Fgf21-Dubosiella axis mediates the protective effects of exercise against NAFLD development.

AIM: To explore the mechanism of gut microbiota mediates protective effects of exercise against non-alcoholic fatty liver disease (NAFLD) development. MAIN METHODS: The male C57BL/6 mice were fed with high fat food (HFD) or normal diet (CON) respectively, and the obese mice were randomly divided into sedentariness (HFD) and exercise groups (HFD + Exe). The total intervention period was 18 weeks. Antibiotic treatment and fecal microbiota transplantation were applied to evaluate gut microbiota mediates the protective effects of exercise against NAFLD development. 16S rDNA profiling of gut microbiota and extracorporeal rehydration of Dubosiella newyorkensis were performed to identify the crucial role of Dubosiella in NAFLD improvement during exercise training. FGF21 knock-out mice were used to reveal the potential mechanism of exercise increased the abundance of Dubosiella. RT-PCR, Western blot, Histopathological examinations and Biochemical testing were performed to evaluate the lipid deposition and function in the liver. KEY FINDINGS: Treadmill exercise significantly ameliorated hepatic function and mitigated lipid accumulation in NAFLD mice, and these hepatoprotective benefits were mostly mediated by the Dubosiella. In addition, the increased abundance of Dubosiella during exercise training was modulated by FGF21 specifically. SIGNIFICANCE: In short, Dubosiella, chiefly regulated by FGF21 signaling during exercise training, has been discovered to govern the protective impacts of exercising counter to the development of NAFLD and exhibits a promising treatment target for NAFLD.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells.

Cancer is a huge challenge for people worldwide. High reactive oxygen species (ROS) levels are a recognized hallmark of cancer and an important aspect of cancer treatment research. Abnormally elevated ROS levels are often attributable to alterations in cellular metabolic activities and increased oxidative stress, which affects both the development and maintenance of cancer. Moderately high levels of ROS are beneficial to maintain tumor cell genesis and development, while toxic levels of ROS have been shown to be an important force in destroying cancer cells. ROS has become an important anticancer target based on the proapoptotic effect of toxic levels of ROS. Therefore, this review summarizes the role of increased ROS in DNA damage and the apoptosis of cancer cells caused by changes in cancer cell metabolism, as well as various anticancer therapies targeting ROS generation, in order to provide references for cancer therapies based on ROS generation.

NRF-2α and mitophagy underlie enhanced mitochondrial functions and biogenesis induced by T-2 toxin in GH3 cells.

T-2 toxin is a natural contaminant in grain cereals produced by species of Fusarium. Studies indicate that T-2 toxin can positively affect mitochondrial function, but the underlying mechanism is unclear. In this study, we examined the role of nuclear respiratory factor 2α (NRF-2α) in T-2 toxin-activated mitochondrial biogenesis and the direct target genes of NRF-2α. Furthermore, we investigated T-2 toxin-induced autophagy and mitophagy, and the role of mitophagy in changes in mitochondrial function and apoptosis. It was found that T-2 toxin significantly increased NRF-2α levels and nuclear localization of NRF-2α was induced. NRF-2α deletion significantly increased the production of reactive oxygen species (ROS), abrogated T-2 toxin-induced increases in ATP and mitochondrial complex I activity, and inhibited the mitochondrial DNA copy number. Meanwhile, With chromatin immunoprecipitation sequencing (ChIP-Seq), various novel NRF-2α target genes were identified, such as mitochondrial iron-sulphur subunits (Ndufs 3,7) and mitochondrial transcription factors (Tfam, Tfb1m, and Tfb2m). Some target genes were also involved in mitochondrial fusion and fission (Drp1), mitochondrial translation (Yars2) and splicing (Ddx55), and mitophagy. Further studies showed that T-2 toxin induced Atg5 dependent autophagy and Atg5/PINK1-dependent mitophagy. In addition, mitophagy defects increase ROS production, inhibit ATP levels and the expression of genes related to mitochondrial dynamics, and promote apoptosis in the presence of T-2 toxins. Altogether, these results suggest that NRF-2α plays a critical role in promoting mitochondrial function and biogenesis through regulation of mitochondrial genes, and, interestingly, mitophagy caused by T-2 toxin positively affected mitochondrial function and protected cell survival against T-2 toxin.

The potential of CD38 protein as a target for autoimmune diseases.

