Inhibition of calcium-sensing receptor by its antagonist promotes gastrointestinal motility in a Parkinson's disease mouse model.

BACKGROUND: The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with Parkinson's disease (PD). METHODS: CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model. FINDINGS: Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips. INTERPRETATION: CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive.

Baohuoside I suppresses the NLRP3 inflammasome activation via targeting GPER to fight against Parkinson's disease.

BACKGROUND: Accumulating evidence indicates the crucial role of microglia-mediated inflammation and the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in the pathogenesis of Parkinson's disease (PD). Baohuoside I, a natural flavonoid extracted from Herba Epimedii, has been shown to possess anti-inflammatory effects, but its potential neuroprotective effects and mechanism against PD have not been documented. STUDY DESIGN AND METHODS: The anti-inflammatory effects of Baohuoside I were evaluated by LPS-induced BV2 cells or primary microglia isolated from wide type or G protein-coupled estrogen receptor (GPER) gene knockout mice. The underlying mechanism related to GPER-mediated NLRP3 inflammasome inhibition was further explored using LPS-induced GPER+/+ or GPER-/- mouse models of PD. The neuroprotective effects of Baohuoside I were detected through western blot analysis, real-time PCR, molecular docking, mouse behavioral tests, immunofluorescence, and immunohistochemistry. RESULTS: Baohuoside I significantly alleviated LPS-induced neuroinflammation by inhibiting the activation of NF-κB signal and the increase of pyroptosis levels as evidenced by the downregulated expression of pyroptosis-related proteins (NLRP3, ASC, pro-Caspase-1, IL-1ß) in microglia cells. Intragastric administration of Baohuoside I protected against LPS-induced motor dysfunction and loss of dopaminergic neurons, reduced pro-inflammatory cytokines expressions, and inhibited microglial (Iba-1) and astrocyte (GFAP) activation in the nigrostriatal pathway in LPS-induced mouse model of PD. Pretreatment with GPER antagonist G15 in microglia cells or GPER gene deletion in mice significantly blocked the inhibitory effects of Baohuoside I on LPS-induced neuroinflammation and activation of the NLRP3/ASC/Caspase-1 pathway. Molecular docking further indicated that Baohuoside I might bind to GPER directly with a binding energy of -10.4 kcal/mol. CONCLUSION: Baohuoside I provides neuroprotective effects against PD by inhibiting the activation of the NF-κB signal and NLRP3/ASC/Caspase-1 pathway. The molecular target for its anti-inflammatory effects is proved to be GPER in the PD mouse model. Baohuoside I may be a valuable anti-neuroinflammatory agent and a drug with well-defined target for the treatment of PD.

Low and high doses of oral maslinic acid protect against Parkinson's disease via distinct gut microbiota-related mechanisms.

The use of oral agents that can modify the gut microbiota (GM) could be a novel preventative or therapeutic option for Parkinson's disease (PD). Maslinic acid (MA), a pentacyclic triterpene acid with GM-dependent biological activities when it is taken orally, has not yet been reported to be effective against PD. The present study found both low and high dose MA treatment significantly prevented dopaminergic neuronal loss in a classical chronic PD mouse model by ameliorating motor functions and improving tyrosine hydroxylase expressions in the substantia nigra pars compacta (SNpc) and increasing dopamine and its metabolite homovanillic acid levels in the striatum. However, the effects of MA in PD mice were not dose-responsive, since similar beneficial effects for low and high doses of MA were observed. Further mechanism studies indicated that low dose MA administration favored probiotic bacterial growth in PD mice, which helped to increase striatal serotonin, 5-hydroxyindole acetic acid, and γ-aminobutyric acid levels. High dose MA treatment did not influence GM composition in PD mice but significantly inhibited neuroinflammation as indicated by reduced levels of tumor necrosis factor alpha and interleukin 1ß in the SNpc; moreover, these effects were mainly mediated by microbially-derived acetic acid in the colon. In conclusion, oral MA at different doses protected against PD via distinct mechanisms related to GM. Nevertheless, our study lacked in-depth investigations of the underlying mechanisms involved; future studies will be designed to further delineate the signaling pathways involved in the interactive actions between different doses of MA and GM.

