Nucleic acid and protein methylation modification in renal diseases.

Although great efforts have been made to elucidate the pathological mechanisms of renal diseases and potential prevention and treatment targets that would allow us to retard kidney disease progression, we still lack specific and effective management methods. Epigenetic mechanisms are able to alter gene expression without requiring DNA mutations. Accumulating evidence suggests the critical roles of epigenetic events and processes in a variety of renal diseases, involving functionally relevant alterations in DNA methylation, histone methylation, RNA methylation, and expression of various non-coding RNAs. In this review, we highlight recent advances in the impact of methylation events (especially RNA m6A methylation, DNA methylation, and histone methylation) on renal disease progression, and their impact on treatments of renal diseases. We believe that a better understanding of methylation modification changes in kidneys may contribute to the development of novel strategies for the prevention and management of renal diseases.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Targeted inhibition of transforming growth factor-ß type I receptor by AZ12601011 improves paraquat poisoning-induced multiple organ fibrosis.

Paraquat (PQ) causes fatal poisoning that leads to systemic multiple organ fibrosis, and transforming growth factor (TGF)-ß1 plays a critical role in this process. In this study, we aimed to investigate the effects of AZ12601011 (a small molecular inhibitor of TGFßRI) on PQ-induced multiple organ fibrosis. We established a mouse model of PQ in vivo and used PQ-treated lung epithelial cell (A549) and renal tubular epithelial cells (TECs) in vitro. Haematoxylin-eosin and Masson staining revealed that AZ12601011 ameliorated pulmonary, hepatic, and renal fibrosis, consistent with the decrease in the levels of fibrotic indicators, alpha-smooth muscle actin (α-SMA) and collagen-1, in the lungs and kidneys of PQ-treated mice. In vitro data showed that AZ12601011 suppressed the induction of α-SMA and collagen-1 in PQ-treated A549 cells and TECs. In addition, AZ12601011 inhibited the release of inflammatory factors, interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α. Mechanistically, TGF-ß and TGFßRI levels were significantly upregulated in the lungs and kidneys of PQ-treated mice. Cellular thermal shift assay and western blotting revealed that AZ12601011 directly bound with TGFßRI and blocked the activation of Smad3 downstream. In conclusion, our findings revealed that AZ12601011 attenuated PQ-induced multiple organ fibrosis by blocking the TGF-ß/Smad3 signalling pathway, suggesting its potential for PQ poisoning treatment.

Dose-response relationship between dietary inflammatory index and diabetic kidney disease in US adults.

OBJECTIVE: The impact of the dietary potential inflammatory effect on diabetic kidney disease (DKD) has not been adequately investigated. The present study aimed to explore the association between dietary inflammatory index (DII) and DKD in US adults. DESIGN: This is a cross-sectional study. SETTING: Data from the National Health and Nutrition Examination Survey (2007-2016) were used. DII was calculated from 24-h dietary recall interviews. DKD was defined as diabetes with albuminuria, impaired glomerular filtration rate or both. Logistic regression and restricted cubic spline models were adopted to evaluate the associations. PARTICIPANTS: Data from the National Health and Nutrition Examination Survey (2007-2016) were used, which can provide the information of participants. RESULTS: Four thousand two-hundred and sixty-four participants were included in this study. The adjusted OR of DKD was 1·04 (95 % CI 0·81, 1·36) for quartile 2, 1·24 (95 % CI 0·97, 1·59) for quartile 3 and 1·64 (95 % CI 1·24, 2·17) for quartile 4, respectively, compared with the quartile 1 of DII. A linear dose-response pattern was observed between DII and DKD (Pnonlinearity = 0·73). In the stratified analyses, the OR for quartile 4 of DII were significant among adults with higher educational level (OR 1·83, 95 % CI 1·26, 2·66) and overweight or obese participants (OR 1·67, 95 % CI 1·23, 2·28), but not among the corresponding another subgroup. The interaction effects between DII and stratified factors on DKD were not statistically significant (all P values for interactions were >0·05). CONCLUSIONS: Our findings suggest that a pro-inflammatory diet, shown by a higher DII score, is associated with increased odd of DKD.