Cluster of differentiation 38 (CD38) is a multifunctional cell surface protein involved in nicotinamide adenine dinucleotide (NAD+) homeostasis in types of cells and tissues, which can be found in many immune cells and non-immune cells. Previous studies have shown that CD38 plays an important role in regulating innate immunity. Recently, many studies have revealed the importance of CD38 in autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D) and inflammatory bowel disease, among others. In this report, we will briefly discuss the complex immunological functions of CD38 and focus on recent advances in the role of CD38 in the development and pathogenesis of autoimmune diseases, as well as their potential as therapeutic targets for systemic diseases, intending to make a comprehensive understanding of CD38 and its promising therapeutic potential in these systemic diseases.

Potentially toxic elements in smoke particles and residual ashes by biomass combustion from Huangshi National Mine Park, China.

This paper investigates the fractional and spatial distribution characteristics of potentially toxic elements (PTEs) in smoke particles and residual ashes from mine-park-biomass combustion. It then evaluates the consequential potential environment risk by using a Geo-accumulation index and Nemerow pollution index methods. Biomass combustibles are comprised of Camphor leaves (CL), Camphor dead-branch (CB), Ramie (RA), Miscanthus sinensis (MS), and Dryopteris (DR). The results show that the products of combustion contain PTEs, As, Cr, Cu, and Zn, etc. Among them, the content of As, Cr, Cu, Pb elements in smoke particles of CB was higher than other combustibles. Moreover, Cr, Mn, Ni, and Pb in residual ashes of CL were higher than others. The proportion of acid-soluble and reducible fraction of As in residual ash was higher, while Cr existed mainly in the oxidizable and residual fraction. Besides, the available state of As gradually decreased from 74% (400 °C) to 41% (800 °C), indicating that the increase of temperature significantly reduced the bioavailability of As. Meanwhile, with the increase of temperature, the concentration of PTEs in smoke particles decreased and PTEs in residual ashes increased in different degrees. The risk evaluation results indicate that PTEs may cause moderate or higher levels of contamination. The overall contamination level of PTEs in the residual ashes of CB was higher than that of other plant. The results show in this study would contribute to understanding the environmental risks of wildfire and prescribed burning in PTEs-contaminated areas.

Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications.

Metformin is the oldest and most commonly used first-line antidiabetic drug because of its good clinical efficacy, high safety, low cost and easy access. At the same time, in recent years, we have found that its role as a therapeutic drug is gradually expanding. A large number of basic studies have shown that metformin may become a promising attractive candidate for drug repurposing. Therefore, it is extremely beneficial to conduct an in-depth discussion on the main mechanism of metformin. As early as the year 1950, studies showed that metformin played a biological role by regulating mitochondria. Then, ground-breaking studies showed that metformin functions by inhibiting complex I in the mitochondrial respiratory chain. Although there are still many controversies about the key molecular targets of metformin, with the emergence of more and more evidence, it gradually came to be concluded that mitochondria play a central role in the application of metformin. Mitochondria are important fulcrums for cell functions. The exact mechanism of action in mitochondria of this pleiotropic anti-hyperglycaemic molecule is still unclear. This review article explores the core role of mitochondria in the pharmacological and toxicological effects of metformin, and summarises the mechanism of action if metformin in mitochondria. It also provides ideas and supporting evidence for the re-development and reuse of metformin as an old drug, as well as new insight into the treatment of human diseases.

The ethanol extract of Involcucrum castaneae ameliorated ovalbumin-induced airway inflammation and smooth muscle thickening in guinea pigs.

ETHNOPHARMACOLOGICAL RELEVANCE: Involucrum castaneae(IC)is used in Chinese folk medicine to treat various lung diseases, as well as for its reducing phlegm and anti-inflammatory properties. AIM OF THE STUDY: The purpose of this experiment is to verify the effect of IC on airway inflammation, responsiveness in ovalbumin (OVA)-induced asthmatic guinea pigs. The main chemical components of IC were also analyzed. MATERIALS AND METHODS: The potential of the ethanol extract of Involucrum castaneae (EEIC) to protect against OVA-induced allergic airway response in guinea pigs was investigated. The latency of asthma in guinea pigs were recorded after the allergic asthma induced. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of immunoglobulin E (IgE), interleukin-5 (IL-5), nerve growth factor (NGF) and interferon-γ (IFN-γ) in asthma allergy. Reverse transcription-PCR (RT-PCR) was used to detect the expression of IL-5 mRNA in asthmatic guinea pig lungs. Paraffin sections of lung tissue were used to analyze pathological changes. The total flavonoid content was determined and the chemical components were analyzed by LC-MS/MS. RESULTS: It was found that EEIC was able to reduce the number of eosinophil (EOS) in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) in the guinea pig model of OVA -induced asthma. Meanwhile, it also significantly reduced the levels of inflammation-related factors IgE and IL-5, decreased the expression of IL-5 mRNA in lung tissue, and increased the level of IFN-γ. Pathological examination of paraffin section of lung tissue showed that EEIC can reduce the thickening of bronchial smooth muscle and reduce the infiltration damage of tissues by various inflammatory cells. The presence of flavonoids, terpenoids and phenolic compounds in EEIC might be responsible for these activities. CONCLUSION: IC alleviated airway inflammation and smooth muscle thickening in guinea pigs with OVA-sensitized allergic asthma. The paper explains the traditional efficacy and material basis of IC and lays a foundation for further development.