Epimedin B exerts neuroprotective effect against MPTP-induced mouse model of Parkinson's disease: GPER as a potential target.

Mitochondrial dysfunction and oxidative stress play important roles in the neuropathogenesis of Parkinson's disease (PD). Epimedin B, the second highest active ingredient in the flavonoids of Herba Epimedii, has been proven effective in treating osteoporosis and oxaliplatin-induced peripheral neuropathy. The present study aims to investigate the neuroprotective effects of Epimedin B in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-induced mouse model of PD, and the involvement of G protein-coupled estrogen receptor (GPER)-mediated anti-apoptosis as well as anti-endoplasmic reticulum stress. Molecular docking revealed that Epimedin B could directly bind to GPER at the same site as GPER agonist G1 and the binding energy was - 7.3 kcal/mol. Epimedin B treatment ameliorated MPTP-induced motor dysfunction and alleviated the decreased contents of DA with its metabolites in the striatum and the loss of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantial nigra pars compacta (SNpc). Epimedin B treatment markedly prevented MPTP-induced changes in apoptosis-related protein Bcl-2 and Bax as well as endoplasmic reticulum stress-related protein glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). Pharmacological blockade with GPER antagonist G15 could antagonize these neuroprotective effects of Epimedin B on the nigrostriatal system. Moreover, the anti-apoptosis and anti-endoplasmic reticulum stress effects of Epimedin B against MPTP toxicity were significantly reduced in GPER knockout (GPER-/-) mice. The present study provides the first evidence that Epimedin B can protect against MPTP-induced PD mice model. GPER may be a potential target for the neuroprotective effect of Epimedin B against PD.

Solid-state-cultured mycelium of Antrodia camphorata exerts potential neuroprotective activities against 6-hydroxydopamine-induced toxicity in PC12 cells.

Antrodia camphorata (A. camphorata) is an edible fungus containing various bioactive compounds generally used for health benefits. This study aimed to explore the potential neuroprotective activities of solid-state-cultured mycelium of A. camphorata (SCMAC) against Parkinson's disease (PD), as well as the underlying mechanism using an in vitro 6-hydroxydopamine (6-OHDA)-induced PC12 cell model. The results showed that SCMAC extracts alleviated cell toxicity induced by 6-OHDA and the loss of dopaminergic neurons, which was confirmed by the increase of cell viabilities, inhibition of cell apoptosis, the upregulation of tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels and the downregulation of α-Synuclein level. After purification, 11 compounds were identified by the NMR technique, including a quinone, four phenolic acid derivatives, three ubiquinone derivatives, two alkaloids, and a triterpenoid. The present study suggests that SCMAC could be an attractive candidate for the prevention or treatment of PD. PRACTICAL APPLICATIONS: Parkinson's disease seriously affects the lifetime and quality of the elder population for a long history. Long-term consumption of L-DOPA will result in side effects, such as developing abnormal involuntary movements called dyskinesia. This study showed that natural SCMAC extracts could be a potential therapeutic agent for the treatment of neurodegenerative disorder.

Polymannuronic acid prebiotic plus Lacticaseibacillus rhamnosus GG probiotic as a novel synbiotic promoted their separate neuroprotection against Parkinson's disease.