Differences in susceptibility to chlorantraniliprole between Chilo suppressalis (Lepidoptera: Crambidae) and two dominant parasitic wasps collected from Sichuan Province, China.

Chilo suppressalis Walker (Lepidoptera: Crambidae) is one of the most destructive pests occurring in the rice-growing regions of Asia. Parasitoids, mainly egg parasitoids, have been of interest for several years even with practical used cases. Therefore, the potential impact of insecticides on natural enemies needs great attention. In this study, chlorantraniliprole was evaluated for its impact on C. suppressalis and two dominant parasitic wasps. Bioassays showed that chlorantraniliprole had negligible toxicity to Eriborus terebrans but was significantly toxic to Chelonus munakatae; the mortality exceeded 50% when the concentration reached 46.83 ng/cm2. Enzyme assays suggested that the significantly different carboxylesterase activity may be involved in the high-level detoxification metabolism of E. terebrans. According to the results of enzyme gene correlation analysis, P450s may be the dominant factor in the detoxification metabolism of C. munakatae. In addition, the ryanodine receptor C-terminus of C. suppressalis (CsRyR), C. munakatae (CmRyR) and E. terebrans (EtRyR) were successfully cloned. Different amino acids at resistance mutation I4758 M between susceptible C. suppressalis (I) and parasitic wasps (M) may be related to susceptibility differences. Simulated docking showed that CsRyR and CmRyR can interact with chlorantraniliprole but not EtRyR. More interaction forces were formed between CsRyR and chlorantraniliprole than CmRyR. Furthermore, a Pi-Pi T-shape formed between 73PHE in CsRyR and the benzene ring in chlorantraniliprole. These results indicated that both detoxification metabolism and the target site could mediate the susceptibility difference between C. suppressalis and its parasitic wasps.

[Secondary metabolites of endophyte fungi Xylaria sp. from Coptis chinensis].

Two new polyketides, lasobutone A(1) and lasobutone B(2), along with three known compounds, guignardianone C(3), guignardic acid(4), and 4-hydroxy-17R-methylincisterol(5), were isolated from the endophytic fungi Xylaria sp. by silica gel, MCI, and preparative HPLC, which was separated from the Chinese medicinal material Coptis chinensis and cultivated through solid fermentation with rice. Their structures were elucidated on the basis of spectroscopic methods, such as MS, NMR, IR, UV, and ECD. Compounds 2 and 4 showed inhibitory activities against the nitric oxide(NO) production in the LPS-induced macrophage RAW264.7 with IC_(50) values of 58.7 and 42.5 µmol·L~(-1) respectively, while compound 5 exhibited cytotoxic activities against HT-29 with IC_(50) value of 14.3 µmol·L~(-1).

Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats.

Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 28 days with aripiprazole (1.0 mg· kg-1· d-1) or olanzapine (1.0 mg· kg-1· d-1) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα, AMPK, and ß-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IRß expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg· kg-1· d-1, ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.

[Correlation between internal damage due to seven emotions in traditional Chinese medicine and pathogenesis of breast cancer from perspective of psychological stress].

Breast cancer is a major chronic disease threatening women's health. It has topped the global cancers as the diagnosed cases outnumbered lung cancer patients in 2020. Internal damage due to the seven emotions is an important cause of breast cancer and the disorders of hypothalamic-pituitary-adrenal(HPA) axis and endocrine system and the abnormal immune defense mechanism in response to psychological stress all affect the occurrence and development of breast cancer. It is noteworthy that the theory of seven emotions in traditional Chinese medicine and the psychological stress theory of modern medicine have something in common in some aspects. Therefore, this study explored the correlation between internal damage due to the seven emotions and psychological stress and analyzed the molecular biological mechanisms of psychological stress influencing breast cancer from the perspective of modern medicine, which is helpful to reasonably prevent breast cancer and other related tumors and improve the prognosis of breast cancer patients through emotion regulation.

