[Berberine inhibits autophagy and promotes apoptosis of fibroblast-like synovial cells from rheumatoid arthritis patients through the ROS/mTOR signaling pathway].

OBJECTIVE: To evaluate the regulatory effect of berberine on autophagy and apoptosis balance of fibroblast-like synoviocytes (FLSs) from patients with in rheumatoid arthritis (RA) and explore the mechanism. METHODS: The inhibitory effect of 10, 20, 30, 40, 50, 60, 70, and 80 µmol/L berberine on RA-FLS proliferation was assessed using CCK-8 method. Annexin V/PI and JC-1 immunofluorescence staining was used to analyze the effect of berberine (30 µmol/L) on apoptosis of 25 ng/mL TNF-α- induced RA-FLSs, and Western blotting was performed to detect the changes in the expression levels of autophagy- and apoptosis-related proteins. The cells were further treated with the autophagy inducer RAPA and the autophagy inhibitor chloroquine to observe the changes in autophagic flow by laser confocal detection of mCherry-EGFP-LC3B. RA-FLSs were treated with the reactive oxygen species (ROS) mimic H2O2 or the ROS inhibitor NAC, and the effects of berberine on ROS, mTOR and p-mTOR levels were observed. RESULTS: The results of CCK-8 assay showed that berberine significantly inhibited the proliferation of RA-FLSs in a time- and concentration-dependent manner. Flow cytometry and JC-1 staining showed that berberine (30 µmol/L) significantly increased apoptosis rate (P < 0.01) and reduced the mitochondrial membrane potential of RA-FLSs (P < 0.05). Berberine treatment obviously decreased the ratios of Bcl-2/Bax (P < 0.05) and LC3B-II/I (P < 0.01) and increased the expression of p62 protein in the cells (P < 0.05). Detection of mCherry-EGFP-LC3B autophagy flow revealed obvious autophagy flow block in berberine-treated RA-FLSs. Berberine significantly reduced the level of ROS in TNF-α-induced RA-FLSs and upregulated the expression level of autophagy-related protein p-mTOR (P < 0.01); this effect was regulated by ROS level, and the combined use of RAPA significantly reduced the pro-apoptotic effect of berberine in RA-FLSs (P < 0.01). CONCLUSION: Berberine can inhibit autophagy and promote apoptosis of RA-FLSs by regulating the ROS-mTOR pathway.

Two-Dimensional Numerical Study of Methane-Air Combustion Within Catalytic and Non-catalytic Porous Medium.

This study numerically investigates a two-dimensional physical model of methane/air mixture combustion in catalytic and non-catalytic porous media. The temperature distribution and flame stability of combustion in inert alumina (Al2O3) pellets and platinum (Pt) catalyst-supported alumina (Al2O3) pellets, were studied by changing the burner structure, operating parameters, and physical properties of alumina pellets. The simulation results indicated that the gas temperature in the inert porous medium is higher than that in a catalytic porous medium, while the solid temperature in an inert porous medium is lower than that in a catalytic porous medium. The flame moved toward the burner exit with the increasing diameter of the packed pellets at a lower equivalence ratio and moved toward upstream with the increased thermal conductivity of packed pellets. The flame location of the catalytic porous burner was more sensitive to the flame velocity and insensitive to thermal conductivity compared to the inert porous burner. The distance of the flame location to the burner inlet is almost constant with the increasing length of the porous media for both the catalytic and inert porous burner, while the relative position of the flame location moved toward the upstream.

The Influence of Fatty Acids on Cold Hardiness of Eogystia hippophaecolus Larvae.

BACKGROUND: Larvae of the Cossidae family moth Eogystia hippophaecolus bore into and overwinter in the roots of sea buckthorn, which damages this plant in China. OBJECTIVE: The primary aims of the current study were to investigate the effects of fatty acids on cold hardness in overwintering larvae. MATERIALS AND METHODS: The supercooling point (SCP), low temperature mortality and fatty acid composition of different overwintering larvae were assessed. RESULTS: E. hippophaecolus larvae could survive for a long time at temperatures far below the SCP. Saturated fatty acids became less abundant as overwintering proceeded, while unsaturated fatty acids did the opposite. C10:0, C16:1, C16:0, C18:0, C20:0, C20:5, C22:0 and C24:0 fatty acids showed significant seasonal variation during the overwintering period. CONCLUSION: E. hippophaecolus is "freezing-tolerant" and cold hardiness is enhanced by increasing fatty acid unsaturation and degrading medium- and long-chain fatty acids and eicosapentaenoic acid.

Correlation between IL-4 gene polymorphismas well as its mRNA expressionand rheumatoid arthritis.

