Magnoflorine improves cognitive deficits and pathology of Alzheimer's disease via inhibiting of JNK signaling pathway.

BACKGROUND: Cognitive deficit is the main clinical feature of Alzheimer's disease (AD), and the massive death of neuronal cells is the leading cause of cognitive deficits. So, there is an urgent clinical need to discover effective drugs to protect brain neurons from damage in order to treat AD. Naturally-derived compounds have always been an important source of new drug discovery because of their diverse pharmacological activities, reliable efficacy and low toxicity. Magnoflorine is a quaternary aporphine alkaloid, which naturally exist in some commonly used herbal medicines, and has good anti-inflammatory and antioxidant effects. However, magnoflorine has not been reported in AD. HYPOTHESIS/PURPOSE: To investigate the therapeutic effect and mechanism of magnoflorine on AD. METHODS: Neuronal damage was detected by flow cytometry, immunofluorescence and western blotting. Oxidative stress was measured by detection of SOD and MDA, as well as JC-1 and reactive oxygen species (ROS) staining. The APP/PS1 mice were given drugs by intraperitoneal injection (I.P.) every day for one month, and then the new object recognition and Morris water maze were used to detect the cognitive ability of the mice. RESULTS: We demonstrated that magnoflorine reduced Aß-induced PC12 cell apoptosis and intracellular ROS generation. Further studies found that magnoflorine significantly improved cognitive deficits and AD-type pathology. Most interestingly, the efficacy of magnoflorine was better than that of the clinical control drug donepezil. Mechanistically, based on RNA-sequencing analysis, we found that magnoflorine significantly inhibited phosphorylated c-Jun N-terminal kinase (JNK) in AD models. This result was further validated using a JNK inhibitor. CONCLUSION: Our results indicate that magnoflorine improves cognitive deficits and pathology of AD through inhibiting of JNK signaling pathway. Thus, magnoflorine may be a potential therapeutic candidate for AD.

Zuoguiwan Ameliorates Cognitive Deficits and Neuro-Inflammation in Streptozotocin-Induced Alzheimer's Disease Rats.

INTRODUCTION: Alzheimer's disease is the most popular neurodegenerative disorder with no effective drugs to stop the progression. Zuoguiwan (ZGW), a traditional Chinese herbal medicine, has been applied in many diseases. Our study aimed to detect the function and mechanisms of ZGW in Alzheimer's disease (AD). METHODS: The rat models of AD were established by streptozotocin (STZ), and the function of ZGW on cognitive dysfunction was measured with the Morris water maze test. The concentration of pro-inflammatory mediators was accessed by enzyme-linked immunosorbent assay. The relative mRNA expression of ERß was detected by real-time quantitative PCR. RESULTS: The treatment with ZGW could suppress the cognitive impairment by the findings of escape latency and time spent in the target quadrant and the increased concentration of IL-1ß, IL-6, and TNF-α induced by STZ. STZ might repress the mRNA levels of ERß, and ZGW management weakened the declined mRNA expression of ERß. ZGW might play a protective role in AD rats against the injury of STZ on cognition and neuro-inflammation by improving the mRNA expression of ERß. CONCLUSION: The results indicated that ZGW might be a novel therapeutic strategy to slow the process of AD by modulating ERß.

Zuogui Pill Attenuates Neuroinflammation and Improves Cognitive Function in Cerebral Ischemia Reperfusion-Injured Rats.

INTRODUCTION: Cerebral ischemia and reperfusion (CI/R) injury is a devasting cerebrovascular disease, accompanied with ischemia stroke, cerebral infarction. Zuogui Pill (ZGP), as a Chinese traditional medicine, is proved to be effective in many diseases and cancers. Our study aimed to detect the roles of ZGP in CI/R injury. METHODS: Neural stem cells were isolated from rats and induced by oxygen and glucose deprivation and recovery. CCK-8 and flow cytometry were applied to assess the function of ZGP on cell viability and apoptosis. Rat CI/R injury models were established by the middle cerebral artery occlusion and reperfusion. The function of ZGP on CI/R injury was identified via evaluating modified neurological severity score, infarct area, and cognitive impairment. RESULTS: Compared to the control, the cell viability was obviously decreased in the oxygen and glucose deprivation and recovery (OGD/R) group, while the adverse influence on cells was reversed by cultured plus 10% ZGP serum. Consistently, ZGP attenuated the influence of OGD/R on cell apoptosis. More importantly, ZGP could alleviate CI/R injury of rats by reducing neurological damage and infarct area and promoting cognitive function. CONCLUSION: This study provided protective roles of ZGP on cell viability and apoptosis induced by OGD/R. In addition, ZGP played protective roles on neuroinflammation and cognitive function in rats.

