Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

Luteolin Attenuates Diabetic Myocardial Hypertrophy by Inhibiting Proteasome Activity.

INTRODUCTION: Luteolin is a flavonoid polyphenolic compound exerting broad pharmacological and medicinal properties. Diabetes-related obesity increases the total blood volume and cardiac output and may increase the myocardial hypertrophy progression. However, the mechanism of luteolin in diabetic myocardial hypertrophy remains uncertain. Therefore, this study aimed to evaluate whether luteolin improved diabetic cardiomyopathy (DCM) by inhibiting the proteasome activity. METHODS: Cardiomyopathy was induced in streptozotocin-treated diabetes mellitus (DM) and db/db mice. Luteolin (20 mg kg-1·day-1) was administrated via gavage for 12 weeks. In vitro, high glucose and high insulin (HGI, glucose at 25.5 mM and insulin at 0.1 µM) inducing primary neonatal rat cardiomyocytes (NRCMs) were treated with or without luteolin for 48 h. Echocardiography, reverse transcription quantitative polymerase chain reaction, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate. RESULTS: Luteolin administration significantly prevented the onset of cardiac hypertrophy, fibrosis, and dysfunction in type 1 DM (T1DM) and type 2 DM (T2DM). Compared with DCM mice, luteolin groups showed lower serum triglyceride and total cholesterol levels. Furthermore, luteolin attenuated HGI-induced myocardial hypertrophy and reduced atrial natriuretic factor mRNA level in NRCMs. Proteasome activities were inhibited by luteolin in vitro. Luteolin also reduces the proteasome subunit levels (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome, as well as proteasome-regulated particles (Rpt) 1 and Rpt4 levels of 19S proteasome. Furthermore, luteolin treatment increased protein kinase B (AKT) and GSK-3α/ß (inactivation of GSK-3) phosphorylation. The phosphorylation level of AMPK activity was also reversed after the treatment with luteolin in comparison with the HGI-treated group. CONCLUSION: This study indicates that luteolin protected against DCM in mice, including T1DM and T2DM, by upregulating phosphorylated protein AMPK and AKT/GSK-3 pathways while decreasing the proteasome activity. These findings suggest that luteolin may be a potential therapeutic agent for DCM.

Validation and derivation of short-term prognostic risk score in acute decompensated heart failure in China.

BACKGROUND: Few prognostic risk scores (PRSs) have been routinely used in acute decompensated heart failure (ADHF). We, therefore, externally validated three published PRSs (3A3B, AHEAD, and OPTIME-CHF) and derived a new PRS to predict the short-term prognosis in ADHF. METHODS: A total of 4550 patients from the Heb-ADHF registry in China were randomly divided into the derivation and validation cohorts (3:2). Discrimination of each PRS was assessed by the area under the receiver operating characteristic curve (AUROC). Logistic regression was exploited to select the predictors and create the new PRS. The Hosmer-Lemeshow goodness-of-fit test was used to assess the calibration of the new PRS. RESULTS: The AUROCs of the 3A3B, AHEAD, and OPTIME-CHF score in the derivation cohort were 0.55 (95% CI 0.53-0.57), 0.54 (95% CI 0.53-0.56), and 0.56 (95% CI 0.54-0.57), respectively. After logistic regression analysis, the new PRS computed as 1 × (diastolic blood pressure < 80 mmHg) + 2 × (lymphocyte > 1.11 × 109/L) + 1 × (creatinine > 80 µmol/L) + 2 × (blood urea nitrogen > 21 mg/dL) + 1 × [BNP 500 to < 1500 pg/mL (NT-proBNP 2500 to < 7500 pg/mL)] or 3 × [BNP ≥ 1500 (NT-proBNP ≥ 7500) pg/mL] + 3 × (QRS fraction of electrocardiogram < 55%) + 4 × (ACEI/ARB not used) + 1 × (rhBNP used), with a better AUROC of 0.67 (95% CI 0.64-0.70) and a good calibration (Hosmer-Lemeshow χ2 = 3.366, P = 0.186). The results in validation cohort verified these findings. CONCLUSIONS: The short-term prognostic values of 3A3B, AHEAD, and OPTIME-CHF score in ADHF patients were all poor, while the new PRS exhibited potential predictive ability. We demonstrated the QRS fraction of electrocardiogram as a novel predictor for the short-term outcomes of ADHF for the first time. Our findings might help to recognize high-risk ADHF patients.