[Pharmacokinetic study on five components in phthalide target areas of Chaxiong and its ß-CD inclusion compounds based on UPLC-MS/MS].

This study aims to establish a method for the determination of the concentration of five main components of phthalide target areas of Chaxiong(CPTA) and its inclusion of ß-CD in the plasma of rats, and determine the pharmacokinetic parameters, absolute bioavailability and relative bioavailability of CPTA/ß-CD inclusion compound in vivo. The plasma concentrations of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide were determined with UPLC-MS/MS. The content determination was conducted at the chromatographic conditions as follows: Shim-pack GIST C_(18)-AQ HP column(2.1 mm×100 mm, 3 µm), mobile phase of 0.1% formic acid solution(A)-acetonitrile(B), gradient elution, flow rate of 0.3 mL·min~(-1), column temperature of 35 ℃ and injection volume of 2 µL. The mass spectra were obtained with electrospray ion source(ESI), positive ion mode and multi reaction monitoring. CPTA/ß-CD inclusion compound was prepared by grinding method, DAS 2.0 software was used to model the data, and the absolute bioavailability of CPTA and relative bioavailability of inclusion compound were calculated. Finally, the methods for the determination of five components of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide in CPTA, were successfully established. The linear relationship among the five components was good within their respective ranges, r>0.99. The absolute bioavailability of the five components in rats was 22.30%, 16.32%, 21.90%, 10.16% and 12.43%, respectively. After CPTA/ß-CD inclusion was prepared, the relative bioavailability of the five components was 138.69%, 198.39%, 218.01%, 224.54% and 363.55%, respectively, significantly improved. This method is rapid, accurate and sensitive, so it is suitable for the pharmacokinetic study of extracts in traditional Chinese medicine and their preparations.

The Mechanisms Involved in Mesenchymal Stem Cell Alleviation of Sepsis-Induced Acute Lung Injury in Mice: A Pilot Study.

BACKGROUND: Acute lung injury is a common complication of sepsis in intensive care unit patients. Inflammation is among the main mechanisms of sepsis. Therefore, suppression of inflammation is an important mechanism for sepsis treatment. Mesenchymal stem cells (MSCs) have been reported to exhibit antimicrobial properties. OBJECTIVE: The present study investigated the effects of MSCs on sepsis-induced acute lung injury. METHODS: Male C57BL/6 mice underwent a cecal ligation and puncture (CLP) operation to induce sepsis and then received either normal saline or MSCs (1 × 106 cells intravenously) at 3 hours after surgery. Survival after surgery was assessed. Lung injury was assessed by histology score, the presence of lung edema, vascular permeability, inflammatory cell infiltration, and cytokine levels in bronchoalveolar lavage fluid. Finally, we tested nuclear factor kappa-light-chain-enhancer of activated B cells activation in lung tissue. RESULTS: As expected, CLP caused lung injury as indicated by significant increases in the histopathology score, lung wet to dry weight ratio, and total protein concentration. However, mice treated with MSCs had amelioration of the lung histopathologic changes, lung wet to dry weight ratio, and total protein concentration. The levels of cytokines tumor necrosis factor alpha, interleukin 6, interleukin 1ß, and interleukin 17 in bronchoalveolar lavage fluid were dramatically decreased after MSCs treatment. In contrast, expression of interleukin 10 was increased after MSCs treatment. Moreover, mice treated with MSCs had a higher survival rate than the CLP group. Neutrophil infiltration into bronchoalveolar lavage fluid was attenuated after MSCs injection, but the amounts of macrophages observed in the MSC group showed no significant differences compared with the CLP group. In addition, MSCs treatment significantly reduced nuclear factor kappa-light-chain-enhancer of activated B cells activation in lung tissue. CONCLUSIONS: Based on the above findings, treatment with MSCs dampened the inflammatory response and inhibited nuclear factor kappa-light-chain-enhancer of activated B cells activation in the mouse CLP model. Thus, MSCs may be a potential new agent for the treatment of sepsis-induced acute lung injury. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

