Thymoquinone induces apoptosis in temozolomide-resistant glioblastoma cells via the p38 mitogen-activated protein kinase signaling pathway.

Temozolomide (TMZ) can cross the blood-brain barrier (BBB) and deliver methyl groups to the purine (guanine) bases of DNA, leading to mispairing during DNA replication and subsequent cell death. However, increased expression of the repair enzyme methyl guanine methyltransferase (MGMT), which removes methyl groups from purine bases, counteracts methylation by TMZ. We evaluated the anticancer potential of thymoquinone (TQ), a hydrophobic flavonoid that inhibits resistance and induces apoptosis in various cancer cells, both in vitro and in vivo. In vitro experiments showed that compared with the Hs683 and M059J cell lines, U251 cells were more sensitive to TMZ. Compared to U251 cells, U251R cells, a TMZ drug-resistant strain established in this study, are characterized by increased expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and MGMT. TQ treatments induced apoptosis in all cell lines. The p38 mitogen-activated protein kinase signal pathway was mainly activated in U251 and U251R cells; however, p-ERK and MGMT upregulation could not suppress TQ effects. Furthermore, si-p38 pretreatment of U251R cells in TQ treatments inhibited cell apoptosis. We speculate that TQ contributed to the phosphorylation and activation of p38, but not of ERK-induced apoptosis (irrespective of TMZ resistance). In vivo, U251R-derived tumors subcutaneously inoculated in nude mice exhibited significant tumor volume reduction after TQ or TQ + TMZ cotreatments. High-performance liquid chromatography assay confirmed the presence of TQ in murine brain tissues. Our findings demonstrate that TQ can effectively cross the BBB and function alone or in combination with TMZ to treat glioblastoma.

A cohort study of T helper 17 cell-related cytokine levels in tear samples of systemic lupus erythematosus and Sjögren's syndrome patients with dry eye disease.

OBJECTIVES: Sjögren's syndrome (SS) is the most common autoimmune disease with dry eye (DE) syndrome and some systemic lupus erythematosus (SLE) patients are also with DE syndrome. The occurrence of immune-related DE disease is closely related to T helper (Th) 17 cells in SS patients, and SLE patients have abnormal levels of multiple Th17 cell-related cytokines in their blood. However, the degree of expression of these cytokines in blood differs from that in tears. We hypothesised that the occurrence of DE symptoms in SLE and SS patients may be related to Th17 cells. METHODS: In this study, Th17 cell-related cytokines, including interleukin (IL)-1ß, IL-2, IL-4, interferon-γ, IL 6, IL-8, IL-17F, tumour necrosis factor (TNF)-α, IL-21, IL-22, and IL-23 were analysed in tear samples of DE, SLE, and SS patients. Ocular surface examinations for patients with DE symptoms, including tear secretion test (Schirmer I Test, SIT) and tests for ocular surface disease index (OSDI), tear break-up time (BUT), and corneal fluorescein stain (CFS), were performed and compared between the following patient groups: normal healthy people (control group, n=30), patients with simple DE disease (DE group, n=13), SLE patients with DE disease (SLE group, n=17), and SS patients with DE disease (SS group, n=18). RESULTS: The expression of Th17 cell-related cytokines in each tear sample was analysed using Luminex assay. The SIT and BUT scores of the SLE group were lower than those of the control (p<0.001) and DE (p<0.05) groups. However, SIT, BUT, CFS, and OSDI scores were not significantly different between SLE and SS patients. TNF-α, IL-6, IL-8, and IL-21 levels in tear samples were higher in DE, SLE, and SS patients (p<0.05) than in control individuals. IL-2 and IL-4 levels in tear samples of SLE patients were higher than DE (p<0.001) but lower than the control (p<0.001) group patients. IL-23 levels in tear samples of DE, SLE, and SS patients were all lower than those in the control group (p<0.001). SIT, BUT, CFS, and OSDI results showed that the DE symptoms of SLE and SS patients were more severe than those of the DE group. CONCLUSIONS: It is known that cytokine expression levels in tears are different from those in blood. Abnormal regulation of the Th17 cell pathway may be related to the occurrence of DE disease in SLE and SS patients, and Th17 cell-related cytokines, such as IL-8 and IL-21, may be potential therapeutic targets for treating SLE or SS DE disease.