Sodium houttuyfonate: A review of its antimicrobial, anti-inflammatory and cardiovascular protective effects.

There is an almost unlimited interest in searching and developing new drugs, especially when we are in an era that are witnessing more and more emerging pathogens. Natural products from traditional medicines represent a large library for searching lead compounds with novel bioactivities. Sodium houttuyfonate is such one bioactive compound derived from Houttuynia cordata Thunb which has been employed in traditional medicine for treating infectious and inflammatory diseases. Sodium houttuyfonate has demonstrated multiple kinds of pharmacological effects, including antifungal, antibacterial, anti-inflammatory, and cardiovascular protective activities, which are discussed here to provide insights into our understanding of the pharmacological effects of SH and the underlying mechanisms.

Design, synthesis, and biological evaluation of novel stachydrine derivatives as potent neuroprotective agents for cerebral ischemic stroke.

Stachydrine is a natural product with multiple protective biological activities, including those involved in preventing cancer, ischemia, and cardiovascular disease. However, its use has been limited by low bioavailability and unsatisfactory efficacy. To address this problem, a series of stachydrine derivatives (A1/A2/A3/A4/B1/B2/B3/B4) were designed and synthesized, and biological studies were carried out in vitro and in vivo. When compared with stachydrine, Compound B1 exhibited better neuroprotective effects in vitro, and significantly reduced infarction size in the model of the middle cerebral artery occlusion rat model. Therefore, Compound B1 was selected for further research on ischemic stroke. Graphical abstract.

Prognosis of limited-stage small cell lung cancer with comprehensive treatment including radical resection.

BACKGROUND: The NCCN (National Comprehensive Cancer Network) Clinical Practice Guidelines in Oncology (NCCN guidelines) recommend radical resection for T1-2N0M0 patients with limited-stage small cell lung cancer (LS-SCLC). However, only about 5% of patients with small cell cancer (SCLC) were initially diagnosed as T1-2N0M0. The purpose of our study was to analyze and compare the effects of the comprehensive treatment including radical surgery and concurrent chemoradiotherapy on the prognosis of patients with LS-SCLC. METHODS: We comprehensively reviewed the medical data of patients with SCLC diagnosed by pathology in our hospital from January 2011 to April 2018. The Ethics Committee of West China Hospital of Sichuan University approved the study. Finally, 50 patients with good follow-up and complete medical data were selected as the surgical group (S group). According to the clinical characteristics of the patients in the S group, 102 LS-SCLC patients who received concurrent chemoradiotherapy in the same period were included in the CCRT group (concurrent chemoradiotherapy group) as the control group. Then according to the orders of the adjuvant treatments, the patients in the S group were divided into the SA group (radical surgery + adjuvant chemotherapy + adjuvant radiotherapy group, 30 cases in total) and the NS group (neoadjuvant chemotherapy + radical surgery + adjuvant chemotherapy ± adjuvant radiotherapy group, 20 cases in total) for subgroup analysis. The SPSS 23.0 software was used for statistical analysis, and the t test was used for group comparison; Kaplan-Meier was used for survival analysis. P < 0.05 demonstrates a statistically significant difference. RESULTS: The median progress-free survival (PFS) in the S group (73 months) was significantly better than that in the CCRT group (10.5 months, P < 0.0001), and the median overall survival (OS) in the S group (79 months) was also significantly better than that in the CCRT group (23 months, P < 0.0001). Subgroup analysis showed that there was no significant difference between the NS group and the SA group. CONCLUSIONS: For LS-SCLC patients, the comprehensive treatment including radical surgery (radical surgery + adjuvant chemotherapy ± adjuvant radiotherapy/neoadjuvant chemotherapy + radical surgery + adjuvant chemotherapy ± adjuvant radiotherapy)may be superior to concurrent chemoradiotherapy.

Antifungal Effects of Saponin Extract from Rhizomes of Dioscorea panthaica Prain et Burk against Candida albicans.