Gut microbiota (GM) dysbiosis plays key roles in aggravating Parkinson's disease (PD) and discovery of agents targeting GM may open new avenues for PD therapy. This study aims to investigate the potentially neuroprotective effects and underlying mechanisms of polymannuronic acid (PM) or Lacticaseibacillus rhamnosus GG (LGG), or their combination in a chronic PD mice model. Our results found oral administration of prebiotic PM or LGG separately or in combination for 5 weeks could prevent dopaminergic neuronal loss via improving reduced walking distance and activity or weakened muscle strength in behavior tests by enhancing tyrosine hydroxylase (TH) gene and/or protein expressions in the midbrain and striatum of PD mice. Strikingly, PM and LGG in combination had a much better neuroprotective effects than separate PM or LGG. PM provided neuroprotection via a short chain fatty acids (SCFAs)-mediated anti-inflammation and anti-apoptosis mechanism. The neuroprotective effects of LGG might be associated with its ability to improve the expression of striatal glial cell-derived neurotrophic factor (GDNF) and to increase bacteria abundance of Clostridiales. When PD mice were administered with PM + LGG, PM as prebiotic favored bacterial growth (from Bacilli class to Lactobacillus genus) in the colon, which helped to improve blood brain barrier (BBB) integrity and increase brain-derived neurotrophic factor (BDNF) and GDNF expressions, thereby inhibiting apoptosis in the striatum. In conclusion, PM and LGG in combination promoted their separate neuroprotection against PD. Our study discovered and testified a novel synbiotic that might be one of the ideal oral agents for PD therapy.

Alginate and its Two Components Acted Differently Against Dopaminergic Neuronal Loss in Parkinson's Disease Mice Model.

SCOPE: This study aims to investigate and compare the potentially neuroprotective effects and underlying mechanisms for brown seaweed polysaccharides (PS) of Alginate (Alg) and its two components, including polymannuronic acid (PM) and polyguluronic acid (PG), against Parkinson's disease (PD) pathogenesis. METHODS AND RESULTS: Model mice of PD are pretreated with Alg or PM or PG, separately via oral gavage once per day for four weeks. Our results found PM improved motor functions of PD mice, but Alg or PG did not. PM or PG, but not Alg, can prevent dopaminergic neuronal loss by increasing tyrosine hydroxylase (TH) expressions in midbrain of PD mice. The neuroprotective effects of PM rely on its anti-inflammation effects and its ability to improve striatal neurotransmitters (serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA)) levels in PD mice. PM inhibits inflammation, but PG or Alg induces inflammation in systemic circulation of PD mice. The neuroprotection provided by PG might be related to its ability to increase striatal neurotransmitter of 5-hydroxyindole acetic acid levels in PD mice. CONCLUSION: PM plays better than PG to provide neuroprotection, but Alg did not show any neuroprotection against PD. Alg and its two components acted differently in preventing dopaminergic neuronal loss in PD mice.

An Investigation of the Risk Factors Associated With Anti-Tuberculosis Drug-Induced Liver Injury or Abnormal Liver Functioning in 757 Patients With Pulmonary Tuberculosis.

Objectives: To identify the risk factors associated with anti-tuberculosis drug-induced liver injury (AT-DILI) or abnormal living functioning from 757 patients with pulmonary tuberculosis (TB) registered at Nanshan Center for Chronic Disease Control (Nanshan CCDC), Shenzhen, Guangdong Province, China. Design and methods: We identified 757 TB patients who met our inclusion criteria by screening the Hospital Information System (HIS) at Nanshan CCDC. Next, we identified positive cases of AT-DILI or abnormal liver functioning based on results of the first-time liver function tests (LFTs) after taking anti-TB drugs. The χ2 test was used to relate the positive rate with a variety of factors. A logistic regression model was also used to identify statistically significant risk factors. Results: Of the 757 patients, the positive rate of AT-DILI or abnormal liver functioning was 37.9% (287/757). Univariate analysis revealed that the positive rate was 42.91% (212/494) for males and 28.52% (75/263) for females. The positive rate was significantly higher in males (p <0.001). Patients with an annual income of 9,231-13,845 USD had a significantly higher positive rate (67.35%; 33/49) than those with an income of 1,540-4616 USD (37.97%; 30/79) (p = 0.022). The most frequent prescription regime among positive cases was a 2 months supply of fixed dose combination Ethambutol Hydrochloride, Pyrazinamide, Rifampicin and Isoniazid Tablets (Ⅱ) 450 mg) followed by a 4 months supply of fixed dose combination Rifampin and Isoniazid Capsules (2FDC-HRZE half/4FDC-HR) at 56.03% (144/257). The least frequent prescription regime was a 2 months supply of fixed dose combination Rifampin, Isoniazid and Pyrazinamide Capsules with Ethambutol independently followed by a 4 months supply of fixed dose combination Rifampin and Isoniazid Capsules (2FDC-HRZ + EMB/4FDC-HR) at 24.27% (25/103). The difference between these two different regimes was significant (p = 0.022). With an increase in the duration of medication, patients under various prescription regimes all showed a gradual increase in the positive rate of AT-DILI or abnormal liver functioning. Conclusion: We identified several risk factors for the occurrence of AT-DILI or abnormal liver functioning, including gender, annual income, prescription regime, dosage, and treatment time.