Erk phosphorylation reduces the thymoquinone toxicity in human hepatocarcinoma.

Although enormous achievements have been made in targeted molecular therapies against hepatocellular carcinoma (HCC), the treatments can only prolong the life of patients with extrahepatic metastases. We evaluated thymoquinone (TQ), a compound from Nigella sativa Linn., for its anti-cancer effect on SK-Hep1 cells and HCC-xenograft nude mice. TQ effectively triggered cell death    and activated p38 and extracellular signal-regulated kinases (Erk) pathways up to 24 h after treatment in cells. TQ-induced cell death was reversed by p38 inhibitor; however, it was enhanced by si-Erk. The caspase3 activation and TUNEL assay revealed a stronger toxic effect upon co-treatment with TQ and si-Erk. Our study suggested that phosphorylation of p38 in SK-Hep1 cells constituted the major factor leading to cell apoptosis, whereas phosphorylation of Erk led to drug resistance. Furthermore, TQ therapeutic effect was improved upon Erk inhibition in HCC-xenograft nude mice. TQ could present excellent anti-HCC potential under suitable p-Erk inhibiting conditions.

Ramipril and resveratrol co-treatment attenuates RhoA/ROCK pathway-regulated early-stage diabetic nephropathy-associated glomerulosclerosis in streptozotocin-induced diabetic rats.

Clinical studies have shown that hyperglycemia can induce early-stage diabetic nephropathy (DN). Furthermore, oxidative stress, tubular epithelial-mesenchymal transition and extracellular matrix accumulation promote the progression of DN to chronic kidney disease and tubulointerstitial fibrosis. It is necessary to initiate treatment at the early stages of DN or even during the early stages of diabetes. In this work, rats with streptozotocin (STZ)-induced diabetes mellitus (DM) presented early DN symptoms within 45 days, and collagen accumulation in the glomerulus of the rats was primarily mediated through the RhoA/ROCK pathway instead of the TGF-ß signaling pathway. Resveratrol (15 mg/kg/day) and ramipril (10 mg/kg/day) co-treatment of STZ-induced DN rats showed that glomerulosclerosis in early-stage DN was reversible (P < .05 compared with that in STZ-induced DM rats). The results of this study support early intervention in diabetes or DN as a more efficient therapeutic strategy.

Oral administration of alcalase potato protein hydrolysate-APPH attenuates high fat diet-induced cardiac complications via TGF-ß/GSN axis in aging rats.

Consumption of high fat diet (HFD) is associated with increased cardiovascular risk factors among elderly people. Aging and obesity induced-cardiac remodeling includes hypertrophy and fibrosis. Gelsolin (GSN) induces cardiac hypertrophy and TGF-ß, a key cytokine, which induces fibrosis. The relationship between TGF-ß and GSN in aging induced cardiac remodeling is still unknown. We evaluated the expressions of TGF-ß and GSN in HFD fed 22 months old aging SD rats, followed by the administration of either probucol or alcalase potato protein hydrolysate (APPH). Western blotting and Masson trichrome staining showed that APPH (45 and 75 mg/kg/day) and probucol (500 mg/kg/day) treatments significantly reduced the aging and HFD-induced hypertrophy and fibrosis. Echocardiograph showed that the performance of the hearts was improved in APPH, and probucol treated HFD aging rats. Serum from all rats was collected and H9c2 cells were cultured with collected serums separately. The GSN dependent hypertrophy was inhibited with an exogenous TGF-ß in H9c2 cells cultured in HFD+ APPH treated serum. Thus, we propose that along with its role in cardiac fibrosis, TGF-ß also acts as an upstream activator of GSN dependent hypertrophy. Hence, TGF-ß in serum could be a promising therapeutic target for cardiac remodeling in aging and/or obese subjects.