Caprylic Acid Improves Lipid Metabolism, Suppresses the Inflammatory Response and Activates the ABCA1/p-JAK2/p-STAT3 Signaling Pathway in C57BL/6J Mice and RAW264.7 Cells.

OBJECTIVE: This study aimed to investigate the effects of caprylic acid (C8:0) on lipid metabolism and inflammation, and examine the mechanisms underlying these effects in mice and cells. METHODS: Fifty-six 6-week-old male C57BL/6J mice were randomly allocated to four groups fed a high-fat diet (HFD) without or with 2% C8:0, palmitic acid (C16:0) or eicosapentaenoic acid (EPA). RAW246.7 cells were randomly divided into five groups: normal, lipopolysaccharide (LPS), LPS+C8:0, LPS+EPA and LPS+cAMP. The serum lipid profiles, inflammatory biomolecules, and ABCA1 and JAK2/STAT3 mRNA and protein expression were measured. RESULTS: C8:0 decreased TC and LDL-C, and increased the HDL-C/LDL-C ratio after injection of LPS. Without LPS, it decreased TC in mice ( P < 0.05). Moreover, C8:0 decreased the inflammatory response after LPS treatment in both mice and cells ( P < 0.05). Mechanistic investigations in C57BL/6J mouse aortas after injection of LPS indicated that C8:0 resulted in higher ABCA1 and JAK2/STAT3 expression than that with HFD, C16:0 and EPA, and resulted in lower TNF-α, NF-κB mRNA expression than that with HFD ( P < 0.05). In RAW 264.7 cells, C8:0 resulted in lower expression of pNF-κBP65 than that in the LPS group, and higher protein expression of ABCA1, p-JAK2 and p-STAT3 than that in the LPS and LPS+cAMP groups ( P < 0.05). CONCLUSION: Our studies demonstrated that C8:0 may play an important role in lipid metabolism and the inflammatory response, and the mechanism may be associated with ABCA1 and the p-JAK2/p-STAT3 signaling pathway.

[Analgesic effect of electroacupuncture on chronic pelvic pain in patients with sequelae of pelvic inflammatory disease].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on chronic pelvic pain in patients with sequelae of pelvic inflammatory disease. METHODS: A total of 144 patients with chronic pelvic pain were randomly divided into an observation group (72 cases, 10 cases dropped off) and a control group (72 cases, 9 cases dropped off). The patients in the control group were treated with ibuprofen sustained-release capsules 10 days before menstruation, 0.3 g each time, once a day. On the basis of the treatment of the control group, the patients in the observation group were treated with EA at Guanyuan (CV 4), Shuidao (ST 28), Guilai (ST 29), Shenshu (BL 23) and Ciliao (BL 32), disperse-dense wave, 2 Hz/15 Hz of frequency, once a day. The patients in both groups were treated for 10 days per menstrual cycle for 3 menstrual cycles. The visual analogue scale (VAS) scores of lower abdomen and lumbosacral area, local sign score, quality of life scale score and pain disappearance rate were compared between the two groups before and after treatment. RESULTS: The VAS scores of lower abdomen and lumbosacral area as well as each item score and total score of local signs in the observation group after treatment were significantly lower than those before treatment and those in the control group (P<0.05). Compared before treatment, the scores of physiological, psychological, social and environmental domains of the quality of life scale in the observation group were significantly increased after treatment (P<0.05); the score of physiological domain in the control group after treatment was significantly higher than that before treatment (P<0.05); the score of physiological domain in the observation group was higher than that in the control group (P<0.05). The pain disappearance rate was 87.1% (54/62) in the observation group, which was higher than 46.0% (29/63) in the control group (P<0.05). CONCLUSION: EA can relieve the pain symptoms in patients with chronic pelvic pain and improve their quality of life.

[Acupuncture combined with western medication on chronic pelvic pain after pelvic inflammatory disease: a multi-center randomized controlled trial].

