provide a robust platform for further study of SCA3 pathogenesis as well as drug testing and gene therapy research.

Background. Carboxypeptidase A4 (CPA4) belongs to a member of the metallocarboxypeptidase family, and its expression in lung cancer samples and clinical significance are still not investigated until now. In this study, we aimed to evaluate the level of CPA4 in non-small-cell lung cancer (NSCLC) samples and correlate its level with clinical outcome. Methods. CPA4 gene expression in lung cancer tissues were analyzed by using the Oncomine database (www.oncomine.org). The expression of CPA4, Survivin and VEGF in lung cancer and adjacent normal tissues were evaluated by IHC using the corresponding primary antibodies on two different commercial tissue arrays (Shanghai Biochip Co., Ltd., Shanghai, China). Their levels in serum were determined by using commercial human enzyme-linked immunosorbent assay kits. We also examined their relations to clinicopathologic parameters, and explored the diagnostic and prognostic value in NSCLC. Results. We identified an elevation of CPA4 in mRNA level and gene amplification in lung cancer tissues in comparison to normal lung tissues. High CPA4 expression was observed in 120/165 (72.7%) NSCLC samples, and significantly correlated with Tumor size, Depth of invasion, Lymph Node Metastasis, Stage, VEGF level and Survivin level. High CPA4 expression is associated with poor prognosis of NSCLC patients. Multivariable Cox regression analysis demonstrated that CPA4 expression was an independent prognostic factor. Furthermore, serum CPA4 level was also significantly higher in NSCLC patients than in healthy controls. Logistic regression analysis revealed that serum CPA4 and CYFRA21-1 level were the significant parameters for detecting NSCLC. Receiver operating characteristic curves (ROC) in NSCLC patients versus normal people yielded the optimal cut-off value was 2.70 ng/ml for CPA4 and 19 ng/ml for CYFRA21-1, respectively. The area under ROC curve (AUC) was 0.830 for the combination of the two tumor markers. Conclusion. Our results demonstrated that overexpression of CPA4 in NSCLC is associated with an unfavorable prognosis, and serum CPA4 level combining with serum CYFRA21-1 level could be used to aid early detection of NSCLC.

Aberrant microenvironment and endoplasmic reticulum (ER) stress are associated with solid-tumor progression. Stress proteins, like heat shock proteins and glucose-regulated proteins, are frequently overexpressed in human tumors. It has been reported that derlin-1 is involved in ER stress response. In vitro studies have demonstrated that derlin-1 participates in the retrotranslocation of misfolded proteins from ER into the cytosol. Because the roles of derlin-1 in human cancer have not yet been characterized, we investigated the expression of derlin-1 in human breast carcinoma and whether it protected cancer cells against ER stress-induced apoptosis.

Fire needle therapy is an ancient external treatment method of traditional Chinese medicine. This therapy is simple to operate and has fewer side effects. Gouty arthritis (GA) is common disease that is often characterized by high excruciating pain on joint. Evidence from clinical studies show that fire needle exerts therapeutic effects on gout arthritis, but no evidence-based medicine is available. This study aimed to evaluate the efficacy and safety of fire acupuncture in the treatment of gout arthritis.

We aimed to explore the active ingredients and molecular mechanism of Tripterygium wilfordii (TW) in the treatment of diabetic nephropathy (DN) through network pharmacology and molecular biology. First, the active ingredients and potential targets of TW were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and related literature materials, and Cytoscape 3.7.2 software was used to construct the active ingredient-target network diagram of TW. Second, the target set of DN was obtained through the disease database, and the potential targets of TW in the treatment of DN were screened through a Venn diagram. A protein interaction network diagram (PPI) was constructed with the help of the String platform and Cytoscape 3.7.2. Third, the ClueGO plug-in tool was used to enrich the GO biological process and the KEGG metabolic pathway. Finally, molecular docking experiments and cell pathway analyses were performed. As a result, a total of 52 active ingredients of TW were screened, and 141 predicted targets and 49 target genes related to DN were identified. The biological process of GO is mediated mainly through the regulation of oxygen metabolism, endothelial cell proliferation, acute inflammation, apoptotic signal transduction pathway, fibroblast proliferation, positive regulation of cyclase activity, adipocyte differentiation and other biological processes. KEGG enrichment analysis showed that the main pathways involved were AGE-RAGE, vascular endothelial growth factor, HIF-1, IL-17, relaxin signalling pathway, TNF, Fc epsilon RI, insulin resistance and other signaling pathways. It can be concluded that TW may treat DN by reducing inflammation, reducing antioxidative stress, regulating immunity, improving vascular disease, reducing insulin resistance, delaying renal fibrosis, repairing podocytes, and reducing cell apoptosis, among others, with multicomponent, multitarget and multisystem characteristics.