Methane-dependent selenate reduction by a bacterial consortium.

Methanotrophic microorganisms play a critical role in controlling the flux of methane from natural sediments into the atmosphere. Methanotrophs have been shown to couple the oxidation of methane to the reduction of diverse electron acceptors (e.g., oxygen, sulfate, nitrate, and metal oxides), either independently or in consortia with other microbial partners. Although several studies have reported the phenomenon of methane oxidation linked to selenate reduction, neither the microorganisms involved nor the underlying trophic interaction has been clearly identified. Here, we provide the first detailed evidence for interspecies electron transfer between bacterial populations in a bioreactor community where the reduction of selenate is linked to methane oxidation. Metagenomic and metaproteomic analyses of the community revealed a novel species of Methylocystis as the most abundant methanotroph, which actively expressed proteins for oxygen-dependent methane oxidation and fermentation pathways, but lacked the genetic potential for selenate reduction. Pseudoxanthomonas, Piscinibacter, and Rhodocyclaceae populations appeared to be responsible for the observed selenate reduction using proteins initially annotated as periplasmic nitrate reductases, with fermentation by-products released by the methanotrophs as electron donors. The ability for the annotated nitrate reductases to reduce selenate was confirmed by gene knockout studies in an isolate of Pseudoxanthomonas. Overall, this study provides novel insights into the metabolic flexibility of the aerobic methanotrophs that likely allows them to thrive across natural oxygen gradients, and highlights the potential role for similar microbial consortia in linking methane and other biogeochemical cycles in environments where oxygen is limited.

Colonic Dopaminergic Neurons Changed Reversely With Those in the Midbrain via Gut Microbiota-Mediated Autophagy in a Chronic Parkinson's Disease Mice Model.

The role of gut-brain axis in the pathogenesis of Parkinson's disease (PD) have become a research hotspot, appropriate animal model to study gut-brain axis in PD is yet to be confirmed. Our study employed a classical PD mice model achieved by chronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection to study concurrent changes of dopaminergic neurons in the midbrain and the colon of mice. Our results showed such a PD model exhibited apparent locomotor deficits but not gastrointestinal dysfunction. Tyrosine hydroxylase expressions and dopamine content reduced greatly in the substantia nigra pars compacta (SNpc) or striatum, but increased in the colon of PD mice. Mechanism investigation indicated autophagy activity and apoptosis were stimulated in the SNpc, but inhibited in the colon of PD mice. Interplay of gut microbiota (GM) and autophagy in response to chronic MPTP injection led to GM dysbiosis and defective autophagy in mice colon. Meanwhile, fecal short chain fatty acids (SCFAs), acetate and propionate in particular, declined greatly in PD mice, which could be attributed to the decreased bacteria abundance of phylum Bacteroidetes, but increased abundance of phylum Firmicutes. GM dysbiosis derived fecal SCFAs might be one of the mediators of downregulated autophagy in the colon of PD mice. In conclusion, colonic dopaminergic neurons changed in the opposition direction with those in the midbrain via GM dysbiosis-mediated autophagy inhibition followed by suppressed apoptosis in response to chronic MPTP injection. Such a chronic PD mice model might not be an ideal model to study role of gut-brain axis in PD progression.

Polymannuronic acid prevents dopaminergic neuronal loss via brain-gut-microbiota axis in Parkinson's disease model.