[Analysis of outcomes of randomized controlled trial on compound Chinese herbal medicine formulas in treatment of vascular cognitive impairment caused by cerebral small vessel].

The purpose of the study is to analyze the outcomes of randomized controlled trial(RCT) of Chinese herbal medicine formula(CHMF) in the treatment of vascular cognitive impairment caused by cerebral small vessel disease(CSVD-VCI), and provide suggestions for future studies in this field. Three English databases, four Chinese databases, and two online registration websites of clinical trials were searched with use of the search strategy established in advance. Relevant RCTs published in recent ten years were screened, and necessary information was extracted to assess the risk of bias and analyze the outcomes of these RCTs. As a result, a total of 10 461 articles were retrieved, of which 8 681 were kept after de-duplication, and 41 RCTs were included after screening, with a generally higher risk of bias. The outcomes of included RCTs were classified into 9 categories, namely, clinical symptom outcomes, neuroimaging outcomes, neuroelectrophysiological outcomes, blood biochemical outcomes, hemorheology outcomes, physical signs, syndrome scores of traditional Chinese medicine(TCM), clinical effective rate, and safety outcomes. Among them, the most frequently reported outcomes of included RCTs were blood biochemical outcomes, and clinical symptom outcomes showed the highest reporting rate. Besides, 9 RCTs reported syndrome scores of TCM as the outcomes and illustrated corresponding evaluation criteria. The analysis showed that the application of RCT outcomes in this field had clinical rationality and limitations, and there were also some deficiencies in the trial design level, namely, no distinction between primary and secondary outcomes, insufficient blind methods, not detailed description of outcomes, disunity of evaluation tools, and despised endpoint outcomes. These limitations and deficiencies were negatively affecting the quality of RCTs of CHMF in the treatment of CSVD-VCI. Therefore, we suggest that future researchers should be well prepared in the top-level design stage, and actively construct the core outcome set of this field, so as to improve the quality of clinical trials.

Endometrial TGF-ß, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis.

BACKGROUND: Chronic endometritis (CE) is a condition which results in reduced receptivity of embryos by dysregulated lymphocyte subsets, abnormal expression of cytokines, chemokines and other regulatory molecules in the endometrium (EM). Macroautophagy (autophagy), the highly conserved cellular homeostasis pathway, plays an essential role in the development and function of T lymphocytes, and supports T cell lineage stability and survival fitness. The possible relationships between autophagy and local cytokine milieus in repeated implantation failure (RIF) with CE have not been elucidated yet. METHODS: This case-control study was performed at a large reproductive medicine center between February 2015 and July 2016. Seventy-five recurrent implantation falliure women with CE who had "strawberry aspect" and 75 women with male factor infertility were included. In this study, endometrial expressions of IL-17, IL-10, TGF-ß and autophagy related molecules, including LC3-II and mTORC1 were investigated by qRT-PCR, Western blot, immunofluorescence and immunohistochemistry assays. RESULTS: The expression of IL-17 was significantly higher in patients with CE compared to women with male factor infertility, while the expressions of IL-10 and TGF-ß were significantly lower. Moreover, the expression of autophagy (LC3-II) is increased, while the expression of mTORC1 was impaired. CONCLUSIONS: CE is associated with shifted cytokine milieu towards Th17 over Treg immunity in endometrium through impaired autophagy by decreased mTORC1.

Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway.

Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation.

Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1-16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.

[Effects of Acupuncture at Zusanli on Plasma Dopamine and Lung Function of Rats with COPD].

