ß-Elemene Promotes Apoptosis Induced by Hyperthermia via Inhibiting HSP70.

Thermotherapy has been presented as a promising strategy to be used as an effective nonsurgical technique for colorectal carcinoma. Although this strategy presents several advantages, including low toxicity and high repeatability, thermotherapy often needs to be combined with other therapies because residual tumor cells that survive hyperthermal treatment often lead to relapse. In this study, we evaluated the effects of ß-elemene, which has been proven to have the potential to reverse chemotherapy drug resistance, on promoting the antitumor effects of hyperthermia. ß-elemene treatment significantly promoted apoptosis after 2 hours of hyperthermia treatment and blocked cell cycle phases at G1/G0. ß-elemene also significantly decreased colony formation and tumor formation abilities after hyperthermia treatment. ß-elemene treatment significantly decreased HSP70, but not HSP90 or HSP27, induced by hyperthermia treatment without disturbing HSP70 mRNA. It was also found that ß-elemene decreased phosphorylated ERK1/2 induced by hyperthermia. Regain of HSP70 reversed ß-elemene-mediated apoptosis, indicating that ß-elemene may induce apoptosis by decreasing HSP70. Moreover, ß-elemene treatment significantly decreased invasion capacity by decreasing the EMT, which was induced by hyperthermia treatment. Taken together, our results offer a potential strategy for CRC therapy via the combination of hyperthermia and ß-elemene.

Astragaloside IV pre-treatment attenuates PM2.5-induced lung injury in rats: Impact on autophagy, apoptosis and inflammation.

BACKGROUND: Fine particulate matter (PM2.5) with an aerodynamic diameter of less than 2.5 µm, exerts serious lung toxicity. At present, effective prevention measures and treatment modalities for pulmonary toxicity caused by PM2.5 are lacking. Astragaloside IV (AS-IV) is a natural product that has received increasing attention from researchers for its unique biological functions. PURPOSE: To investigate the protective effects of AS-IV on PM2.5-induced pulmonary toxicity and identify its potential mechanisms. METHODS: The rat model of PM2.5-induced lung toxicity was created by intratracheal instillation of PM2.5 dust suspension. The investigation was performed with AS-IV or in combination with autophagic flux inhibitor (Chloroquine) or AMP-sensitive protein kinase (AMPK)-specific inhibitor (Compound C). Apoptosis was detected by terminal deoxy-nucleotidyl transferase dUTP nick end labeling (TUNEL) and western blotting. Autophagy was detected by immunofluorescence staining, autophagic flux measurement, western blotting, and transmission electron microscopy. The AMPK/mTOR pathway was analyzed by western blotting. Inflammation was analyzed by western blotting and suspension array. RESULTS: AS-IV prevented histopathological injury, inflammation, autophagy dysfunction, apoptosis, and changes in AMPK levels induced by PM2.5. AS-IV increased autophagic flux and inhibited apoptosis and inflammation by activating the AMPK/ mammalian target of rapamycin (mTOR) pathway. However, AS-IV had no protective effect on PM2.5-induced lung injury following treatment with Compound C or Chloroquine. CONCLUSION: AS-IV prevented PM2.5-induced lung toxicity by restoring the balance among autophagy, apoptosis, and inflammation in rats by activating the AMPK/mTOR signaling pathway.

Astragaloside IV Protects from PM2.5-Induced Lung Injury by Regulating Autophagy via Inhibition of PI3K/Akt/mTOR Signaling in vivo and in vitro.