Attenuation of Oxidative Stress-Induced Cell Apoptosis in Schwann RSC96 Cells by Ocimum Gratissimum Aqueous Extract.

Objectives: Cell transplantation therapy of Schwann cells (SCs) is a promising therapeutic strategy after spinal cord injury. However, challenges such as oxidative stress hinder satisfactory cell viability and intervention for enhancing SCs survival is critical throughout the transplantation procedures. Ocimum gratissimum, widely used as a folk medicine in many countries, has therapeutic and anti-oxidative properties and may protect SCs survival. Methods: We examined the protective effects of aqueous O. gratissimum extract (OGE) against cell damage caused by H2O2-induced oxidative stress in RSC96 Schwann cells. Results: Our results showed that the RSC96 cells, damaged by H2O2 oxidative stress, decreased their viability up to 32% after treatment with different concentrations of up to 300 µM H2O2, but OGE pretreatment (150 or 200 µg/mL) increased cell viability by approximately 62% or 66%, respectively. Cell cycle analysis indicated a high (43%) sub-G1 cell population in the H2O2-treated RSC96 cells compared with untreated cells (1%); whereas OGE pretreatment (150 and 200 µg/mL) of RSC96 cells significantly reduced the sub-G1 cells (7% and 8%, respectively). Furthermore, Western blot analysis revealed that OGE pretreatment inhibited H2O2-induced apoptotic protein caspase-3 activation and PARP cleavage, as well as it reversed Bax up-regulation and Bcl-2 down-regulation. The amelioration of OGE of cell stress and stress-induced apoptosis was proved by the HSP70 and HSP72 decrease. Conclusion: Our data suggest that OGE may minimize the cytotoxic effects of H2O2-induced SCs apoptosis by modulating the apoptotic pathway and could potentially supplement cell transplantation therapy.

Isolation and determination of four potential antimicrobial components from Pseudomonas aeruginosa extracts.

Background:Pseudomonas aeruginosa can cause disease and also can be isolated from the skin of healthy people. Additionally, it exhibits certain antimicrobial effects against other microorganisms.Methods: We collected 60 strains of P. aeruginosa and screened their antimicrobial effects against Staphylococcus aureus (ATCC 25923) using the filter paper-disk method, the cross-streaking method and the co-culture method and then evaluated the antimicrobial activity of the chloroform-isolated S. aureus extracts against methicillin-resistant S. aureus (MRSA, Gram-positive cocci), vancomycin intermediate-resistant S. aureus (VISA, Gram-positive cocci), Corynebacterium spp. (CS, Gram-positive bacilli), Acinetobacter baumannii (AB, Gram-negative bacilli), Moraxella catarrhalis (MC, Gram-negative diplococcus), Candida albicans (CA, fungi), Candida tropicalis (CT, fungi), Candida glabrata (CG, fungi) and Candida parapsilosis (CP, fungi). Results: The PA06 and PA46 strains have strong antimicrobial effects. High-performance liquid chromatography (HPLC) analysis revealed that the major components of PA06 and PA46 that exhibit antimicrobial activity are functionally similar to phenazine-1-carboxylic acid (PCA) and pyocyanin. Preparative HPLC was performed to separate and isolate the 4 major potential antimicrobial components: PA06ER10, PA06ER16, PA06ER23 and PA06ER31. Further, the molecular masses of PA06ER10 (260.1), PA06ER16 (274.1), PA06ER23 (286.1) and PA06ER31 (318.2) were determined by electrospray ionization (ESI) mass spectrometry. Conclusion:P. aeruginosa can produce small molecules with potential antimicrobial activities against MRSA, VISA, CS, MC, CA, CT, CG and CP but not against AB.

Treatment with 17ß-Estradiol Reduced Body Weight and the Risk of Cardiovascular Disease in a High-Fat Diet-Induced Animal Model of Obesity.