The study aims to investigate the potentially neuroprotective effects and underlying mechanisms for brown seaweed polysaccharide of polymannuronic acid (PM) against Parkinson's disease (PD) pathogenesis. PD model mice were pretreated with PM via oral gavage once per day for 4 weeks and the preventative effects of PM against neuronal loss together with its modulation on brain-gut-microbiota axis were systematically explored. The results showed PM administration improved motor functions by preventing dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) and enhanced contents of striatal homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA) and γ-aminobutyric acid (GABA) in PD mice. PM significantly alleviated inflammation in gut, brain and systemic circulation as shown by reduced levels or expressions of pro-inflammatory cytokines concurrently and inhibited mitogen-activated protein kinases (MAPK) signaling pathway in mice colon. Meanwhile, PM greatly improved integrity of intestinal barrier and blood brain barrier (BBB) as indicated by increased expressions of tight junction associated proteins in both mice colon and SNpc. Further studies indicated PM treatment resulted in changes of gut microbial compositions, together with great alterations of digestion and metabolism of dietary proteins and fats, which led to surge increase of fecal short chain fatty acids (SCFAs) in the colon of PD mice. In conclusion, pre-administration of PM could provide neuroprotective effects against PD pathogenesis by suppressing inflammation in gut, brain and systemic circulation, and by improving integrity of intestinal barrier and BBB. PM might modulate brain-gut-microbiota axis, at least in part, via gut microbiota derived SCFAs as mediators.

Chuanxiong (Rhizome of Ligusticum chuanxiong) Protects Ovariectomized Hyperlipidemic Rats from Bone Loss.

Oxidative stress (OS) is the common mechanism for age-related diseases. The co-occurrence of osteoporosis (OP) and cardiovascular disease (CVD) in postmenopausal women makes it warranted to find a holistic approach for treatment of multiple diseases or conditions. The rhizome of Ligusticum chuanxiong Hort. (CX), which has high anti-oxidant properties and is widely used for CVD treatment in China, might be the potential candidate. In the present study, CX ethanol extract (CXE) was applied to H2O2 induced MG63 cells to study its effects and mechanisms on osteoblastogenesis against OS. CXE was then administered to six-month-old Sprague Dawley sham or ovariectomized (OVX) rats fed either a low saturated fat-sucrose (LFS) or a high fat-sucrose (HFS) diet for 12 weeks, to confirm its anti-osteoporotic effects. The results demonstrated that CXE directly improved proliferation and differentiation in vitro in an H2O2-induced osteoblast cell model by attenuating cellular reactive oxygen species levels and inhibiting osteoblast apoptosis via PI3K/Akt signaling pathway. CXE significantly improved bone properties as revealed by the increase in trabecular bone mineral density and decrease in trabecular separation at proximal metaphysis of the tibia (PT) in HFS-fed OVX rats but not in LFS-fed OVX rats. CXE ameliorated dyslipidemia, greatly reduced lipid deposition and malondialdehyde levels, improved activities of superoxide dismutase, catalase and glutathione peroxidase in the livers of HFS-fed OVX rats. In conclusion, CXE could favor osteoblastogenesis against OS. The ability of CXE to reduce bone loss in HFS-fed OVX rats was associated with its abilities to correct dyslipidemia, and reduce lipid deposition and OS levels.

Paricalcitol alleviates lipopolysaccharide-induced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation.

Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant activated microglia play a pivotal role in the pathogenesis of depression. Paricalcitol (Pari), a vitamin D2 analogue, has been demonstrated to exert anti-inflammative effects on renal and cardiovascular diseases. In this study, mice were pretreated with Pari before being induced to acute depression-like behaviors by systemic lipopolysaccharide (LPS) injection. To determine the therapeutic effects of Pari, alterations in acute body weight, sucrose preference, forced swimming and tail suspension tests were assessed. Then, alterations of pro-inflammation cytokine IL1-ß level and microglia activity in the hypothalamus, which are involved in the pathophysiology of depression, were examined. The results showed that Pari significantly alleviated systemic LPS injection induced depressive-like behaviors as shown by increased sucrose preference and decreased TST and FST immobility. Pari could specifically regulate microglia-mediated neuroinflammation process and local activity of renin-angiotensin system to exert its anti-depressant effects. This study demonstrated a potential for paricalcitol in treating depressive symptoms induced by systemic inflammation, particularly in patients with chronic hypertension.