INTRODUCTION: Prolonged exposure to air polluted with airborne fine particulate matter (PM2.5) can increase respiratory disease risk. Astragaloside IV (AS-IV) is one of the main bioactive substances in the traditional Chinese medicinal herb, Astragalus membranaceus Bunge. AS-IV has numerous pharmacological properties; whereas there are few reports on the prevention of PM2.5-induced lung injury by AS-IV through modulation of the autophagic pathway. This study aimed to investigate the protective effects and the underlying mechanisms of AS-IV in PM2.5-induced lung injury rats and rat alveolar macrophages (NR8383 cells). METHODS: The pneumotoxicity model was established by intratracheal injection of PM2.5 in rats, and PM2.5 challenge in NR8383 cells. The severity of lung injury was evaluated by wet weight to dry weight ratio and McGuigan pathology scoring. Inflammatory factors and oxidative stress were detected through ELISA. The expressions of p-PI3K, p-Akt, and p-mTOR proteins were analyzed by immunohistochemistry. Immunofluorescence and transmission electron microscopy were used to detect autophagosomes. The expressions of autophagy marker protein (LC3B and p62), PI3K/Akt/mTOR signaling and NF-κB translocation were detected by Western blot in lung tissue and NR8383 cells. RESULTS: After PM2.5 stimulation, rats showed severe inflammation and oxidative stress, along with inhibition of autophagy in lung tissue. AS-IV not only decreased pulmonary inflammation and oxidative stress by inhibiting nuclear factor kappa B translocation, but also regulated autophagy by inhibiting PI3K/Akt/mTOR signaling. After treatment with 3-methyladenine (a classic PI3K inhibitor, blocking the formation of autophagosomes), the protective effect of AS-IV on PM2.5-induced lung injury was further strengthened. In parallel, using Western blot, immunohistochemistry, and transmission electron microscopy, we demonstrated that AS-IV restore autophagic flux mainly through regulating the degradation of autophagosomes rather than suppressing the formation in vivo and in vitro. CONCLUSION: Our data indicated that AS-IV protects from PM2.5-induced lung injury in vivo and in vitro by inhibiting the PI3K/Akt/mTOR pathway to regulate autophagy and inflammation.

Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: Pharmacology and mechanisms.

Epidemiological studies showed that the metabolic syndromes (MetS) and cardiovascular diseases (CVDs) are responsible for a serious threat to human health worldwide. MetS is a syndromes characterized by fat metabolism disorder, obesity, diabetes, insulin resistance and other risk factors, which increases the risk of CVDs initiation and development. Although certain drugs play a role in lowering blood sugar and lipid, some side effects also occur. Considering the multiple pathogenesis, a great deal of natural products have been attempted to treat metabolic syndromes. Ginsenosides, as the active components isolated from Panax ginseng C.A.Mey, have been reported to have therapeutic effects on MetS and CVDs, of which pharmacological mechanisms were further studied as well. This review aims to systematically summarize current pharmacological effects of ginsenosides on MetS and CVDs, potential mechanisms and clinic trials, which will greatly contribute to the development of potential agents for related disease treatment.

Effect of myrtol on chronic bronchitis or chronic obstructive pulmonary disease: A protocol for systematic review and meta-analysis.

BACKGROUND: The key to the management of chronic obstructive (CB) and chronic obstructive pulmonary disease (COPD) is to control symptoms of the disease and to prevent deterioration in the health of affected patients. Myrtol has been proved to be effective in treating the symptoms of patients with CB and COPD and preventing the deterioration in their health. However, there has been no systematic review of the efficacy and safety of myrtol in the treatment of CB or COPD. The purpose of this study is going to evaluate the effects of myrtol on the management of CB or COPD based on randomized controlled trials. METHODS: Electronic literature and other ongoing studies will be searched before November 31, 2019. Randomized controlled trials that report the use of myrtol in the treatment of CB or COPD (in the absence and presence of concurrent treatments) will be selected for inclusion regardless of language. Primary outcomes will include cumulative numbers of exacerbation events and the number of days of disability including days in bed, days off work due to breathing complications, and days on which the participant was unable to undertake normal activities due to breathing complications. Study selection, data extraction, and deviation the derivation risk assessment will be carried out by 2 independent investigators. Meta-analysis will be carried out by the RevMan5.3 software. RESULTS: The study will provide summary results for estimating the efficacy and safety of myrtol for future treatments of CB or COPD. CONCLUSIONS: This systematic review will determine if myrtol is an effective and a safe intervention on the symptoms and the prevention of exacerbation of CB or COPD. ETHICS AND DISSEMINATION: Ethical approval will not be required for this study because no identifying patient data will be used. The review will be published as an article or a conference presentation in a peer-reviewed journal. REGISTRATION: OSF registration number: DOI 10.17605/OSF.IO/PXRBV.

Therapeutic effect of methylprednisolone combined with high frequency electrotherapy on acute spinal cord injury in rats.

