6-Shogaol, an Active Ingredient of Ginger, Improves Intestinal and Brain Abnormalities in Proteus Mirabilis-Induced Parkinson's Disease Mouse Model.

Parkinson's disease (PD) which has various pathological mechanisms, recently, it is attracting attention to the mechanism via microbiome-gut-brain axis. 6-Shogaol, a representative compound of ginger, have been known for improving PD phenotypes by reducing neuroinflammatory responses. In the present study, we investigated whether 6-shogaol and ginger attenuate degeneration induced by Proteus mirabilis (P. mirabilis) on the intestine and brain, simultaneously. C57BL/6J mice received P. mirabilis for 5 days. Ginger (300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 22 days including the period of P. mirabilis treatment. Results showed that 6-shogaol and ginger improved motor dysfunction and dopaminergic neuronal death induced by P. mirabilis treatment. In addition, they suppressed P. mirabilis-induced intestinal barrier disruption, pro-inflammatory signals such as toll-like receptor and TNF-α, and intestinal α-synuclein aggregation. Moreover, ginger and 6-shogaol significantly inhibited neuroinflammation and α-synuclein in the brain. Taken together, 6-shogaol and ginger have the potential to ameliorate PD-like motor behavior and degeneration of dopaminergic neurons induced by P. mirabilis in mice. Here, these findings are meaningful in that they provide the first experimental evidence that 6-shogaol might attenuate PD via regulating gut-brain axis.

Formic acid dehydrogenation over PdNi alloys supported on N-doped carbon: synergistic effect of Pd-Ni alloying on hydrogen release.

Bimetallic Pd1Nix alloys supported on nitrogen-doped carbon (Pd1Nix/N-C, x = 0.37, 1.3 and 3.6) exhibit higher activities than Pd/N-C towards dehydrogenation of formic acid (HCO2H, FA). Density functional theory (DFT) calculations provided electronic and atomic structures, energetics and reaction pathways on Pd(111) and Pd1Nix(111) surfaces of different Pd/Ni compositions. A density of states (DOS) analysis disclosed the electronic interactions between Pd and Ni revealing novel active sites for FA dehydrogenation. Theoretical analysis of FA dehydrogenation on Pd1Nix(111) (x = 0.33, 1 and 3) shows that the Pd1Ni1(111) surface provides optimum H2-release efficiency via a favorable 'HCOO pathway', in which a hydrogen atom and one of the two oxygen atoms of FA interact directly with surface Ni atoms producing adsorbed CO2 and H2. The enhanced efficiency is also attributed to the blocking of an unfavorable 'COOH pathway' through which a C-O bond is broken and side products of CO and H2O are generated.

Inhibition of RIPK3 Pathway Attenuates Intestinal Inflammation and Cell Death of Inflammatory Bowel Disease and Suppresses Necroptosis in Peripheral Mononuclear Cells of Ulcerative Colitis Patients.

Receptor-interacting serine/threonine-protein kinase (RIPK) 3 is a member of the TNF receptor-I signaling complex and mediates necroptosis, an inflammatory cell death. Ulcerative colitis (UC) is an excessive inflammatory disease caused by uncontrolled T cell activation. The current study is aimed to determine whether RIPK3 inhibitor attenuates UC development inhibiting inflammation and necroptosis using experimental colitis mice model. Dextran sulfate sodium-induced colitis mice were administered RIPK3 inhibitor (3 mg/ml) 3 times and their tissues were analyzed by immunohistochemistry. RIPK3, mixed lineage kinase domain-like (MLKL), phosphorylated MLKL, IL-17, and CD4 in colitis patient colon tissues were detected using confocal microscopy. Protein levels were measured using immunohistochemistry and ELISA. The differentiation of Th17 cells was evaluated using flow cytometry. The expression of proinflammatory cytokines and necroptosis in peripheral blood mononuclear cells from UC patients was decreased markedly by RIPK3 inhibitor treatment. We also observed that the injection of RIPK3 inhibitor improves colitis severity and protects intestinal destruction. RIPK3 inhibitor reduced necroptosis factors and proinflammatory cytokines in the colon and consequently protected colon devastation. The expression of inflammatory mediators in experimental colitis mice splenocytes was decreased significantly by RIPK3 inhibitor treatment. These results suggest that RIPK3 inhibitor ameliorates severity of experimental colitis and reduces inflammation through the inhibition of inflammatory response and necroptosis and support RIPK3-targeting substances for treatment of UC.