Estrogen receptor α (ERα) and estrogen receptor ß (ERß) play important roles in cardiovascular disease (CVD) prevention. Recently, these estrogen receptors were reconsidered as an important treatment target of obesity leading to CVD. In this study, 17ß-estradiol (17ß-E) replacement therapy applied to high-fat diet-induced obese C57B male mice and ovariectomized (OVX) rats were evaluated, and the protective effects against high-fat diet-induced obesity were assessed in C57B mouse hearts. The results showed that 17ß-E treatment activated both ERα and ERß, and ERß levels increased in a dose-dependent manner in high-fat diet C57B mouse cardiomyocytes following 17ß-E treatment. Notably, an almost 16% reduction in body weight was observed in the 17ß-E-treated (12 µg/kg/day for 60 days) high-fat diet-induced obese C57B male mice. These results suggested that 17ß-E supplements may reduce CVD risk due to obesity.

Ocimum gratissmum aqueous extract reduces plasma lipid in hypercholesterol-fed hamsters.

Objectives: Hyperlipidemia is a significant risk factor in the development of atherosclerosis and related diseases which are major health problem in many developed and developing countries that can lead to fatality due to the changes in lifestyle and dietary habits in this modern age. Methods: In the present study, the Ocimum gratissimum aqueous extract (OGE) was tested for the lowering effect on the serum lipid level of male hamsters on a high-fat (12%) and high-cholesterol (0.2%) diet (HFCD). Results: The results showed that the levels of serum high-density-lipoprotein-cholesterol (HDL-C) low-density-lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and triglycerols (TG) were increased in the HFCD group (113±11, 259±87, 629±175 and 625±262, respectively), as compared to the control normal diet group (51±8, 19±5, 77±16 and 101±44, respectively). When co-treated with various doses (10 and 20 mg/kg) of the OGE or rosuvastatin, the rats exhibited the restoration of normal serum LDL-C, TC, and TG levels. Conclusion: Therefore, we suggest that the Ocimum gratissimum aqueous extract may have the potential function of lowering serum lipid in rats.

San Huang Shel Shin Tang beta-cyclodextrin complex augmented the hepatoprotective effects against carbon tetrachloride-induced acute hepatotoxicity in rats.

BACKGROUND: San Huang Shel Shin Tang (SHSST) is a traditional herbal decoction used as a hepato-protective agent and is composed of Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (2:1:1 w/w). Beta-cyclodextrin (ß-CD) modification may potentially increase the solubility and spectral properties of SHSST. METHODS: In this research, the hepato-protective effects of unmodified SHSST, ß-CD modified SHSST complex (SHSSTc) and silymarin were evaluated in carbon tetrachloride (CCl4) induced acute hepatotoxicity in rats. RESULTS: SHHSTc (40 mg/kg/day) and silymarin (100 mg/kg/day) both decreased the CCl4-induced cirrhosis pathway-related transforming growth factor beta (TGF-ß) and apoptosis pathway-related caspase-8 protein expressions, but SHSST (40 mg/kg/day) did not reduce TGF-ß and caspase-8 significantly . Moreover, SHHSTc (40 mg/kg/day) enhanced the activation of insulin-like growth factor 1 receptor (IGF1R) mediated survival pathway than the silymarin (100 mg/kg/day) to protect the liver from damage induced by CCl4. CONCLUSIONS: ß-CD modification promotes hepato-protective effects of SHSST and reduces the required-dosage of the SHSST.

Mitotic arrest induced in human DU145 prostate cancer cells in response to KHC-4 treatment.