OBJECTIVE: To compare the therapeutic effect between acupuncture combined with ibuprofen sustained-release capsule and simple ibuprofen sustained-release capsule on chronic pelvic pain (CPP) after pelvic inflammatory disease (PID). METHODS: A total of 144 patients were randomized into an observation group (72 cases, 10 cases dropped off) and a control group (72 cases, 9 cases dropped off). Ibuprofen sustained-release capsule was given orally in the control group, one capsule a time. On the basis of the treatment in the control group, acupuncture was applied at Guanyuan (CV 4), Shuidao (ST 28), Guilai (ST 29), Shenshu (BL 23) and Ciliao (BL 32), and Shuidao (ST 28), Guilai (ST 29), Shenshu (BL 23) and Ciliao (BL 32) were connected to electroacupuncture in the observation group. The treatment was given 10 days before menstruation, once a day for 3 menstrual cycles in both groups, and the follow-up was adopted 3 menstrual cycles after treatment. The visual analogue scale (VAS) scores of hypogastrium and lumbosacral region before treatment, after treatment, and at the follow-up, the score of local signs and the score of World Health Organization quality of life questionnaire-brief version (WHOQOL-BREF) before and after treatment were observed in the both groups. RESULTS: After treatment and at the follow-up, the VAS scores of hypogastrium and lumbosacral region were decreased compared before treatment in both groups (P<0.05), and those in the observation group were lower than the control group (P<0.05). After treatment, except for the score of uterosacral ligament tenderness in the control group, the scores of local signs were decreased compared before treatment in both groups (P<0.05), and the score of uterine appendages tenderness, the total score of local signs in the observation group were lower than the control group (P<0.05). Compared before treatment, the physiological scores of WHOQOL-BREF were increased in both groups (P<0.05), the scores of psychology, social relations and environment were increased in the observation group (P<0.05), and the physiological score was higher than the control group (P<0.05). CONCLUSION: Acupuncture combined with ibuprofen sustained-release capsule can effectively improve the symptoms, signs and quality of life in patients with CPP after PID, the therapeutic effect is superior to simple ibuprofen sustained-release capsule.

Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress.

Antiepileptic drug zonisamide has been shown to be curative for Parkinson's disease (PD) through increasing HMG-CoA reductase degradation protein 1 (Hrd1) level and mitigating endoplasmic reticulum (ER) stress. Hrd1 is an ER-transmembrane E3 ubiquitin ligase, which is involved in cardiac dysfunction and cardiac hypertrophy in a mouse model of pressure overload. In this study, we investigated whether zonisamide alleviated cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting ER stress. The beneficial effects of zonisamide were assessed in two experimental models of cardiac hypertrophy: in rats subjected to abdominal aorta constriction (AAC) and treated with zonisamide (14, 28, 56 mg · kg-1 · d-1, i.g.) for 6 weeks as well as in neonatal rat cardiomyocytes (NRCMs) co-treated with Ang II (10 µM) and zonisamide (0.3 µM). Echocardiography analysis revealed that zonsiamide treatment significantly improved cardiac function in AAC rats. We found that zonsiamide treatment significantly attenuated cardiac hypertrophy and fibrosis, and suppressed apoptosis and ER stress in the hearts of AAC rats and in Ang II-treated NRCMs. Importantly, zonisamide markedly increased the expression of Hrd1 in the hearts of AAC rats and in Ang II-treated NRCMs. Furthermore, we demonstrated that zonisamide accelerated ER-associated protein degradation (ERAD) in Ang II-treated NRCMs; knockdown of Hrd1 abrogated the inhibitory effects of zonisamide on ER stress and cardiac hypertrophy. Taken together, our results demonstrate that zonisamide is effective in preserving heart structure and function in the experimental models of pathological cardiac hypertrophy. Zonisamide increases Hrd1 expression, thus preventing cardiac hypertrophy and improving the cardiac function of AAC rats.