Design and fabrication of new infrared (IR) nonlinear optical (NLO) materials with balanced properties are urgently needed since commercial chalcopyrite-like (CL) NLO crystals are suffering from their intrinsic drawbacks. Herein, the first defect-CL (DCL) alkali-earth metal (AEM) selenide IR NLO material, DCL-MgGa2 Se4 , has been rationally designed and fabricated by a structure prediction and experiment combined strategy. The introduction of AEM tetrahedral unit MgSe4 effectively widens the band gap of DCL compounds. The title compound exhibits a wide band gap of 2.96 eV, resulting in a high laser induced damage threshold (LIDT) of ≈3.0 × AgGaS2 (AGS). Furthermore, the compound shows a suitable second harmonic generation (SHG) response (≈0.9 × AGS) with a type-I phase-matching (PM) behavior and a wide IR transparent range. The results indicate that DCL-MgGa2 Se4 is a promising mid-to-far IR NLO material and give some insights into the design of new CL compound with outstanding IR NLO properties based on the AEM tetrahedra and the structure predication and experiment combined strategy.

Patients with heart failure with preserved ejection fraction (HFpEF) have large individual differences, unclear risk stratification, and imperfect treatment plans. Risk prediction models are helpful for the dynamic assessment of patients' prognostic risk and early intensive therapy of high-risk patients. The purpose of this study is to systematically summarize the existing risk prediction models and novel prognostic factors for HFpEF, to provide a reference for the construction of convenient and efficient HFpEF risk prediction models.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease that causes multi-organ complications, seriously affecting patients' quality of life and survival. Understanding its pathogenesis remains challenging, with current clinical treatment regimens often proving ineffective.

Objectives: To evaluate the current evidence whether Chinese medicine compound (CMC) can reduce the serum levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP). Methods: We comprehensively searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), the Database for Chinese Technical Periodicals (VIP), and Wanfang data. We then performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) assessing the CMC therapy methods. This study is registered with PROSPERO, number CRD42020216284. Results: In total, 65 studies were eligible for inclusion, including 6099 patients. The result of the meta-analysis showed that compared with common Western medicine therapy, CMC monotherapy or combined with Western medicine was able to reduce serum RF (SMD= -0.85, 95%CI -1.04 to -0.67) and anti-CCP (SMD= -0.56, 95%CI -0.79 to -0.32) levels to some extent. In the efficacy meta-analysis, a greater number of CMC-treated patients achieved the efficacy criteria after a period of treatment, where the relative risk (RR) was 1.20 [1.08, 1.33] for achieving ACR20, 1.57 [1.38, 1.78] for ACR50, and 2.21 [1.72, 2.84] for ACR70. At the same time, there was a statistically significant difference in the effective rate of the patient's TCM symptoms (RR = 1.22, 95%CI 1.19-1.26). Conclusions: Through this meta-analysis and systematic review, we found that CMC for the treatment of RA is effective in reducing RF and anti-CCP levels and might have better clinical efficacy than Western medicine monotherapy. Some active components are responsible for this efficacy and worth further exploring.

To explore the relationship between serum levels of inflammatory markers and symptomatic severity of bipolar disorder (BD).

CRISPR/Cas9-mediated genome editing provides potential for therapeutic development. Efficacy and long-term safety represent major concerns that remain to be adequately addressed in preclinical studies. Here we show that CRISPR/Cas9-mediated genome editing in two distinct SOD1-amyotrophic lateral sclerosis (ALS) transgenic mouse models prevented the development of ALS-like disease and pathology. The disease-linked transgene was effectively edited, with rare off-target editing events. We observed frequent large DNA deletions, ranging from a few hundred to several thousand base pairs. We determined that these large deletions were mediated by proximate identical sequences in Alu elements. No evidence of other diseases was observed beyond 2 years of age in these genome edited mice. Our data provide preclinical evidence of the efficacy and long-term safety of the CRISPR/Cas9 therapeutic approach. Moreover, the molecular mechanism of proximate identical sequences-mediated recombination provides mechanistic information to optimize therapeutic targeting design, and to avoid or minimize unintended and potentially deleterious recombination events.

Gastric cancer stem cells (GCSCs) have been used as a therapeutic target. This study aims to estimate the role of miR-98-5p (termed miR-98) in the development of GCSCs.

Ras-related protein 39B (RAB39B) mutation has been reported as a potential cause of X-linked Parkinson's disease (PD), a rare form of familial PD. Recently, a novel RAB39B mutation was identified in an X-linked juvenile parkinsonism family and the dermal fibroblasts of the patient were obtained and successfully induced to induced pluripotent stem cells (iPSCs) by the human OSKM transcription factors using the Sendai-virus delivery system. Our model may offer a good platform for further research of the pathomechanism, drug testing, and gene therapy of this disease.