OBJECTIVE: This study sought to explore the correlation between IL-4-590C/T polymorphism as well as mRNA expression and the occurrence of rheumatoid arthritis (RA). PATIENTS AND METHODS: IL-4-590C/T polymorphisms, detected by a TaqMan probe from 150 RA patients who were treated in Yantaishan Hospital from June 2014 to June 2016, and from 150 healthy people, all from the Han population, were selected for the study. Interleukin-4 (IL-4) mRNA expression was detected by Real-time Polymerase Chain Reaction (PCR), and the differences in IL-4mRNA expressions of different genotypes in RA patients were compared. RESULTS: The difference in CC, CT and TT genotype distributions between the RA group and the healthy group were statistically significant (p<0.05). The mutation frequency of the T allele in IL-4 of the RA group was significantly higher than that of the healthy group (p<0.01). The mRNA expression of IL-4 in the RA group was significantly lower than that in the healthy group (p<0.01). The mRNA expression of IL-4 in RA patients was gradually decreased in the following order: CC, CT and TT, and the differences among these genotypes were significant (p<0.01). CONCLUSIONS: IL-4-590C/T polymorphism may be correlated with the incidence of RA in the Chinese Han population. Carrying the T allele can significantly increase the risk of RA and reduce the mRNA expression of IL-4.

Close association between intestinal microbiota and irritable bowel syndrome.

Trillions of microbes inhabiting the intestine form a complex ecological community, affecting the normal physiology and pathological susceptibility through their collective metabolic activities and interactions with the host. Increased numbers of diseases have been found to be associated with disturbances in this ecosystem. There is evidence that intestinal microflora undergoes alterations in patients with irritable bowel syndrome (IBS). IBS is a frequent functional gut disease with negative impact on the patient's quality of life. Although the etiology and pathology of IBS remain largely unknown, it is generally accepted that the interaction between the microbiota and the host is associated with IBS. However, there are no specific or effective therapies for the treatment of IBS at present. In recent years, researchers have shown a growing interest in seeking safer and more effective alternatives for the treatment of IBS by focusing their attention on the potential role of probiotics and prebiotics. In this review, we will discuss alterations in intestinal microbiota and how these alterations may exacerbate IBS, and introduce several new IBS treatment options aiming at re-establishing a healthy and beneficial ecosystem.

Targeting G-protein coupled receptor-related signaling pathway in a murine xenograft model of appendiceal pseudomyxoma peritonei.

Cancer cells aberrantly express mucins to enhance their survival. Relative chemoresistance of appendiceal pseudomyxoma peritonei (PMP) is attributed to abundant extracellular mucin 2 (MUC2) protein production. We hypothesized that simultaneous MUC2 inhibition and apoptosis induction would be effective against mucinous tumors. In vitro studies were conducted using LS174T cells (MUC2-secreting human colorectal cancer cells), PMP explant tissue, and epithelial organoid cultures (colonoids) derived from mucinous appendix cancers. In vivo studies were conducted using murine intraperitoneal patient-derived xenograft model of PMP. We found COX-2 over-expression in PMP explant tissue, which is known to activate G-protein coupled EP4/cAMP/PKA/CREB signaling pathway. MUC2 expression was reduced in vitro by small molecule inhibitors targeting EP4/PKA/CREB molecules and celecoxib (COX-2 inhibitor), and this was mediated by reduced CREB transcription factor binding to the MUC2 promoter. While celecoxib (5-40 µM) reduced MUC2 expression in vitro in a dose-dependent fashion, only high-dose celecoxib (≥ 20 µM) decreased cell viability and induced apoptosis. Chronic oral administration of celecoxib decreased mucinous tumor growth in our in vivo PMP model via a combination of MUC2 inhibition and induction of apoptosis. We provide a preclinical rationale for using drugs that simultaneously inhibit MUC2 production and induce apoptosis to treat patients with PMP.

Relative contributions of testosterone deficiency and metabolism syndrome at the risk of reduced quality of life: A cross-sectional study among Chinese mid-aged and elderly men.

Testosterone deficiency and metabolism syndrome (MetS) are universal among ageing males, and they have been suggested responsible for poorer quality of life (QoL). We aimed to evaluate the relative contributions of reproductive hormones and components of MetS at the risk of reduced QoL among Chinese mid-aged and elderly men. A cross-sectional study recruited 2,364 males aged 40-79 years, and 2,165 was included for analysis eventually. The Chinese version of ageing male symptoms scale, 36-item Short Form and Beck Depression Inventory were applied to assess QoL. Bivariate correlation analysis and multiple linear regression analysis were used to assess the relative contributions of reproductive hormones and components of MetS at the risk of reduced QoL. Testosterone deficiency and MetS contributed to poorer QoL, of which higher fasting blood glucose made the primary contribution, lower total testosterone mainly contributed to poorer physical functioning.

[Diagnosis and management of spontaneous cerebral spinal fluid otorrhea].