Oleanolic Acid and Ursolic Acid Improve Bone Properties and Calcium Balance and Modulate Vitamin D Metabolism in Aged Female Rats.

Oleanolic acid (OA) and ursolic acid (UA) are the major chemical constituents in Fructus Ligustri Lucidi (FLL), a kidney-tonifying Chinese herb that is previously shown to improve bone properties and enhance calcium balance in aged female rats. The present study was designed to study if OA and UA act as the active ingredients in FLL to exert the positive effects on bone and mineral metabolism in aged rats. Aged (13-month-old) Sprague-Dawley female rats were randomly assigned to four groups with oral administration of drug or vehicle treatment for 12 weeks: medium calcium diet (MCD, 0.6% calcium), high calcium diet (HCD, 1.2% calcium), MCD + FLL (700 mg/kg/day), MCD + OA (23.6 mg/kg/day) + UA (8.6 mg/kg/day). A group of mature (3-month-old) female rats fed with MCD was included as positive control. The results demonstrated that FLL and OA+UA increased bone mineral density and improved microarchitectural properties of aged female rats. The osteoprotective effects of FLL and OA+UA might be, at least in part, associated with their actions on enhancing calcium balance and suppressing age-induced secondary hyperparathyroidism in aged female rats. FLL and OA+UA also significantly induced renal CYP27B1 protein expression and OA+UA treatment decreased CYP24A1 mRNA and protein expressions in aged female rats. In addition, FLL and OA+UA significantly increased the promoter activity, mRNA and protein expressions of renal CYP27B1 in vitro in human proximal tubule HKC-8 cells. The present findings suggest that OA+UA can be regarded as the active ingredients of FLL and might be a potential drug candidate for prevention and treatment of osteoporosis.

Bone Protective Effects of Danggui Buxue Tang Alone and in Combination With Tamoxifen or Raloxifene in vivo and in vitro.

Danggui Buxue Tang (DBT), a traditional Chinese Medicine decoction containing Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), is commonly prescribed for women in China as a remedy for menopausal symptoms. Previous study indicated that DBT stimulated cell growth and differentiation of human osteosarcoma MG-63 cells and exhibited estrogenic properties via estrogen receptors (ERs). The present study aimed to study the bone protective effects of DBT and its potential interactions with selective estrogen receptor modulators (SERMs, tamoxifen and raloxifene) in both in vivo and in vitro models as they act via similar ERs. Six-month-old Sprague-Dawley rats were randomly assigned to the following treatments for 12 weeks: (1) sham-operated control group with vehicle (sham), (2) ovariectomized group with vehicle (OVX), (3) OVX with 17ß-estradiol (E2, 2.0 mg/kg day), (4) OVX with tamoxifen (Tamo, 1.0 mg/kg day), (5) OVX with raloxifene (Ralo, 3.0 mg/kg day), (6) OVX with DBT (DBT, 3.0 g/kg day), (7) OVX with DBT+Tamoxifen (DBT+Tamo), and (8) OVX with DBT+Raloxifene (DBT+Ralo). Effects of DBT and potential interactions between DBT and SERMs were also evaluated in MG-63 cells. DBT, tamoxifen, raloxifene, and their combinations significantly increased bone mineral density (BMD) and improved trabecular bone properties, including bone surface (BS), trabecular bone number (Tb.N), and trabecular bone separation (Tb.Sp), as well as restored changes in bone turnover biomarkers and mRNA expression of genes involved in bone metabolism in OVX rats. Furthermore, DBT, SERMs, and their combinations significantly increased serum estradiol and suppressed follicle stimulating hormone and luteinizing hormone in OVX rats, suggesting the possible involvement of the hypothalamus-pituitary-gonadal axis in mediating their bone protective effects. However, SERMs, but not DBT, significantly increased uterus index in OVX rats. DBT significantly induced ALP activity and estrogen response element-dependent transcription in MG-63 cells. Our study demonstrated that DBT alone and in combinations with SERMs could exert bone protective effects in vitro and in vivo.