Closed Formulas for Some New Degree Based Topological Descriptors Using M-polynomial and Boron Triangular Nanotube.

In this article, we provide new formulas to compute the reduced reciprocal randic index, Arithmetic geometric1 index, SK index, SK 1 index, SK 2 index, edge version of the first zagreb index, sum connectivity index, general sum connectivity index, and the forgotten index using the M-polynomial and finding these topological indices for a boron triangular nanotube. We also elaborate the results with graphical representations.

Retinoic Acid Receptor-Related Receptor Alpha Ameliorates Autoimmune Arthritis via Inhibiting of Th17 Cells and Osteoclastogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis characterized by progressive joint destruction. IL-17-producing CD4+ T (Th17) cells play pivotal roles in RA development and progression. Retinoic acid receptor-related orphan receptor alpha (RORα) is a negative regulator of inflammatory responses, whereas RORγt, another member of the ROR family, is a Th17 lineage-specific transcription factor. Here, we investigated the immunoregulatory potential of RORα in collagen-induced arthritis (CIA) mice, an experimental model of RA. Cholesterol sulfate (CS) or SR1078, a ligand of RORα, inhibited RORγt expression and Th17 differentiation in vitro. In addition, fortification of RORα in T cells inhibited the expression levels of glycolysis-associated genes. We found that RORα overexpression in CIA mice attenuated the clinical and histological severities of inflammatory arthritis. The anti-arthritic effect of RORα was associated with suppressed Th17 differentiation and attenuated mTOR-STAT3 signaling in T cells. Furthermore, altered RORα activity could directly affect osteoclastogenesis implicated in progressive bone destruction in human RA. Our findings defined a critical role of RORα in the pathogenesis of RA. These data suggest that RORα may have novel therapeutic uses in the treatment of RA.

Inhibition of STAT3 signaling induces apoptosis and suppresses growth of lung cancer: good and bad.

Signal transducer and activator of transcription 3 (STAT3) modulates a variety of genes involved in the regulation of critical functions, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, and immunity. For many cancers, elevated levels of STAT3 signaling have been associated with a poor prognosis and the development of chemotherapy resistance. In this study, we investigated the inhibitory effects of a novel small-molecule inhibitor of STAT3, STX-0119, on the cell viability and survival of human lung cancer cells. STX-0119 inhibited activated STAT3 and the expression of STAT3-regulated oncoproteins such as c-Myc, cyclin D1, and survivin in lung cancer cells. STX-0119 also decreased the amount of STAT3 in the nuclear fraction as well as induced apoptosis of these lung cancer cell lines as evidenced by increases in apoptotic cells (Annexin V positive) and poly (ADP-ribose) polymerase (PARP) cleavage. The efficacy of STX-0119 in a mouse xenograft model was confirmed. However, a hematological side effect, which had not been previously reported, was observed. The level of white blood cells was significantly lowered when treated at the dose at which STX-0119 alone showed a significant tumor-suppressive effect. In conclusion, we suggest that STX-0119 may be a potent therapeutic agent against lung cancer. Consideration of the side effect suggests, it is necessary to study whether low-dose STX-0119 is effective for lung treatment with a combination of classic lung cancer therapeutics.

Kartogenin inhibits pain behavior, chondrocyte inflammation, and attenuates osteoarthritis progression in mice through induction of IL-10.