Spontaneous cerebral spinal fluidotorrhea (SCSFO) is a type of CSF otorrhea without obvious causes including previous trauma, surgery, infection or neoplasm. The etiology of SCSFO remains unclear, the diagnosis can be overlooked because of the untypical clinical features. In this paper, we reviewed etiology, clinical features, diagnosis and therapy of SCSFO from recent relative literatures.

Total hip replacement for developmental dysplasia of hip and postoperative nursing.

This study was designed to determine the clinical effect of total hip replacement for the treatment of developmental dysplasia of the hip (DDH) and analyze the postoperative nursing. Sixty patients (78 hips) aged 18-75 years (average 58.6±2.31 years) who received total hip replacement for treatment of DDH at the Zhengzhou People’s Hospital, Henan, China, from April 2013 to June 2016 were selected as research subjects. Twenty-four patients were male (30 hips) and 36 were female (48 hips). Of the 60 patients, according to Crowe typing, 24 were type I (30 hips), 26 were type II (34 hips), 6 were type III (8 hips) and 4 were type IV (6 hips). According to the Harris hip score system, the score of all hips was 39.46±3.56 points average (18-56 points) before treatment and resulted as 89.60±4.25 points (79-98 points) at the last follow-up, showing a statistically significant difference (P < 0.05). Complications such as wound infection, dislocation, fracture of femoral shaft, femoral nerve and injury of sciatic nerve were not found after treatment. A total of 48 cases (58 hips) obtained excellent curative results (93.33% recovery), 8 cases (14 hips) good (92.31% recovery), and 4 cases (6 hips) medium. Total hip replacement proved to be effective in treating DDH and secondary osteoarthritis. Moreover, soft tissue release and an optimum degree recovery of anatomic form and physiological function of the diseased hip is an important basis for reconstructing the acetabulum and stabilizing acetabulum prosthesis.

Oncolysis by paramyxoviruses: preclinical and clinical studies.

Preclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using para-myxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1-3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches.

Oncolysis by paramyxoviruses: multiple mechanisms contribute to therapeutic efficiency.

Oncolytic paramyxoviruses include some strains of Measles, Mumps, Newcastle disease, and Sendai viruses. All these viruses are well equipped for promoting highly specific and efficient malignant cell death, which can be direct and/or immuno-mediated. A number of proteins that serve as natural receptors for oncolytic paramyxoviruses are frequently overexpressed in malignant cells. Therefore, the preferential interaction of paramyxoviruses with malignant cells rather than with normal cells is promoted. Due to specific genetic defects of cancer cells in the interferon (IFN) and apoptotic pathways, viral replication has the potential to be promoted specifically in tumors. Viral mediation of syncytium formation (a polykaryonic structure) promotes intratumoral paramyxo-virus replication and spreading, without exposure to host neutralizing antibodies. So, two related processes: efficient intratumoral infection spread as well as the consequent mass malignant cell death, both are enhanced. In general, the paramyxoviruses elicit strong anticancer innate and adaptive immune responses by triggering multiple danger signals. The paramyxoviruses are powerful inducers of IFN and other immuno-stimulating cytokines. These viruses efficiently promote anticancer activity of natural killer cells, dendritic cells, and cytotoxic T lymphocytes. Moreover, a neuraminidase (sialidase), a component of the viral envelope of Newcastle Disease, Mumps, and Sendai viruses, can cleave sialic acids on the surface of malignant cells thereby unmasking cancer antigens and exposing them to the immune system. These multiple mechanisms contribute to therapeutic efficacy of oncolytic paramyxovi-ruses and are responsible for encouraging results in preclinical and clinical studies.

Sensilla on the Antennae and Ovipositor of the Sea Buckthorn Carpenter Moth, Holcocerus hippophaecolus Hua et al (Lepidoptera: Cossidae).

Holcocerus hippophaecolus Hua et al (Lepidoptera: Cossidae) is an important boring pest that damages the sea buckthorn Hippophae rhamnoides. Larvae of H. hippophaecolus cause major losses of this shrub in Northern China, with severe economic and ecological consequences. In this study, we used scanning electron microscopy to investigate the typology, morphology, and distribution of sensilla on the antennae and ovipositor of H. hippophaecolus. In total, seven subtypes of sensilla were found on the antennae, i.e., chaetica, trichodea (two subtypes), basiconica (two subtypes), coeloconica, and Böhm bristles. In addition, three types of sensilla were detected on the ovipositor, i.e., chaetica, trichodea, and basiconica. The identification of these sensilla types could provide morphological evidence to facilitate a better understanding of the host location, mate finding, and oviposition processes of this important species.

Areas of potential suitability and survival of Dendroctonus valens in China under extreme climate warming scenario.