Zonisamide, an antiepileptic drug, alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum stress (ER stress) plays a key role in the development of cardiac hypertrophy and diabetic cardiomyopathy (DCM). Zonisamide (ZNS) was originally developed as an antiepileptic drug. Studies have shown that ZNS suppresses ER stress-induced neuronal cell damage in the experimental models of Parkinson's disease. Herein, we investigated whether ZNS improved DCM by attenuating ER stress-induced apoptosis. C57BL/6J mice were fed with high-fat diet (HFD) and intraperitoneally injected with low-dose streptozotocin (STZ) to induce type 2 diabetes mellitus (T2DM), and then treated with ZNS (40 mg·kg-1·d-1, i.g.) for 16 weeks. We showed that ZNS administration slightly ameliorated the blood glucose levels, but significantly alleviated diabetes-induced cardiac dysfunction and hypertrophy. Furthermore, ZNS administration significantly inhibited the Bax and caspase-3 activity, upregulated Bcl-2 activity, and decreased the proportion of TUNEL-positive cells in heart tissues. We analyzed the hallmarks of ER stress in heart tissues, and revealed that ZNS administration significantly decreased the protein levels of GRP78, XBP-1s, ATF6, PERK, ATF4, and CHOP, and elevated Hrd1 protein. In high glucose (HG)-treated primary cardiomyocytes, application of ZNS (3 µM) significantly alleviated HG-induced cardiomyocyte hypertrophy and apoptosis. ZNS application also suppressed activated ER stress in HG-treated cardiomyocytes. Moreover, preapplication of the specific ER stress inducer tunicamycin (10 ng/mL) eliminated the protective effects of ZNS against HG-induced cardiac hypertrophy and ER stress-mediated apoptosis. Our findings suggest that ZNS improves the cardiac diastolic function in diabetic mice and prevents T2DM-induced cardiac hypertrophy by attenuating ER stress-mediated apoptosis.

Subchronic toxicity study in rats evaluating herbicide-tolerant soybean DAS-68416-4.

A subchronic toxicity study was conducted in Wistar rats to evaluate the potential health effects of genetically modified (GM) herbicide-tolerant soybean DAS-68416-4. Rats were fed with diets containing toasted meal produced from GM soybean engineered with aad-12 and pat genes or containing non-GM soybean at a dose of 30.0, 15.0, or 7.5%,w/w% and 0% (control group) for 90 consecutive days. Animals were evaluated for general behavior, body weight gain, food consumption, food use efficiency, etc. At the middle and end of the study, blood and serum samples were collected for routine and biochemical assays. Internal organs were taken for calculating relative weights and doing histopathological examination. The rats were active and healthy without any abnormal symptoms during the entire study period. No biological differences in hematological or biochemical indices were detected. No histopathological changes were observed. Under the conditions of this study, herbicide-tolerant soybean DAS-68416-4 did not cause any treatment-related effects in Wistar rats following 90 days of dietary administration.

Perianorectal abscesses and fistula due to ingested jujube pit in infant: Two case reports.

BACKGROUND: About 90% of perianal infection is caused by cryptoglandular infection. Only a few cases of peritonitis or intra-abdominal abscesses secondary to perforation of the digestive tract by an ingested foreign body have been reported. The most common sites of impaction and perforation include the appendix, cecum and the terminal ileum. The rectum is an unusual site of foreign body impaction. This report intends to highlight that ingested foreign body impacted in the rectum is an extremely rare cause of perianal abscess and subsequent fistula in infants. CASE SUMMARY: Two cases of perianal abscess and fistula due to ingested jujube pit impacted in the rectum are reported. Both cases are infants with free previous medical history suffered from recurrent perianal infection. The caregivers of the two patients denied ingestion of a foreign body or any history of trauma. Physical examination combined with ultrasound or computed tomography scan established the diagnosis. Both of the patients underwent operation under general anesthesia. In case 1, a jujube pit with sharp ends was discovered embedded within a subcutaneous fistula. The jujube pit was then removed intact along with fistula resection. The wound was successfully laid open to allow healing by secondary intention. In case 2, a jujube pit was found with its sharp end puncturing the rectum, surrounded by pus and necrotic tissue. Subsequent incision and adequate drainage were performed. The whole jujube pit was then removed from the abscess cavity at the same time. Both patients received colonoscopy to rule out inflammatory bowel disease or other potential damages by the ingested jujube pit. The postoperative period was uneventful. At 1.5 year follow-up, no recurrent abscess or fistula were found in either patient. CONCLUSION: An impacted foreign body must not be overlooked as an unusual cause of perianal abscess and fistula, especially in young children.