OBJECTIVE: To explore the mechanism of acupuncture in regulating chronic inflammation through dopamine in rats with chronic obstructive pulmonary disease (COPD). METHODS: 32 SD rats were randomly divided into control, model, sham acupuncture and acupuncture groups (n=8) . COPD condition was induced by eight-week exposure to cigarette smoking and lipopolysaccharides (LPS) of the rats, except for those in the control group. From the beginning of the 7th week, the acupuncture group received bilateral electroacupuncture on the Zusanli (ST-36), while the sham acupuncture group received bilateral electroacupuncture on the non-points, 30 min/time, 1/day, for 2 weeks prior to exposure to cigarette smoking. Post treatment changes in plasma dopamine and inflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8)], lung function [total lung capacity (TLC), functional residual capacity (FRC), the 50 µs forced expiratory volume (FEV) vs. forced vital capacity (FVC)( FEV50/FVC), the 100 µs FEV vs. FVC (FEV100/FVC), total airway resistance (RL), lung dynamic compliance (Cdyn)], and the ratio of total alveolus area to tissue area (A/t) and cell counts in the alveolar lavage fluid (BALF) were measured. Pearson correlations between plasma dopamine and the above indicators were calculated. RESULTS: Acupuncture increased plasma dopamine and improved the inflammatory factors, lung function, A/t and BALF cell counts. Compared with the model rats, the rats that received acupuncture had higher levels of TNF-α and IL-1ß, A/t and BALF cell counts, and lung function (FEV50/FVC, FEV100/FVC, RL, Cdyn) (P<0.05). The effects of acupuncture were superior on the ST-36 points compared with the non-points. Significant correlations between lung function (FRC, RL, Cdyn) and inflammatory factors (TNF-α, IL-1ß, IL-6, IL-8) were found (P<0.001) . TLC was correlated with IL-8, IL-1ß and A/t (P<0.05). Plasma dopamine was correlated with FRC, TLC, FEV50/FVC, FEV100/FVC (P<0.05). CONCLUSION: Acupuncture can alleviate inflammation, improve lung function and raise plasma dopamine level in COPD rats, and the effect of acupuncture on lung function may be related to reducing inflammatory factors and increasing dopamine level.

PPARα Mediates the Hepatoprotective Effects of Nutmeg.

Nutmeg is a Traditional Chinese Medicine used to treat gastrointestinal diseases. Some reports have indicated that nutmeg has hepatoprotective activity. In this study, a thioacetamide (TAA)-induced acute liver injury model in mice was used to explore the mechanism of the protective effects of nutmeg extract (NME), including its major bioactive component myrislignan. The results indicated that NME could effectively protect TAA-induced liver damage as assessed by recovery of increased serumtransaminases, decrease in hepatic oxidative stress, and lower hepatic inflammation. Metabolomics analysis further revealed that treatment with NME led to the recovery of a series of lipids including lysophosphatidylcholines that were decreased and a lowering of acylcarnitines that were increased in mouse plasma and liver after TAA exposure. Gene expression analysis demonstrated that the hepatoprotective effect of NME was achieved by modulation of the peroxisome proliferator-activated receptor alpha (PPARα) as well as the decrease in oxidative stress. NME could not protect from TAA-induced liver injury in Ppara-null mice, suggesting that its protective effect was dependent on PPARα. Myrislignan, a representative neolignan in nutmeg, showed potent protective activity against TAA-induced liver toxicity. These data demonstrate that nutmeg alleviates TAA-induced liver injury through the modulation of PPARα and that the lignan compounds in nutmeg such as myrislignan partly contributed to this action.

A case report: autosomal recessive Myotonia congenita caused by a novel splice mutation (c.1401 + 1G > A) in CLCN1 gene of a Chinese Han patient.