miR-1b overexpression suppressed proliferation and migration of RSC96 and increased cell apoptosis.

Peripheral nerve injury (PNI) is a global problem that leads to severe disability and high healthcare expenditure. Accumulating evidence suggested that the phenotypes of Schwann cells (SCs) could be regulated by microRNAs (miRNAs) and expressions of various miRNAs are altered after PNI. In this study, the expression of miR-1b in the injured nerve and hypoxia-treated SCs was detected through qRT-PCR. The target genes of miR-1b were predicted by bioinformatics prediction and dual-luciferase reporter assay and verified through qRT-PCR and western blot. The effects of miR-1b and its specific target gene on the proliferation, migration and apoptosis of SCs were determined and the regulation of miR-1b on peripheral nerve regeneration after PNI was further investigated in vivo. We found that miR-1b was obviously downregulated in the injured nerve in a rat sciatic nerve transection model and directly targeted N-myc downstream-regulated gene 3 (NDRG3) by binding to its 3'-UTR and caused both mRNA degradation and translation suppression of NDRG3. Overexpression of miR-1b or knockdown of NDRG3 decreased the proliferation and migration as well as increased the apoptosis of SCs. NDRG3 reversed the effects of miR-1b overexpression on proliferation/migration/apoptosis of RSC96. In addition, injection of miR-1b antagomir promoted the expression of NDRG3 in the injured nerve following sciatic nerve injury. Compared to the model group, the rats treated with miR-1b agomir had lower functional recovery rate, and downregulation of miR-1b through injection of specific antagomir improved the functional recovery rate according to the results of sciatic functional index and nerve conduction velocity. Overall, our results will contribute to the development of novel targets for promoting nerve regeneration after PNI.

Electroacupuncture and moxibustion promote regeneration of injured sciatic nerve through Schwann cell proliferation and nerve growth factor secretion.

Using electroacupuncture and moxibustion to treat peripheral nerve injury is highly efficient with low side effects. However, the electroacupuncture- and moxibustion-based mechanisms underlying nerve repair are still unclear. Here, in vivo and in vitro experiments uncovered one mechanism through which electroacupuncture and moxibustion affect regeneration after peripheral nerve injury. We first established rat models of sciatic nerve injury using neurotomy. Rats were treated with electroacupuncture or moxibustion at acupoints Huantiao (GB30) and Zusanli (ST36). Each treatment lasted 15 minutes, and treatments were given six times a week for 4 consecutive weeks. Behavioral testing was used to determine the sciatic functional index. We used electrophysiological detection to measure sciatic nerve conduction velocity and performed hematoxylin-eosin staining to determine any changes in the gastrocnemius muscle. We used immunohistochemistry to observe changes in the expression of S100-a specific marker for Schwann cells-and an enzyme-linked immunosorbent assay to detect serum level of nerve growth factor. Results showed that compared with the model-only group, sciatic functional index, recovery rate of conduction velocity, diameter recovery of the gastrocnemius muscle fibers, number of S100-immunoreactive cells, and level of nerve growth factor were greater in the electroacupuncture and moxibustion groups. The efficacy did not differ between treatment groups. The serum from treated rats was collected and used to stimulate Schwann cells cultured in vitro. Results showed that the viability of Schwann cells was much higher in the treatment groups than in the model group at 3 and 5 days after treatment. These findings indicate that electroacupuncture and moxibustion promoted nerve regeneration and functional recovery; its mechanism might be associated with the enhancement of Schwann cell proliferation and upregulation of nerve growth factor.