Oleanolic Acid Exerts Osteoprotective Effects and Modulates Vitamin D Metabolism.

Oleanolic acid (OA) is a triterpenoid with reported bone anti-resorption activities. The present study aimed to characterize its bone protective effects in vivo and to study its effects on vitamin D metabolism, both in vivo and in vitro. OA significantly increased bone mineral density, improved micro-architectural properties, reduced urinary Ca excretion, increased 1,25(OH)2D3 and renal CYP27B1 mRNA expression in mature C57BL/6 ovariectomised (OVX) mice. OA also improved bone properties, Ca balance, and exerted modulatory effects on renal CYP27B1 and CYP24A1 expressions in aged normal female Sprague-Dawley rats. In addition, OA significantly increased renal CYP27B1 mRNA and promoter activity, and suppressed CYP24A1 mRNA and protein expressions in human proximal tubule HKC-8 cells. OA exerted bone protective effects in mature OVX mice and aged female rats. This action on bone might be, at least in part, associated with its effects on Ca and vitamin D metabolism. The present findings suggest that OA is a potential drug candidate for the management of postmenopausal osteoporosis.

Reye syndrome and sudden death symptoms after oral administration of nimesulide due to upper respiratory tract infection in a boy / 中国当代儿科杂志

A boy aged 6 years and 3 months developed upper respiratory tract infection and pyrexia 2 months ago and was given oral administration of nimesulide by his parents according to directions. Half an hour later, the boy experienced convulsions and cardiopulmonary arrest, and emergency examination found hypoketotic hypoglycemia, metabolic acidosis, significant increases in serum aminotransferases and creatine kinase, and renal damage. Recovery of consciousness and vital signs was achieved after cardiopulmonary resuscitation, but severe mental and movement regression was observed. The boy had a significant reduction in free carnitine in blood and significant increases in medium- and long-chain fatty acyl carnitine, urinary glutaric acid, 3-hydroxy glutaric acid, isovalerylglycine, and ethylmalonic acid, suggesting the possibility of multiple acyl-CoA dehydrogenase deficiency. After the treatment with vitamin B2, L-carnitine, and bezafibrate, the boy gradually improved, and reexamination after 3 months showed normal biochemical parameters. The boy had compound heterozygous mutations in the ETFDH gene, i.e., a known mutation, c.341G>A (p.R114H), from his mother and a novel mutation, c.1484C>G (p.P495R), from his father. Finally, he was diagnosed with multiple acyl-CoA dehydrogenase deficiency. Reye syndrome and sudden death symptoms were caused by nimesulide-induced acute metabolic crisis. It is concluded that inherited metabolic diseases may be main causes of Reye syndrome and sudden death, and biochemical and genetic analyses are the key to identifying underlying diseases.

Neuroprotection against hydrogen peroxide-induced toxicity by Dictyophora echinovolvata polysaccharide via inhibiting the mitochondria-dependent apoptotic pathway.

Neuronal apoptosis caused by toxic stimuli such as oxidative stress is believed to be one of the major reasons in the pathologenesis of neurodegenerative diseases. In the current study, the neuroprotective effects of the crude polysaccharide fraction of edible Dictyophora echinovolvata (DEVP) against H2O2-induced cytotoxicity were investigated using PC12 cells. Following exposure of PC12 cells to 750µM H2O2, a significant reduction in cell viability and the number of FDA-stained viable neurons as well as an increase in the number of PI-stained dead cells were observed. Furthermore, H2O2 treatment significantly upregulated the protein expression of Bax, cleaved caspases 3 and cytosolic cytochrome c, and down-regulated Bcl-2 levels. 2h pre-treatment with VP reversed these changes caused by H2O2, including inhibiting neuronal loss and decreasing Bax, cleaved caspases 3 and cytosolic cytochrome c levels, as well as increasing Bcl-2 levels. These results taken together demonstrated that DEVP provided a substantial neuroprotection against H2O2-induced toxicity in PC12 cells, at least partly through inhibiting the mitochondrial apoptotic pathway. These findings suggested that DEVP might be a potential candidate for further preclinical study for preventing neurodegenerative diseases in which oxidative stress and apoptosis are involved.