In this study, the antitumor activity of KHC-4 was analyzed using human prostate cancer (CaP) cells and the underlining anticancer mechanisms of KHC-4 were identified. KHC-4 inhibited cell proliferation and induced cytotoxicity in the castration-resistant CaP DU145 cell line. The most effective concentration of KHC-4 was 0.1 µM. Cell cycle analysis demonstrated that KHC-4 treatment caused G2/M arrest and a subsequent increase in the sub-G1 population. Furthermore, KHC-4 is up-regulated p21, p27, and p53 in a time- and concentration-dependent manner. The exposure of cells to KHC-4 induced Cdk1/cyclin B1 complex activity, which led to cell cycle arrest. Moreover, KHC-4 inhibited the activities of MMP-2 and MMP-9 to inhibit tumor cell metastasis. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1879-1887, 2016.

Anti-apoptotic effect of San Huang Shel Shin Tang cyclodextrin complex (SHSSTc) on CCl4 -induced hepatotoxicity in rats.

The metabolic loading is heavier in liver especially when injured or inflammation. San Huang Shel Shin Tang (SHSST) was an old traditional herbal decoction, which composed with Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (1:1:2 in weight), can provide a liver protection effects. We used a beta-cyclodextrin (ß-CD) drug modification method in reduce of the necessary dose of the SHSST. As the results, the FAS-FADD expressions leaded apoptosis in CCl4 intraperitoneal (IP) injection induced acute liver injury in rats. Silymarin, baicalein, SHSST, and SHSST ß-CD complex (SHSSTc) pretreatments protected liver through the decreasing of the expressions of FAS-FADD and downstream caspase-3 and caspase-8. Particularly, SHSSTc (30 mg/kg day) treatment enhanced cell survival pathway activation through the PI3K, Akt and Bad phosphorylation. Compared with SHSST as well as silymarin and baicalein, SHSSTc provided a magnificent liver protection effect, especially in survival pathway activation/TUNEL-apoptotic cell reduction/serum cholesterol level suppression. All these data suggested that ß-CD complex modified the SHSST and promoted the bioavailability and liver protection effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 663-670, 2016.

Supplementary heat-killed Lactobacillus reuteri GMNL-263 ameliorates hyperlipidaemic and cardiac apoptosis in high-fat diet-fed hamsters to maintain cardiovascular function.

Obesity and hyperlipidaemia increase the risk of CVD. Some strains of probiotics have been suggested to have potential applications in cardiovascular health by lowering serum LDL-cholesterol. In this work, high-fat diet-induced hyperlipidaemia in hamsters was treated with different doses (5×108 and 2·5×109 cells/kg per d) of heat-killed Lactobacillus reuteri GMNL-263 (Lr263) by oral gavage for 8 weeks. The serum lipid profile analysis showed that LDL-cholesterol and plasma malondialdehyde (P-MDA) were reduced in the GMNL-263 5×108 cells/kg per d treatment group. Total cholesterol and P-MDA were reduced in the GMNL-263 2·5×109 cells/kg per d treatment group. In terms of heart function, the GMNL-263 2·5×109 cells/kg per d treatments improved the ejection fraction from 85·71 to 91·81 % and fractional shortening from 46·93 to 57·92 % in the high-fat diet-fed hamster hearts. Moreover, the GMNL-263-treated, high-fat diet-fed hamster hearts exhibited reduced Fas-induced myocardial apoptosis and a reactivated IGF1R/PI3K/Akt cell survival pathway. Interestingly, the GMNL-263 treatments also enhanced the heat-shock protein 27 expression in a dose-dependent manner, but the mechanism for this increase remains unclear. In conclusion, supplementary heat-killed L. reuteri GMNL-263 can slightly reduce serum cholesterol. The anti-hyperlipidaemia effects of GMNL-263 may reactivate the IGF1R/PI3K/Akt cell survival pathway and reduce Fas-induced myocardial apoptosis in high-fat diet-fed hamster hearts.

Anti-apoptosis effects on hearts of SHSST cyclodextrin complex in a carbon tetrachloride-induced cirrhotic cardiomyopathy rat model.