Zonisamide Ameliorates Cognitive Impairment by Inhibiting ER Stress in a Mouse Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) increases the risk of Alzheimer's disease (AD)-like dementia and pathology. Endoplasmic reticulum stress (ERS) plays a key role in the development of cognitive impairment in T2DM. Zonisamide (ZNS) was found to suppress ERS-induced neuronal cell damage in the experimental models of Parkinson's disease (PD). However, the protective effect of Zonisamide in the treatment of diabetes-related dementia is not determined. Here, we studied whether ZNS can attenuate cognitive impairments in T2DM mice. C57BL/6J mice were fed with a high-fat diet (HFD) and received one intraperitoneal injection of streptozotocin (STZ) to develop T2DM. After the 9-week diet, the mice were orally gavaged with ZNS or vehicle for 16 consecutive weeks. We found that ZNS improved spatial learning and memory ability and slightly attenuated hyperglycemia. In addition, the expression levels of synaptic-related proteins, such as postsynaptic density 95 (PSD95) and synaptophysin, were increased along with the activation of the cyclic AMP response element-binding (CREB) protein and cAMP-dependent protein kinase (PKA) both in the hippocampus and cortex of T2DM mice. Meanwhile, ZNS attenuated Aß deposition, Tau hyperphosphorylation at Ser-396/404, and also decreased the activity of Tau upstream kinases including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Moreover, ZNS also decreased the ERS hallmark protein levels. These data suggest that ZNS can efficiently prevent cognitive impairment and improve AD-like pathologies by attenuating ERS in T2DM mice.

[Textual research on traditional application of Moringa].

Moringa has a long history of edible and medicinal use in foreign countries, this paper collected and sorted out the traditional application of Moringa recorded in the ancient medical books and historical materials of countries and regions along the ancient Silk Road. According to preliminary research, the earliest record of Moringa in China can be traced back to The Bower Manuscript(volume Ⅱ)(about the 4 th-6 th century A.D.) unearthed in Kuqa, Xinjiang. Around the 8 th century, with the communication between countries along the ancient Silk Road becoming prosperous, more and more medical books containing Moringa and its prescriptions were introduced to Tibet, Xinjiang and other places in today's China. The leaves, root bark, seeds and stem bark of Moringa all can be used for medicinal purposes and are recorded in The Ayurvedic Pharmacopoeia of India(API). Among them, Moringa leaves have been approved as a new resource food in China. According to the API, it is of cold property and sweet taste, its post-digestive effect is sweet and has the functions of removing wind, bile and fat, relieving pain, killing abdominal worms, moistening skin, brightening eyes and clearing brain. It can be used to treat edema, parasitic diseases, spleen diseases, abscess, tumor, pharyngeal swelling and other diseases. This study explored and organized the historical evidence of communication through the Silk Road and traditional application records of Moringa, in order to provide the evidence of traditional medicine basis, medicine property and efficacy application reference for the realization of the introduction of Moringa as a new resource of traditional Chinese medicine.

Increased expression of Sonic hedgehog restores diabetic endothelial progenitor cells and improves cardiac repair after acute myocardial infarction in diabetic mice.