Candida albicans is the most common fungal pathogen causing serious diseases, while there are only a paucity of antifungal drugs. Therefore, the present study was performed to investigate the antifungal effects of saponin extract from rhizomes of Dioscorea panthaica Prain et Burk (Huangshanyao Saponin extract, HSE) against C. albicans. HSE inhibits the planktonic growth and biofilm formation and development of C. albicans. 16-64 µg/mL of HSE could inhibit adhesion to polystyrene surfaces, transition from yeast to filamentous growth, and production of secreted phospholipase and could also induce endogenous reactive oxygen species (ROS) production and disrupt cell membrane in planktonic cells. Inhibitory activities against extracellular exopolysaccharide (EPS) production and ROS production in preformed biofilms could be inhibited by 64-256 µg/mL of HSE. Cytotoxicity against human Chang's liver cells is low, with a half maximal inhibitory concentration (IC50) of about 256 µg/mL. In sum, our study suggested that HSE might be used as a potential antifungal therapeutic against C. albicans.

Phenolic alkaloids from Menispermum dauricum inhibits BxPC-3 pancreatic cancer cells by blocking of Hedgehog signaling pathway.

BACKGROUND: The Hedgehog (Hh) signaling pathway plays an important role in pancreatic cancer (PC) cells. Phenolic alkaloids from Menispermum dauricum (PAMD), a traditional Chinese medicine used for the treatment of immune disorders, have been reported to have antitumor activity recently. OBJECTIVE: To investigate the efficacy and mechanism of PAMD against PC cell BxPC-3. MATERIALS AND METHODS: F assay was used to assess cell proliferation inhibition of PAMD; the apoptotic induction and cell cycle arrest was detected by flow cytometry; the BxPC-3 xenograft was established to evaluate the tumor growth inhibition of PAMD; hematoxylin-eosin staining was applied to analyze the pathological morphology of tumor tissues; immunohistochemistry (IHC) and Western blot was adopted to detect the protein levels; quantitative real-time polymerase chain reaction was used to determine the mRNA expressions. RESULTS: PAMD shows time-and dose-dependent proliferation inhibition on the BxPC-3 cell, induced G0/G1 phase arrest and cell apoptosis in vitro. PAMD also showed better inhibition of tumor growth and a preferable safety profile compared with chemotherapeutic regimen 5-fluoro-2, 4 (1 H, 3 H) pyrimidinedione in BxPC-3 xenograft in vivo. Furthermore, PAMD directly decreases the protein and mRNA levels of Sonic Hedgehog (Shh) and its downstream transcription factor Gli-1 in the BxPC-3 tumor tissues. CONCLUSION: The treatment of PAMD displayed Hh signaling pathway blockade through decreasing the protein and mRNA levels of Shh and its downstream transcription factor Gli-1, suggesting a promising strategy in treating human PC.

Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy.

Evodiamine, an alkaloid isolated from Evodia rutaecarpa, possesses potent anticancer activity. Although many reports have elucidated the cytotoxic effects of evodiamine in a variety of cancer cells, little is known about the mechanism of evodiamine-induced cytotoxic activity in gastric cancer cells. To date, no report has addressed the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity. This study was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. The MTT assay was used to examine the cytotoxicity of evodiamine against SGC-7901 gastric adenocarcinoma cells. The effects of evodiamine on the cell cycle and apoptosis were measured by flow cyto-metry and cellular morphology was observed under a phase contrast microscope. Acridine orange (AO) staining was used to detect autophagy. The expression levels of Bcl-2 and Bax were detected by Western blotting. The expression level of Beclin­1 in SGC-7901 cells was monitored by reverse transcription-polymerase chain reaction (RT-PCR). Here, we found that evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell cycle arrest. Furthermore, both autophagy and apoptosis were activated during the evodiamine-induced death of SGC-7901 cells. Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Additionally, Beclin-1 is involved in evodiamine-induced autophagy and the pro-apoptotic mechanisms of evodiamine may be associated with down-regulation of Bcl-2 and up-regulation of Bax expression. The inhibitory effects on SGC-7901 cells were associated with apoptosis, autophagy and cell cycle arrest at the G2/M phase in a dose-dependent manner. These results suggest that evodiamine is an effective natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combined antitumor therapies.