Cirrhotic cardiomyopathy (CCM) is a common cardiac dysfunction in patients waiting for orthotopic liver transplantation (OLT). Carbon tetrachloride (CCl4) intraperitoneal (IP) injection has been reported as successful in a cirrhosis-induced CCM model. In this work, we used the same assay for CCM induction using CCl4 (0.2 mg/kg) IP injection twice per day for 14 days during the cardiac protection drugs treatment process. The cardiac protection drugs were silymarin (100 mg/kg/day), baicalein (30 mg/kg/day), San Huang Shel Shin Tang (SHSST, 30 mg/kg/day) and ß-cyclodextrin modified SHSST (SHSSTc, 30 mg/kg/day and 300 mg/kg/day). After 4 weeks of treatment, the SHSSTc cardiac protection effects were determined through activation of the IGF1R cell survival pathway and inhibition of Fas-FADD death domain induced-apoptosis. SHSSTc cardiac protection was enhanced through ß-cyclodextrin modification, which increased bio-availability, and displayed stronger protective effects than silymarin and baicalein, both of which are well-known liver protection drugs. Thus, SHSSTc might provide the best therapeutic benefit in CCM treatment.

The Heart Protection Effect of Alcalase Potato Protein Hydrolysate Is through IGF1R-PI3K-Akt Compensatory Reactivation in Aging Rats on High Fat Diets.

The prevalence of obesity is high in older adults. Alcalase potato protein hydrolysate (APPH), a nutraceutical food, might have greater benefits and be more economical than hypolipidemic drugs. In this study, serum lipid profiles and heart protective effects were evaluated in high fat diet (HFD) induced hyperlipidemia in aging rats treated with APPH (15, 45 and 75 mg/kg/day) and probucol (500 mg/kg/day). APPH treatments reduced serum triacylglycerol (TG), total cholesterol (TC), and low density lipoprotein (LDL) levels to the normal levels expressed in the control group. Additionally, the IGF1R-PI3K-Akt survival pathway was reactivated, and Fas-FADD (Fas-associated death domain) induced apoptosis was inhibited by APPH treatments (15 and 45 mg/kg/day) in HFD aging rat hearts. APPH (75 mg/kg/day) rather than probucol (500 mg/kg/day) treatment could reduce serum lipids without affecting HDL expression. The heart protective effect of APPH in aging rats with hyperlipidemia was through lowering serum lipids and enhancing the activation of the compensatory IGF1R-PI3K-Akt survival pathway.

Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-ß Suppression.

Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD), and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD). Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263) probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD)-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day) were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor ß (TGF-ß) expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease.

Electrochemical sensing of hepatocyte viability.

We investigated the use of amperometric and chronoamperometric methods with a double mediator system and screen-printed electrodes (SPEs) for the electrochemical sensing of hepatocyte viability. Cell counts were determined based on measuring cellular respiration via interaction of electroactive redox mediators. The oxidation currents of chronoamperometric measurement were proportional to the concentrations of ferrocyanide which was produced via interaction of cellular respiration, succinate and ferricyanide. The integrated oxidation charges increased linearly with the density of the cultured primary rat hepatocytes over a range of 1 × 10(5) to 5 × 10(5) cells per well (slope = 1.98 (±0.08) µC per 10(5) cells; R(2) = 0.9969), and the detection limit was 7600 (±300) cells per well based on S/N = 3. Each density of cells was cultured in triple replicates and individual cell samples were evaluated. The results of the cytotoxic effect of the chronoamperometric method are comparable to those of the tetrazolium-based colorimetric assay. The chronoamperometric method with ferricyanide and succinate mediators is an efficient, alternative method for assessing the viability of primary hepatocytes which can be completed in 20 min. Succinate did not provide an efficient electron shuttle between cytosolic respiratory redox activity of cancer cells and extracellular ferricyanide, an effect that may be useful for distinguishing hepatocarcinoma cells from healthy hepatocytes.

Induction of apoptosis in human DU145 prostate cancer cells by KHC-4 treatment.