The areas in China with climates suitable for the potential distribution of the pest species red turpentine beetle (RTB) Dendroctonus valens LeConte (Coleoptera: Scolytidae) were predicted by CLIMEX based on historical climate data and future climate data with warming estimated. The model used a historical climate data set (1971-2000) and a simulated climate data set (2010-2039) provided by the Tyndall Centre for Climate Change (TYN SC 2.0). Based on the historical climate data, a wide area was available in China with a suitable climate for the beetle in which every province might contain suitable habitats for this pest, particularly all of the southern provinces. The northern limit of the distribution of the beetle was predicted to reach Yakeshi and Elunchun in Inner Mongolia, and the western boundary would reach to Keerkezi in Xinjiang Province. Based on a global-warming scenario, the area with a potential climate suited to RTB in the next 30 years (2010-2039) may extend further to the northeast. The northern limit of the distribution could reach most parts of south Heilongjiang Province, whereas the western limit would remain unchanged. Combined with the tendency for RTB to spread, the variation in suitable habitats within the scenario of extreme climate warming and the multiple geographical elements of China led us to assume that, within the next 30 years, RTB would spread towards the northeast, northwest, and central regions of China and could be a potentially serious problem for the forests of China.

Mitogen-activated protein kinase inhibition reduces mucin 2 production and mucinous tumor growth.

Excessive accumulation of mucin 2 (MUC2) protein (a gel-forming secreted mucin) within the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP), a unique mucinous malignancy of the appendix. Mitogen-activated protein kinase (MAPK) signaling pathway is upregulated in PMP and has been shown to modulate MUC2 promoter activity. We hypothesized that targeted inhibition of the MAPK pathway would be a novel, effective, and safe therapeutic strategy to reduce MUC2 production and mucinous tumor growth. We tested RDEA119, a specific MEK1/2 (MAPK extracellular signal-regulated kinase [ERK] kinase) inhibitor, in MUC2-secreting LS174T cells, human PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. RDEA119 reduced ERK1/2 phosphorylation and inhibited MUC2 messenger RNA and protein expression in vitro. In the xenograft model, chronic oral therapy with RDEA119 inhibited mucinous tumor growth in an MAPK pathway-dependent manner and this translated into a significant improvement in survival. RDEA119 downregulated phosphorylated ERK1/2 and nuclear factor κB p65 protein signaling and reduced activating protein 1 (AP1) transcription factor binding to the MUC2 promoter in LS174T cells. This study provides a preclinical rationale for the use of MEK inhibitors to treat patients with PMP.

Pharmacokinetics, safety and tolerability of triflusal and its main active metabolite HTB in healthy Chinese subjects.

Triflusal presents comparable antiplatelet activity to aspirin while presenting a more favourable safety profile, and is used in the treatment of thrombosis. The study aimed to evaluate the pharmacokinetics and safety of triflusal and its major metabolite 2-(hydroxyl)-4-(trifluoromethyl)- benzoic acid (HTB) in healthy Chinese subjects.30 healthy subjects were recruited in this randomized, single-center, and open-label, parallel, single ascending doses (300, 600, 900 mg) and multiple doses (600 mg, once daily for 7 days) study. Plasma samples were analyzed with a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Safety was assessed by adverse events, ECG, laboratory testing, and vital signs.Triflusal was safe and well tolerated. After single-dose administration, triflusal was rapidly absorbed with a mean Tmax of 0.55-0.92 h and a mean t1/2 kel of 0.35-0.65 h, HTB was absorbed with a mean Tmax of 2.35-3.03 h and a mean t1/2 kel of 52.5-65.57 h. Cmax and AUC for triflusal and HTB were approximately dose proportional over the 300-900 mg dose range. In the steady state, the accumulation index (R) indicated that the exposure of triflusal increased slightly with repeated dosing, and the exposure of HTB increased obviously. 3 adverse events certainly related to the investigational drugs occurred in the multiple-dose phase.Following oral dosing under fasting condition, triflusal is promptly absorbed and rapidly depleted from the systemic circulation. HTB is quickly generated from triflusal and slowly eliminated. Triflusal accumulates slightly in the body. HTB plasma concentration builds up progressively toward steady-state.

Chemical and bioactive diversities of the genus Chaetomium secondary metabolites.

The genus Chaetomium fungi are considered to be a rich source of novel and bioactive secondary metabolites of great importance. Up till now, a variety of more than 200 secondary metabolites belonging to diverse structural types of chaetoglobosins, epipolythiodioxopiperazines, azaphilones, xanthones, anthraquinones, chromones, depsidones, terpenoids, and steroids have been discovered. Most of these fungal metabolites exhibited antitumor, cytotoxic, antimalarial, enzyme inhibitory, antibiotic, and other activities. This review covers the extraction, structure elucidation, structural diversity, and biological activities of natural products isolated from about 30 fungi associated with marine- and terrestrial- origins, and highlights some bioactive compounds as well as their mechanisms of action and structure-activity relationships.