Osteoarthritis (OA) is a major degenerative joint condition that causes articular cartilage destruction. It was recently found that enhancement of chondroclasts and suppression in Treg cell differentiation are involved in the pathogenesis of OA. Kartogenin (KGN) is a small drug-like molecule that induces chondrogenesis in mesenchymal stem cells (MSCs). This study aimed to identify whether KGN can enhance severe pain behavior and improve cartilage repair in OA rat model. Induction of OA model was loaded by IA-injection of MIA. In the OA rat model, treatment an intra-articular injection of KGN. Pain levels were evaluated by analyzing PWL and PWT response in animals. Histological analysis and micro-CT images of femurs were used to analyze cartilage destruction. Gene expression was measured by real-time PCR. Immunohistochemistry was analyzed to detect protein expression. KGN injection significantly decreased pain severity and joint destruction in the MIA-induced OA model. KGN also increased mRNA levels of the anti-inflammatory cytokine IL-10 in OA patients' chondrocytes stimulated by IL-1ß. Decreased chondroclast expression, and increased Treg cell expression. KGN revealed therapeutic activity with the potential to reduce pain and improve cartilage destruction. Thus, KGN could be a therapeutic molecule for OA that inhibits cartilage damage.

Hierarchical cobalt-nitride and -oxide co-doped porous carbon nanostructures for highly efficient and durable bifunctional oxygen reaction electrocatalysts.

Here we report the preparation of hollow microspheres with a thin shell composed of mixed cobalt nitride (Co-N) and cobalt oxide (Co-O) nanofragments encapsulated in thin layers of nitrogen-doped carbon (N-C) nanostructure (Co-N/Co-O@N-C) arrays with enhanced bifunctional oxygen electrochemical performance. The hybrid structures are synthesized via heat treatment of N-doped hollow carbon microspheres with cobalt nitrate, and both the specific ratio of these precursors and the selected annealing temperature are found to be the key factors for the formation of the unique hybrid structure. The as-obtained product (Co-N/Co-O@N-C) presents a large specific surface area (493 m2 g-1), high-level heteroatom doping (Co-N, Co-O, and N-C), and hierarchical porous nanoarchitecture containing macroporous frameworks and mesoporous walls. Electronic interaction between the thin N-C layers and the encapsulated Co-N and Co-O nanofragments efficiently optimizes oxygen adsorption properties on the Co-N/Co-O@N-C and thereby triggers bifunctional oxygen electrochemical activity at the surface. The Co-N/Co-O@N-C nanohybrid exhibited a high onset potential of 0.93 V, and a limiting current density of 5.6 mA cm-2 indicating 4-electron oxygen reduction reaction (ORR), afforded high catalytic activity for the oxygen evolution reaction (OER) and even exceeded the catalytic stability of the commercial precious electrocatalysts; furthermore, when integrated into the oxygen electrode of a regenerative fuel cell device, it exhibited high-performance oxygen electrodes for both the ORR and the OER.

Coenzyme Q10 Inhibits Th17 and STAT3 Signaling Pathways to Ameliorate Colitis in Mice.

Coenzyme Q10 (CoQ10) is a powerful antioxidant substance synthesized in the body. The current study aimed to determine whether CoQ10 suppresses inflammation and inhibits p-STAT3 expression in an experimental colitis mouse model. The mice were orally fed with CoQ10 once a day for 13 days. Histological analysis of the colons was performed by immunohistochemistry. Expression of IL-17, FOXP3, p53, AMPK, and mTOR and activation of p-STAT3 and p-STAT5 in lymph node and spleen tissues were detected by confocal microscopy of stained tissue sections. The relative mRNA expression was measured with real-time PCR, and protein levels were examined by western blot. CoQ10 reduced the disease activity index score and the colon histological score. It also reduced inflammatory mediators in the colon and increased the colon length. The expression of IL-17 and p-STAT3 was decreased with CoQ10 treatment. In contrast, CoQ10 treatment increased the expression of p-AMPK and FOXP3. Expression of anti-inflammatory cytokines was shown to increase in colitis mice treated with CoQ10. These results suggested that CoQ10 may reduce the severity of colitis and suppress inflammation through the inhibition of p-STAT3 and IL-17. These results support the use of CoQ10 as a potential targeted therapy for the treatment of colitis.

Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs.

Acute graft-versus-host disease (aGVHD), caused by donor T cell-mediated injury to host tissues, is a problem in allogeneic bone marrow transplantation. The transition from naïve to effector T cells is accompanied by shift in metabolism main pathway; from glucose oxidative phosphorylation to aerobic glycolysis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase that is a metabolic sensor that helps maintain cellular energy homeostasis. Although AMPK activation can exert anti-inflammatory properties by negatively regulating pro-inflammatory mediators, its role as a therapeutic potential of graft-versus-host disease development remains unclear. In this study, we found that the intraperitoneal administration of metformin, which activates AMPK signaling significantly, ameliorated the clinical severity of aGHVD and lethality. This was associated with reductions in type I T helper (Th1) and Th17 and rises in Th2 and regulatory T (Treg) cell. The enhanced signal transducer and activator of transcription 3 activation noted during the development of aGVHD was reduced by metformin treatment. Furthermore, metformin-treated Th17 cells became converted into Treg cells via enhanced autophagy. The reduction in mortality associated with metformin treatment was associated with inhibition of the mammalian target of rapamycin/signal transducer and activator of transcription 3 pathway. These results suggest that metformin might be of significant use in the treatment of patients with aGVHD.

STX0119 ameliorates arthritis in SKG mice via inhibiting T helper 17.

Rheumatoid arthritis (RA) is an autoimmune disease with chronic and excessive inflammation. Upregulation of interleukin (IL)-17 is involved in the pathogenesis of RA. STX0119 is a specific inhibitor of signal transducer and activator of transcription 3 (STAT3) as a potential target for the treatment of RA. STAT3 is a member of DNA-binding molecules that regulates the expression of proinflammatory cytokines involved in the pathogenesis of RA. The objective of this study was to determine whether STX0119 could inhibit STAT3 and IL-17. We demonstrated that STX0119 decreased T helper (Th) 17 differentiation and IL-17 expression in vitro. STX0119 also improved the severity of zymosan induced arthritis and reduced joint inflammation. STX0119 reduced the proliferation of Th17 and phosphorylated STAT3 expression while increasing Treg differentiation and phosphorylated STAT5 expression. Moreover, STX0119 decreased the expression of IL-6 and -17 but not IL-10. These findings suggest that STX0119 can be used to treat autoimmune RA through inhibiting the activation of STAT3.

Highly Durable and Active PtFe Nanocatalyst for Electrochemical Oxygen Reduction Reaction.

Demand on the practical synthetic approach to the high performance electrocatalyst is rapidly increasing for fuel cell commercialization. Here we present a synthesis of highly durable and active intermetallic ordered face-centered tetragonal (fct)-PtFe nanoparticles (NPs) coated with a "dual purpose" N-doped carbon shell. Ordered fct-PtFe NPs with the size of only a few nanometers are obtained by thermal annealing of polydopamine-coated PtFe NPs, and the N-doped carbon shell that is in situ formed from dopamine coating could effectively prevent the coalescence of NPs. This carbon shell also protects the NPs from detachment and agglomeration as well as dissolution throughout the harsh fuel cell operating conditions. By controlling the thickness of the shell below 1 nm, we achieved excellent protection of the NPs as well as high catalytic activity, as the thin carbon shell is highly permeable for the reactant molecules. Our ordered fct-PtFe/C nanocatalyst coated with an N-doped carbon shell shows 11.4 times-higher mass activity and 10.5 times-higher specific activity than commercial Pt/C catalyst. Moreover, we accomplished the long-term stability in membrane electrode assembly (MEA) for 100 h without significant activity loss. From in situ XANES, EDS, and first-principles calculations, we confirmed that an ordered fct-PtFe structure is critical for the long-term stability of our nanocatalyst. This strategy utilizing an N-doped carbon shell for obtaining a small ordered-fct PtFe nanocatalyst as well as protecting the catalyst during fuel cell cycling is expected to open a new simple and effective route for the commercialization of fuel cells.