Damaged endothelial progenitor cells (EPCs) are associated with poor prognosis in diabetic myocardial infarction (DMI). Our previous studies revealed that an impaired Sonic hedgehog (Shh) pathway contributes to insufficient function in diabetic EPCs; however, the roles of the Shh pathway in diabetic EPC apoptosis under basal and hypoxic/ischemic conditions remain unknown. Therefore, the present study investigated whether Shh revitalized diabetic EPCs and consequently improved the deteriorative status of DMI. For this purpose, streptozotocin injection was used in male C57/BL6 mice to induce type­1 diabetes, and diabetic EPCs were isolated from the bone marrow. Apoptosis, cell function, and protein expression were investigated in EPCs in vitro. Mouse hearts were injected with adenovirus Shh­modified diabetic EPCs (DM­EPCShh) or control DM­EPCNull immediately after coronary artery ligation in vivo. Cardiac function, capillary numbers, fibrosis, and cell apoptosis were then detected. First, the in vitro results demonstrated that the apoptosis of diabetic EPCs was reduced following treatment with Shh protein for 24 h, under normal or hypoxic conditions. BMI1 proto­oncogene (Bmi1), an antiapoptotic protein found in several cells, was reduced in diabetic EPCs under normal or hypoxic conditions, but was upregulated after Shh protein stimulation. When Bmi1­siRNA was administered, the antiapoptotic effect of Shh protein was significantly reversed. In addition, p53, a Bmi1­targeted gene, was demonstrated to mediate the antiapoptotic effect of the Shh/Bmi1 pathway in diabetic EPCs. The Shh/Bmi1/p53 axis also enhanced the diabetic EPC function. In vivo, Shh­modified diabetic EPCs exhibited increased EPC retention and decreased apoptosis at 3 days post­DMI. At 14 days post­DMI, these cells presented enhanced capillary density, reduced myocardial fibrosis and improved cardiac function. In conclusion, the present results demonstrated that the Shh pathway restored diabetic EPCs through the Shh/Bmi1/p53 axis, suppressed myocardial apoptosis and improved myocardial angiogenesis, thus reducing cardiac fibrosis and finally restoring myocardial repair and cardiac function in DMI. Thus, the Shh pathway may serve as a potential target for autologous cell therapy in diabetic myocardial ischemia.

Minocycline protects against myocardial ischemia/reperfusion injury in rats by upregulating MCPIP1 to inhibit NF-κB activation.

Minocycline is a tetracycline antibiotic and has been shown to play a protective role in cerebral and myocardial ischemia/reperfusion (I/R). However, the underlying mechanism remains unclear. Herein, we investigated whether monocyte chemotactic protein-induced protein-1 (MCPIP1), a negative regulator of inflammation, was involved in the minocycline-induced cardioprotection in myocardial I/R in vivo and in vitro models. Myocardial ischemia was induced in rats by left anterior descending coronary artery occlusion for 1 h and followed by 48 h reperfusion. Minocycline was administered prior to ischemia (45 mg/kg, ip, BID, for 1 d) and over the course of reperfusion (22.5 mg/kg, ip, BID, for 2 d). Cardiac function and infarct sizes were assessed. Administration of minocycline significantly decreased the infarct size, alleviated myocardial cell damage, elevated left ventricle ejection fraction, and left ventricle fractional shortening following I/R injury along with significantly decreased pro-inflammatory cytokine IL-1ß and monocyte chemoattractant protein-1 (MCP-1) levels in heart tissue. H9c2 cardiomyocytes were subjected to oxygen glucose deprivation (OGD) followed by reoxygenation (OGD/R). Pretreatment with minocycline (1-50 µmol/L) dose-dependently increased the cell viability and inhibited OGD/R-induced expression of MCP-1 and IL-6. Furthermore, minocycline dose-dependently inhibited nuclear translocation of NF-κB p65 in H9c2 cells subjected to OGD/R. In both the in vivo and in vitro models, minocycline significantly increased MCPIP1 protein expression; knockdown of MCPIP1 with siRNA in H9c2 cells abolished all the protective effects of minocycline against OGD/R-induced injury. Our results demonstrate that minocycline alleviates myocardial I/R injury via upregulating MCPIP1, then subsequently inhibiting NF-κB activation and pro-inflammatory cytokine secretion.

Effects of oral selenium and magnesium co-supplementation on lipid metabolism, antioxidative status, histopathological lesions, and related gene expression in rats fed a high-fat diet.