Acute spinal cord injury (SCI) has a high rate of disability and mortality. Although secondary SCI results in local tissue hypoxia and the release of inflammatory mediators, it is both controllable and reversible. Therefore, timely rehabilitation treatment is beneficial for the partial recovery of patients with SCI. The present study aimed to investigate the use of methylprednisolone combined with high-frequency electrotherapy as a method of rehabilitation treatment in rats with SCI. The rat SCI model was prepared using the modified Allen's method with the animals randomly divided into the following 4 groups (n=10 for each group): SCI; methylprednisolone (300 mg/kg); high-frequency electrotherapy; and combination treatment with electrotherapy combined with methylprednisolone (300 mg/kg). The Basso, Beattie and Bresnahan (BBB) score, somatosensory evoked potential (SEP) and motor evoked potential (MEP) were used to assess spinal function. Brain-derived neurotrophic factor (BDNF) and NF-κB expression levels were detected using reverse transcription-quantitative PCR and western blotting. Tumor necrosis factor (TNF)-α and IL-2 expression levels were determined by ELISA, and caspase 3 activity was also assessed. In all treatment groups, BDNF mRNA and protein expression levels were significantly increased, whilst those of NF-κB were reduced. Additionally, an elevated BBB score, improved SEPs and MEPs, inhibited caspase 3 activity and downregulated TNF-α and IL-2 expression levels were observed, compared with the SCI group (P<0.05). However, the combination group exhibited more significant effects on SCI. In conclusion, methylprednisolone combined with high frequency electrotherapy may improve the symptoms of SCI by increasing the expression level of BDNF, reducing that of NF-κB, and suppressing the secretion of inflammatory factors.

Citrate attenuates vascular calcification in chronic renal failure rats.

Vascular calcification (VC) is a major contributor of cardiovascular dysfunction in chronic renal failure (CRF). Citrate binds calcium and inhibits the growth of calcium crystals. This present study intends to evaluate the effect of citrate on VC in adenine-induced CRF rats. The rats were randomly divided into five groups: the control group, the citrate control group, model group, model rats with low-dose treatment of citrate (216 mg/kg) and model rats with high-dose treatment of citrate (746 mg/kg). The rats were euthanized at 5 weeks with their blood and aorta in detection. The results showed that serum level of blood urea nitrogen, serum creatinine, phosphorus, calcium, and related renal failure function marker were elevated in the model group. Furthermore, the aortic calcium accumulation and alkaline phosphatase activity were significantly increased in the model group compared with control groups. Additionally, hematoxylin-eosin staining results demonstrated that the vascular calcification in aorta is significantly increased in the model group. Finally, the expression of VC-related proteins including bone morphogenetic protein and osteocalcin were increased in the model group, whereas alpha-smooth muscle actin was decreased in the model group compared with the control group. However, treatment with citrate caused a reversal effect of all the above events in a dose-dependent manner. In conclusion, citrate may attenuate vascular calcification in adenine-induced CRF rats.

Sodium Citrate Inhibits Endoplasmic Reticulum Stress in Rats with Adenine-Induced Chronic Renal Failure.

BACKGROUND/AIMS: Endoplasmic reticulum stress (ERS) is an important self-protective cellular response to harmful stimuli that contribute to various diseases, including chronic renal failure (CRF). Sodium citrate plays an important role in antioxidant and cellular immunity, but whether it improves ERS in CRF is unclear. METHODS: The rats were randomly divided into five groups: the control group, the sodium citrate control group, the model group, model rats with low dose sodium citrate (216 mg/kg), and model rats with a high dose of sodium citrate (746 mg/kg). The rats were euthanized at 6, 8, 12, and 16 weeks with their blood and renal tissue in detection. RESULTS: The increased concentrations of blood urea nitrogen and serum creatinine in the model group were significantly decreased by sodium citrate treatment. Hematoxylin-eosin and Masson staining showed that sodium citrate treatment apparently improved renal pathological changes in CRF rats. Western blot analysis showed that sodium citrate treatment decreased the protein levels of transforming growth factor-beta 1 and collagen type IV, which were increased in model rats. Moreover, immunohistochemical staining demonstrated that sodium citrate could effectively reduce the protein expression of glucose-regulated protein 78 kDa and CCAAT/enhancer-binding protein homologous protein in the model rats, which was consistent with western blot results. Additionally, the high dose of sodium citrate had a stronger protective effect in CRF rats than the low dose of sodium citrate. CONCLUSIONS: Sodium citrate has a protective effect on CRF through its effects on ERS.