Diabetic encephalopathy may lead to cognitive deficits in diabetic patients and diminish quality of life. It has been shown that protracted hyperglycaemia is directly associated with neuronal apoptosis, which is involved in diabetic encephalopathy. The anaphase-promoting complex (APC) is essential for the survival of post-mitotic neurons. In our previous study, we found that the mitotic arrest deficient protein MAD2B, one of APC inhibitors, was expressed in neurons in central nervous system. However, whether MAD2B is involved in hyperglycaemia-induced apoptosis and thus takes part in diabetic encephalopathy is still unknown. To address this issue, we first explored the expression of MAD2B and cyclin B1 detected by immunofluorescence and Western blot. It was found that hyperglycaemia remarkably increased the expression of MAD2B and accumulation of cyclin B1 in cortices of diabetes mellitus rat model and in cultured primary neurons. To further explore the role of MAD2B in hyperglycaemia-induced neuronal injury, we depleted MAD2B expression by a specifically targeted shRNA against MAD2B. We observed that MAD2B deficiency alleviated cyclin B1 expression and apoptotic neuronal death. These results demonstrate that MAD2B expression is the main culprit for accumulation of cyclin B1 and apoptosis in neurons under high glucose. Moreover, inhibition of the expression of MAD2B prevented neurons from entering an aberrant S phase that led differentiated neurons into apoptotic cell death. These results suggest that hyperglycaemia induced neuronal apoptosis through inducing expression of MAD2B, which represents a novel mechanism of diabetic encephalopathy.

AChR is concentrated at the postjunctional membrane at the neuromuscular junction. However, the underlying mechanism is unclear. We show that α-actinin, a protein known to cross-link F-actin, interacts with rapsyn, a scaffold protein essential for neuromuscular junction formation. α-Actinin, rapsyn, and surface AChR form a ternary complex. Moreover, the rapsyn-α-actinin interaction is increased by agrin, a factor known to stimulate AChR clustering. Downregulation of α-actinin expression inhibits agrin-mediated AChR clustering. Furthermore, the rapsyn-α-actinin interaction can be disrupted by inhibiting Abl and by cholinergic stimulation. Together these results indicate a role for α-actinin in AChR clustering.

The development of liver cancer would undergo a sequential progression from chronic inflammatory liver disease, cirrhosis to neoplasia. During these pathophysiological changes, abnormal liver microenvironment might induce the hepatocytes to die, abnormally proliferate and initiate cancer stem cells. Metallocarboxypeptidases (MCPs) involved in multiple biological functions including inflammation, fibrosis and stem cell niche formation. This study aimed to evaluate the expression of carboxypeptidase 4 (CPA4) in hepatitis, liver cirrhosis and liver cancer tissues, and revealed its clinical significance in liver cancer progression. We firstly found that the CPA4 levels in tissues were significantly higher in liver cancer patients than those in other three groups. Then, elevated levels of CPA4 was observed in 57/100 (57%) liver cancer samples, and significantly correlated with Grade and Stage. We also identified a significant positive correlation between aberrant elevation of CPA4 and overexpression of stem cell markers including CD90, AFP and CD34 with follow-up data (n=100). Further Kaplan-Meier analysis confirmed that high levels of CPA4 and CD90 were significant predictors of poor overall survival. Multivariate Cox regression model showed that CPA4 was an independent prognostic factor for patients with liver cancer. This study demonstrated for the first time that high CPA4 expression was closely correlated with hepatocarcinogenesis, and might be used as an independent poor prognostic factor in liver cancer.

Extracellular matrix metalloproteinase inducer (EMMPRIN) reportedly has a key regulatory role in matrix metalloproteinase (MMP) activities and the progression of atherosclerosis. Statins, which are anti-atherosclerotic pharmacological agents, are widely applied in clinical settings. The aim of the present study was to investigate the pharmaceutical effect of atorvastatin on EMMPRIN expression in atherosclerotic plaques. An atherosclerotic mouse model was established using apoliprotein E-deficient (ApoE-/-) mice raised on a high-fat diet. Additionally, a low (5 mg/kg/day) or high dosage (10 mg/kg/day) of atorvastatin suspension was administered orally for eight weeks, beginning on week 7 or 11 respectively. The effects of atorvastatin on atherosclerotic plaque formation and EMMPRIN expression were subsequently determined. The THP-1 cell line was used to investigate the effect of atorvastatin on EMMPRIN expression in vitro. The results demonstrated that the high-fat diet led to vulnerable plaques (VPs) and increased EMMPRIN expression in VPs in ApoE-/- mice. Atorvastatin treatment decreased EMMPRIN expression in the aortas and plaques of ApoE-/- mice. In vitro, oxidized low-density lipoprotein (ox-LDL) induced the expression of cyclooxygenase-2 (COX-2) and EMMPRIN in THP-1 macrophages, and atorvastatin inhibited ox-LDL-induced expression of PGE2, EMMPRIN and COX-2 in THP-1 macrophages. Therefore, the present data indicated that atorvastatin treatment reduces the vulnerability of atherosclerotic plaques and expression of EMMPRIN, and that the inhibitory effect of atorvastatin on EMMPRIN may occur via the COX-2/PGE2 signaling pathway in macrophages.