BACKGROUND: Supplementation with Selenium (Se) has been shown to lower blood cholesterol and increase tissue concentrations of the antioxidant glutathione (GSH); however, the effects of Se supplementation, in combination with supplemental magnesium, on high fat-induced hyperlipidemia have not been studied. This study was designed to elucidate the effects of oral selenium and magnesium co-supplementation on antihyperlipidemic and hepatoprotective, antioxidative activities, and related gene expression in a hyperlipidemic rat model. METHODS: Forty male Sprague Dawley rats were divided into 4 groups: one group served as control group (CT), provided control diet; The other groups were made hyperlipidemic with high-fat diet; specifically, a high-fat diet group (HF); low-dose selenium (0.05 mg/kg·bw) + low-dose magnesium (5.83 mg/kg·bw) supplement high-fat diet group (HF + LSe + LMg) and high-dose selenium (0.10 mg/kg·bw) + high-dose magnesium (58.33 mg/kg·bw) supplement high-fat diet group (HF + HSe + HMg). The first 4 weeks of the experiment was a hyperlipidemia inducing period using high-fat diet and the following 8 weeks involved in selenium and magnesium co-supplementation. On day 0, 20, 40 and 60 of the intervention, lipid profile was measured. At the end of the 12-week experiments, final blood and liver samples were collected for the measurements of lipid profile, antioxidative indexes, pathological examination, and liver lipid metabolism related gene expression. RESULTS: The elevated levels of serum and liver total cholesterol (TC) and serum LDL-C induced by feeding high-fat diets were significantly reduced by low-dose Se and Mg co-supplementation. Both doses of selenium and magnesium co-supplementation notably decreased the blood and liver TG levels, liver function indexes ALT and AST and the ratio of TC/HDL-C and TG/HDL-C. In contrast, Se and Mg supplementation showed a substantial increase in Se-dependent glutathione peroxidase (GSH-Px) and SOD activities and an significant reduce of level of MDA of hyperlipidemic rats. Oil Red O staining showed that selenium and magnesium co-supplementation significantly reduced hepatic intracellular triacylglycerol accumulation. H&E staining also showed that selenium and magnesium co-supplementation can attenuate liver steatosis. Selenium and magnesium co-supplementation remarkably inhibited the mRNA expression level of hepatic lipogenesis genes liver X receptor alpha (LXRα),SREBP-1c and FASN (fatty acid synthase), regulated the mRNA expression levels of liver enzymes related to cholesterol metabolism, including the down regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and the upregulation of cholesterol 7α-hydroxylase (CYP7A1) and lecithin cholesterol acyltransferase (LCAT) in the liver of hyperlipidemia rats. CONCLUSIONS: Oral selenium and magnesium co-supplementation inhibited an increase of lipid and liver profile and liver function index induced by a high-fat diet, and enhanced the activity of the antioxidant enzymes. Selenium combined with magnesium is a promising therapeutic strategy with lipid-lowering and antioxidative effects that protects the liver against hyperlipidemia.

Subchronic toxicity study in rats evaluating genetically modified DAS-81419-2 soybean.

A 90-day feeding study in rats was conducted to evaluate the subchronic oral toxicity of genetically modified (GM) DAS-81419-2 soybean. Wistar rats were fed with diets containing toasted soybean meal produced from DAS-81419-2 soybean grain that expresses the Cry1F, Cry1Ac, and Pat proteins or containing conventional soybean at doses of 30.0%, 15.0%, 7.5%, or 0% (control group) for 90 consecutive days. The general behavior, body weight and food consumption were observed. At the middle and end of the experiment, blood, serum, and urine samples were collected for biochemical assays. At the conclusion of the study, the internal organs were weighed and histopathological examination was completed. The rats exhibited free movement and shiny coats without any abnormal symptoms or abnormal secretions in their noses, eyes, or mouths. There were no adverse effects on body weight in GM soybean groups and conventional soybean groups. No biological differences in hematological, biochemical, or urine indices were observed. No significant differences in relative organ weights were detected between the experimental groups and the control group. No histopathological changes were observed. Under the conditions of this study, DAS-81419-2 soybean did not cause any treatment-related effects in Wistar rats following 90 days of dietary administration.

Identification of a sustainable two-plant diet that effectively prevents age-related metabolic syndrome and extends lifespan in aged mice.