BACKGROUND: Autosomal recessive Myotonia congenita (Becker's disease) is caused by mutations in the CLCN1 gene. The condition is characterized by muscle stiffness during sustained muscle contraction and variable degree of muscle weakness that tends to improve with repeated contractions. CASE PRESENTATION: A 21-year-old man presented with transient muscle stiffness since the last 10 years. He had difficulty in initiating movement and experienced muscle weakness after rest, which typically improved after repeated contraction (warm-up phenomenon). There was no significant family history. Medical examination showed generalized muscle hypertrophy. Serum creatine kinase level was 2-fold higher than the normal value. Electromyogram showed myotonic discharges. DNA sequence analysis identified a novel splice mutation (c.1401 + 1G > A) and a known mutation (c.1657A > T,p.Ile553Phe). He rapidly responded to treatment with mexiletine 100 mg three times a day for 6 months. CONCLUSIONS: This case report of autosomal recessive Myotonia congenita caused by a novel compound heterozygous mutation expands the genotypic spectrum of CLCN1 gene.

A case report: a heterozygous deletion (2791_2805 del) in exon 18 of the filamin C gene causing filamin C-related myofibrillar myopathies in a Chinese family.

BACKGROUND: Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. CASE PRESENTATION: We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. CONCLUSIONS: A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.

[Measurement of Soil Organic Matter with Near Infrared Spectroscopy Combined with Genetic Algorithm and Successive Projection Algorithm].

Visible near infrared spectroscopy combined with genetic algorithm and successive projection algorithm was investigated to detect soil organic matter (OM). A total of 394 soil samples were collected from Wencheng, Zhejiang province. In order to simplify calibration model, a total of 18 characteristic wavelengths were selected with using genetic algorithm and successive projections algorithm. These characteristic wavelengths were subjected to partial least squares regression (PLSR) with leave-one-out cross validation to establish calibration model of soil organic matter (OM) with coefficient of determination (R2) of 0.81, 0.83, RMSEP of 0.22, 0.20 and residual prediction deviation (RPD) of 2.31, 2.45 for the calibration set and prediction set respectively. The results showed that using genetic algorithm and successive projections algorithm can simplify the model greatly while the assessing indexes of model such as R2, RMSEP and RPD were not reduced greatly compared with indexes of model using full spectra data to develop calibration model. Therefore, genetic algorithm combined with successive projections algorithm can be used to simply the model to predict soil organic matter.

[Measurement of Water COD Based on UV-Vis Spectroscopy Technology].

Ultraviolet/visible (UV/Vis) spectroscopy technology was used to measure water COD. A total of 135 water samples were collected from Zhejiang province. Raw spectra with 3 different pretreatment methods (Multiplicative Scatter Correction (MSC), Standard Normal Variate (SNV) and 1st Derivatives were compared to determine the optimal pretreatment method for analysis. Spectral variable selection is an important strategy in spectrum modeling analysis, because it tends to parsimonious data representation and can lead to multivariate models with better performance. In order to simply calibration models, the preprocessed spectra were then used to select sensitive wavelengths by competitive adaptive reweighted sampling (CARS), Random frog and Successive Genetic Algorithm (GA) methods. Different numbers of sensitive wavelengths were selected by different variable selection methods with SNV preprocessing method. Partial least squares (PLS) was used to build models with the full spectra, and Extreme Learning Machine (ELM) was applied to build models with the selected wavelength variables. The overall results showed that ELM model performed better than PLS model, and the ELM model with the selected wavelengths based on CARS obtained the best results with the determination coefficient (R2), RMSEP and RPD were 0.82, 14.48 and 2.34 for prediction set. The results indicated that it was feasible to use UV/Vis with characteristic wavelengths which were obtained by CARS variable selection method, combined with ELM calibration could apply for the rapid and accurate determination of COD in aquaculture water. Moreover, this study laid the foundation for further implementation of online analysis of aquaculture water and rapid determination of other water quality parameters.