Metformin Ameliorates Inflammatory Bowel Disease by Suppression of the STAT3 Signaling Pathway and Regulation of the between Th17/Treg Balance.

OBJECTIVE: Metformin is used to treat type 2 diabetes. We sought to determine whether metformin reduces inflammation, by regulating p-signal transducer and activator of transcription 3 (STAT3) expression and T-helper 17 (Th17) cell proliferation, in a mouse model of inflammatory bowel disease (IBD). METHODS: IBD mice were administered metformin for 16 days and their tissues were analyzed. AMP-activated protein kinase (AMPK), the mammalian target of rapamycin (mTOR), p-STAT3 and p-STAT5 in the spleen and lymph nodes were detected using immunohistochemistry and confocal microscopy. Gene expression was determined using quantitative PCR assays, and protein expression levels were measured using western blotting and enzyme-linked immunosorbent assays. Human HT-29 cell proliferation was evaluated using MTT assays. RESULTS: Metformin reduced disease activity index scores and inhibited weight loss. Metformin also decreased the colonic histological score and inflammatory mediators and increased colon lengths increased. Treatment with metformin inhibited the expression of interleukin (IL)-17, p-STAT3, and p-mTOR. In contrast, metformin treatment increased expression levels of p-AMPK and Foxp3. In addition, expression of inflammatory cytokines decreased in a dose-dependent manner in inflamed human HT-29 cells cultured with metformin at various concentrations. CONCLUSIONS: Metformin attenuates IBD severity and reduces inflammation through the inhibition of p-STAT3 and IL-17 expression. Our results have increased our understanding of this chronic inflammatory disease, and support the strategy of using p-STAT3 inhibitors to treat IBD.

Neuroprotective effect of 6-paradol in focal cerebral ischemia involves the attenuation of neuroinflammatory responses in activated microglia.

Paradols are non-pungent and biotransformed metabolites of shogaols and reduce inflammatory responses as well as oxidative stress as shogaols. Recently, shogaol has been noted to possess therapeutic potential against several central nervous system (CNS) disorders, including cerebral ischemia, by reducing neuroinflammation in microglia. Therefore, paradol could be used to improve neuroinflammation-associated CNS disorders. Here, we synthesized paradol derivatives (2- to 10-paradols). Through the initial screening for anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated BV2 microglia, 6-paradol was chosen to be the most effective compound without cytotoxicity. Pretreatment with 6-paradol reduced neuroinflammatory responses in LPS-stimulated BV2 microglia by a concentration-dependent manner, which includes reduced NO production by inhibiting iNOS upregulation and lowered secretion of proinflammatory cytokines (IL-6 and TNF-α). To pursue whether the beneficial in vitro effects of 6-paradol leads towards in vivo therapeutic effects on transient focal cerebral ischemia characterized by neuroinflammation, we employed middle cerebral artery occlusion (MCAO)/reperfusion (M/R). Administration of 6-paradol immediately after reperfusion significantly reduced brain damage in M/R-challenged mice as assessed by brain infarction, neurological deficit, and neural cell survival and death. Furthermore, as observed in cultured microglia, 6-paradol administration markedly reduced neuroinflammation in M/R-challenged brains by attenuating microglial activation and reducing the number of cells expressing iNOS and TNF-α, both of which are known to be produced in microglia following M/R challenge. Collectively, this study provides evidences that 6-paradol effectively protects brain after cerebral ischemia, likely by attenuating neuroinflammation in microglia, suggesting it as a potential therapeutic agent to treat cerebral ischemia.