The current system of food production is linked to both the increasing prevalence of chronic disease and the deterioration of the environment, and thereby calls for novel ways of producing nutritious foods in a sustainable manner. In the "longevity village" of Bama, China, we have identified two plant foods, hemp seed and bitter vegetable (Sonchus oleraceus), that are commonly consumed by its residents and grow abundantly in unfarmed land without fertilizers or pesticides. Here, we show that a diet composed of these two foods (the "HB diet") provides a sufficient variety of nutrients and confers significant health benefits. Aged mice allowed ad libitum access to the HB diet not only had longer life spans and improved cognitive function but were also protected against age-related metabolic syndrome, fatty liver, gut dysbiosis and chronic inflammation compared to aged mice fed a control Western diet. Furthermore, longevity-related genes (including 5'adenosine monophosphate-activated protein kinase, sirtuin 1, nuclear respiratory factor 1 and forkhead box O3) were significantly up-regulated, while aging-related genes (including mammalian target of rapamycin and nuclear factor kappa B) were down-regulated. These results demonstrate that the HB diet is capable of promoting health and longevity, and present a sustainable source of healthy foods that can help control the prevalence of chronic diseases and reduce agricultural impact on the environment.

Handgrip Strength as a Predictor of Nutritional Status in Chinese Elderly Inpatients at Hospital Admission.

OBJECTIVE: To assess nutritional status and define gender- and age-specific handgrip strength (HGS) cut-point values for malnutrition or nutritional risk in elderly inpatients. METHODS: A cross-sectional study of 1,343 elderly inpatients was conducted in the Chinese PLA General Hospital. Nutrition Risk Screening (NRS 2002) and Subjective Global Assessment (SGA) were administered. Anthropometric measurements and blood biochemical indicators were obtained using standard techniques. The gender- and age-specific receiver operating characteristic (ROC) curves were constructed to evaluate the HGS for nutritional status by SGA and NRS 2002. Sensitivity, specificity, and areas under the curves (AUCs) were calculated. RESULTS: According to NRS 2002 and SGA, 63.81% of elderly inpatients were at nutritional risk and 28.22% were malnourished. Patients with higher HGS had an independently decreased risk of malnutrition and nutritional risk. The AUCs varied between 0.670 and 0.761. According to NRS 2002, the optimal HGS cut-points were 27.5 kg (65-74 years) and 21.0 kg (75-90 years) for men and 17.0 kg (65-74 years) and 14.6 kg (75-90 years) for women. According to SGA, the optimal HGS cut-points were 24.9 kg (65-74 years) and 20.8 kg (75-90 years) for men and 15.2 kg (65-74 years) and 13.5 kg (75-90 years) for women. CONCLUSION: Elderly inpatients had increased incidence of malnutrition or nutritional risk. HGS cut-points can be used for assessing nutritional status in elderly inpatients at hospital admission in China.

Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids.

BACKGROUND: Exposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed. METHODS: We used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed. RESULTS: We discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure). CONCLUSIONS: These results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure. GENERAL SIGNIFICANCE: Our findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution.

The Association of Maternal Body Composition and Dietary Intake with the Risk of Gestational Diabetes Mellitus during the Second Trimester in a Cohort of Chinese Pregnant Women.

OBJECTIVE: To investigate the association of maternal body composition and dietary intake with the risk of gestational diabetes mellitus (GDM). METHODS: A total 154 GDM subjects and 981 controls were enrolled in a prospective cohort study in 11 hospitals from May 20, 2012 to December 31, 2013. Bioelectrical impedance analysis and dietary surveys were used to determine body composition and to evaluate the intake of nutrients in subjects at 21-24 weeks' gestation (WG). Logistic regression analysis was applied to explore the relationships of maternal body composition and dietary intake with the risk of GDM morbidity. RESULTS: Age, pre-pregnant body weight (BW), and body mass index (BMI) were associated with increased risk of GDM. Fat mass (FM), fat mass percentage (FMP), extracellular water (ECW), BMI, BW, energy, protein, fat, and carbohydrates at 21-24 WG were associated with an increased risk of GDM. In contrast, fat free mass (FFM), muscular mass (MM), and intracellular water (ICW) were associated with a decreased risk of GDM. CONCLUSION: Maternal body composition and dietary intake during the second trimester of pregnancy were associated with the risk of GDM morbidity.