Clinical study of DSA combined with dual-chamber Fogarty catheter in venous crisis / 天津医药

Objective To observe the clinical effect of digital subtraction angiography (DSA) combined with double-chamber Fogarty catheter in venous crisis after replantation of severed extremities. Methods A total of 12 cases with venous crisis after replantation of severed extremities treated by DSA combined with double-chamber Fogarty catheter from June 2011 to January 2016 were included in this study. Results Eleven cases survived after operation. Healing status of surgical incisions was stageⅠfor all patients. Of which osteofascial compartment syndrome was found in 1 case, and it was cured by surgical incision treatment; liver damage was found in another case, and acute liver damage was treated by comprehensive treatment of internal medicine. The postoperative venous thrombosis was found again in one case. The patient underwent exploratory surgery, and venous thrombosis was found again, limb partial necrosis was found, amputation was perform, and the incision was healed in Ⅰ stage. Complications including vascular rupture, air embolism, infection and sepsis were not found in all patients. Thrombosis was presented in the vein, the length of 0.6-4.2 cm. A total of 11 patients were treated with Fogarty catheters and followed up for 11 months (7 months to 29 months). The limb shape of the patient was satisfactory, blood supply of limb was improved, and capillary filling time was 1.5-3.3 s, swelling degree was improved, skin temperature was normal or lower than the limb 0.6-1.5℃, the skin color was normal, the activity improved, the feeling of recovery S0-S4 levels, the average in the S3 + level, two-point discrimination was 3-8 mm with an average of 4.5 mm. According to the evaluation criteria of the replantation function of the limb replantation of the Chinese Medical Association, 5 cases were excellent, 4 cases were good and 2 cases were poor. Conclusion The application of DSA combined with double-chamber Fogarty balloon catheter for the treatment of venous crisis shows precise localization of thrombosis, increased targeting venous branch in blood vessels, minimally invasion, quick, and satisfactory clinical results.

Clinical study of DSA combined with dual-chamber Fogarty catheter in venous crisis / 天津医药

Objective To observe the clinical effect of digital subtraction angiography (DSA) combined with double-chamber Fogarty catheter in venous crisis after replantation of severed extremities. Methods A total of 12 cases with venous crisis after replantation of severed extremities treated by DSA combined with double-chamber Fogarty catheter from June 2011 to January 2016 were included in this study. Results Eleven cases survived after operation. Healing status of surgical incisions was stageⅠfor all patients. Of which osteofascial compartment syndrome was found in 1 case, and it was cured by surgical incision treatment; liver damage was found in another case, and acute liver damage was treated by comprehensive treatment of internal medicine. The postoperative venous thrombosis was found again in one case. The patient underwent exploratory surgery, and venous thrombosis was found again, limb partial necrosis was found, amputation was perform, and the incision was healed in Ⅰ stage. Complications including vascular rupture, air embolism, infection and sepsis were not found in all patients. Thrombosis was presented in the vein, the length of 0.6-4.2 cm. A total of 11 patients were treated with Fogarty catheters and followed up for 11 months (7 months to 29 months). The limb shape of the patient was satisfactory, blood supply of limb was improved, and capillary filling time was 1.5-3.3 s, swelling degree was improved, skin temperature was normal or lower than the limb 0.6-1.5℃, the skin color was normal, the activity improved, the feeling of recovery S0-S4 levels, the average in the S3 + level, two-point discrimination was 3-8 mm with an average of 4.5 mm. According to the evaluation criteria of the replantation function of the limb replantation of the Chinese Medical Association, 5 cases were excellent, 4 cases were good and 2 cases were poor. Conclusion The application of DSA combined with double-chamber Fogarty balloon catheter for the treatment of venous crisis shows precise localization of thrombosis, increased targeting venous branch in blood vessels, minimally invasion, quick, and satisfactory clinical results.