Prostate cancer (CaP) is one of the most prevalent cancers worldwide and the incidence and mortality rates have been rapidly increasing in recent years in Taiwan. Therefore, it is important to development anti-cancer therapy. In this study, KHC-4 was identified from 2-phenyl-4-quionolone derivatives in human prostate cancer cells and as a potential antitumor agent. In this study, we have identified KHC-4 induced apoptosis effects in castration-resistant prostate cancer DU145 cells, and the IC50 value of KHC-4 was 0.1 µM. KHC-4 suppressed the survival signaling p-PI3K and p-Akt and protein levels of Bcl-2 and Bcl-xL, upregulated Bax, cytochrome c and Caspase 8/9 and induced apoptosis by mitochondrial-dependent pathway. In JC-1 assay monitored the loss of membrane potential in KHC-4 treatments. TUNEL assay results showed DNA fragmentation in KHC-4 induced apoptosis. We concluded that KHC-4 exerted anti-tumor effects in DU145 cells by induction of apoptosis.

SHSST cyclodextrin complex prevents the fibrosis effect on CCl4-induced cirrhotic cardiomyopathy in rats through TGF-ß pathway inhibition effects.

Patients with liver cirrhosis also have subtle cardiac structure or function abnormalities. This cardiac dysfunction commonly occurs in 56% of waiting orthotopic liver transplantation (OLT) patients and is defined as cirrhotic cardiomyopathy (CCM). Up to now, there is no standard treatment because CCM does not have a solidly established diagnosis and is based on high clinical suspicion. The liver function of CCM is particularly limited, making patients vulnerable to more drug treatments. Here, we use silymarin (100 mg/kg/day), baicalein (30 mg/kg/day), San Huang Shel Shin Tang (SHSST, 30 mg/kg/day) and ß-cyclodextrin modified SHSST (SHSSTc, 30 and 300 mg/kg/day) treatments for a CCl4-induced CCM rat model. The results show that silymarin, baicalein and SHSST treatments can only slightly reduce the collagen accumulation in CCM rat hearts. However, SHSSTc treatment protects the heart in CCM and significantly inhibits collagen acumination and the fibrosis regulating transforming growth factor-ß (TGF-ß) pathway expression. SHSSTc treatments further reduced the heart weight and the ratio between left ventricular weight (LVW) and tibia length (TL). This experimental data show that water solubility improved ß-cyclodextrin modified Chinese herbal medicine formula (SHSSTc) can provide an excellent heart protection effect through TGF-ß pathway inhibition.

Effects of bilateral subthalamic nucleus deep brain stimulation on motor symptoms in Parkinson's disease: a retrospective cohort study.

Deep brain stimulation of the bilateral subthalamic nucleus (STN) is a therapeutic option for patients with Parkinson's disease (PD) in whom medical therapies have been ineffective. This retrospective cohort study analyzed the motor function of 27 patients with advanced PD, from the First Affiliated Hospital of Guangzhou Medical University, China, who received deep brain stimulation of the bilateral subthalamic nucleus and evaluated its therapeutic effects. The 10-year follow-up data of patients was analyzed in Qingyuan People's Hospital, Sixth Affiliated Hospital of Guangzhou Medical University, China. The follow-up data were divided into two categories based on patients during levodopa treatment (on-medication) and without levodopa treatment (off-medication). Compared with baseline, the motor function of on-medication PD patients improved after deep brain stimulation of the bilateral subthalamic nucleus. Even 2 years later, the motor function of off-medication PD patients had improved. On-medication PD patients exhibited better therapeutic effects over the 5 years than off-medication PD patients. On-medication patients' akinesia, speech, postural stability, gait, and cognitive function worsened only after 5 years. These results suggest that the motor function of patients with advanced PD benefitted from treatment with deep brain stimulation of the bilateral subthalamic nucleus over a period up to 5 years. The overall therapeutic effects were more pronounced when levodopa treatment was combined with deep brain stimulation of the bilateral subthalamic nucleus. This study was approved by Institutional Review Board of Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, China (approval No. QPH-IRB-A0140) on January 11, 2018.