Effects of pH control and concentration on microbial oil production from Chlorella vulgaris cultivated in the effluent of a low-cost organic waste fermentation system producing volatile fatty acids.

The objective of this study was to investigate the feasibility of applying volatile fatty acids (VFAs) produced from low-cost organic waste to the major carbon sources of microalgae cultivation for highly efficient biofuel production. An integrated process that consists of a sewage sludge fermentation system producing VFAs (SSFV) and mixotrophic cultivation of Chlorella vulgaris (C. vulgaris) was operated to produce microbial lipids economically. The effluents from the SSFV diluted to different concentrations at the level of 100%, 50%, and 15% were prepared for the C. vulgaris cultivation and the highest biomass productivity (433±11.9 mg/L/d) was achieved in the 100% culture controlling pH at 7.0. The harvested biomass included lipid contents ranging from 12.87% to 20.01% under the three different effluent concentrations with and without pH control. The composition of fatty acids from C. vulgaris grown on the effluents from the SSFV complied with the requirements of high-quality biodiesel. These results demonstrated that VFAs produced from the SSFV are favorable carbon sources for cultivating C. vulgaris.

Biodiesel production from Scenedesmus bijuga grown in anaerobically digested food wastewater effluent.

Microalgae, Scenedesmus bijuga, was cultivated in anaerobically digested food wastewater effluent (FWE) to treat the wastewater and produce biodiesel simultaneously. Three different mixing ratios with municipal wastewater were compared for finding out proper dilution ratio in biodiesel production. Of these, 1/20 diluted FWE showed the highest biomass production (1.49 g/L). Lipid content was highest in 1/10 diluted FWE (35.06%), and the lipid productivity showed maximum value in 1/20 diluted FWE (15.59 mg/L/d). Nutrient removal was also measured in the cultivation. FAME compositions were mainly composed of C16-C18 (Over 98.94%) in S. bijuga. In addition, quality of FAMEs was evaluated by Cetane Number (CN) and Bis-allylic Position Equivalent (BAPE).

P-modified and carbon shell coated Co nanoparticles for efficient alkaline oxygen reduction catalysis.

Described herein is the development of a novel Co-based oxygen electrode catalyst coupled with unique carbon structures. The present carbon shell coated Co nanoparticles of which the surface composites are modified by phosphorus incorporation, exhibit efficient oxygen reduction activities as well as oxygen evolving properties.

Carbon dioxide conversion into hydrocarbon fuels on defective graphene-supported Cu nanoparticles from first principles.

Density functional theory studies demonstrate that defective graphene-supported Cu nanoparticles can modify the structural and electronic properties of copper for enhancing electrochemical reduction of carbon dioxide (CO2) into hydrocarbon fuels (CH4, CO, and HCOOH). We not only provide improved understanding of CO2 conversion mechanisms on both Cu and the Cu nanoparticle system, but also explain a key factor for enhanced CO2 conversion. A promising catalytic material for CO2 conversion into hydrocarbon fuels may allow for geometry flexibility upon interaction with a key intermediate of CHO*.

The structure-activity relationships of mansonone F, a potent anti-MRSA sesquiterpenoid quinone: SAR studies on the C6 and C9 analogs.

For the systematic SAR study on mansonone F, a series of C6 and C9 analogs of mansonone F have been synthesized and their anti-MRSA activities were evaluated. Most of the analogs exhibited good or excellent anti-MRSA activities. In particular, the 6-n-butylmansonone F showed fourfold higher antibacterial activities compared to that of vancomycin.

Syntheses and anti-MRSA activities of the C3 analogs of mansonone F, a potent anti-bacterial sesquiterpenoid: insights into its structural requirements for anti-MRSA activity.

Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of mansonone F are essential for anti-MRSA activities.