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Genetic disruption of the inflammasome adaptor ASC has minimal impact on the pathogenesis of Duchenne muscular dystrophy in mdx mice

Lau YS, Zhao L, Zhang C, Li H, Han R

Life Sci, 2020 Jul 10.
PMID: 32659370 DOI: 10.1016/j.lfs.2020.118069

AIM: Up-regulation of inflammasome proteins was reported in dystrophin-deficient muscles. However, it remains to be determined whether inflammasome activation plays a role in the pathogenesis of Duchenne muscular dystrophy. This study was therefore set out to investigate whether genetic disruption of the inflammasome pathway impacts the disease progression in mdx mice.
MAIN METHODS: Mice deficient in both dystrophin and ASC (encoded by Pycard [PYD And CARD Domain Containing]) were generated. The impact of ASC deficiency on muscular dystrophy of mdx mice were assessed by measurements of serum cytokines, Western blot, real-time PCR and histopathological staining.
KEY FINDINGS: The pro-inflammatory cytokines such as TNF-α, IL-6, KC/GRO and IL-10 were markedly increased in the sera of 8-week-old mdx mice compared to WT. Western blotting showed that P2X7, caspase-1, ASC and IL-18 were upregulated. Disruption of ASC and dystrophin expression in the mdx/ASC-/- mice was verified by Western blot analysis. Histopathological analysis did not find significant alterations in the muscular dystrophy phenotype in mdx/ASC-/- mice as compared to mdx mice.
SIGNIFICANCE: Taken together, our results show that disruption of the central adaptor ASC of the inflammasome is insufficient to alleviate muscular dystrophy phenotype in mdx mice.
Fulltext Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth

Li H, Zhao L, Lau YS, Zhang C, Han R

Oncogene, 2021 01;40(1):177-188.
PMID: 33110234 DOI: 10.1038/s41388-020-01523-5

Colorectal cancer is the third leading cause of cancer-related deaths in the United States and the third most common cancer in men and women. Around 20% colon cancer cases are closely linked with colitis. Both environmental and genetic factors are thought to contribute to colon inflammation and tumor development. However, the genetic factors regulating colitis and colon tumorigenesis remain elusive. Since reactive oxygen species (ROS) is vitally involved in tissue inflammation and tumorigenesis, here we employed a genome-wide CRISPR knockout screening approach to systemically identify the genetic factors involved in the regulation of oxidative stress. Next generation sequencing (NGS) showed that over 600 gRNAs including the ones targeting LGALS2 were highly enriched in cells survived after sublethal H2O2 challenge. LGALS2 encodes the glycan-binding protein Galectin 2 (Gal2), which is predominantly expressed in the gastrointestinal tract and downregulated in human colon tumors. To examine the role of Gal2 in colitis, we employed the dextran sodium sulfate (DSS)-induced acute colitis model in mice with (WT) or without Lgals2 (Gal2-KO) and showed that Gal2 deficiency ameliorated DSS-induced colitis. We further demonstrated that Gal2-KO mice developed significantly larger tumors than WT mice using Azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal cancer model. We found that STAT3 phosphorylation was significantly increased in Gal2-deficient tumors as compared to those in WT mice. Gal2 overexpression decreased the proliferation of human colon tumor epithelial cells and blunted H2O2-induced STAT3 phosphorylation. Overall, our results demonstrate that Gal2 plays a suppressive role in colon tumor growth and highlights the therapeutic potential of Gal2 in colon cancer.
Reduced graphene oxide coated porous carbon-sulfur nanofiber as a flexible paper electrode for lithium-sulfur batteries

Chu RX, Lin J, Wu CQ, Zheng J, Chen YL, Zhang J, et al.

Nanoscale, 2017 Jun 23.
PMID: 28644506 DOI: 10.1039/c7nr02423a

Lithium-sulfur (Li-S) batteries have attracted great attention owing to their excellent electrochemical properties, such as the high discharge voltage of 2.3 V, specific capacity of 1675 mA h g(-1) and energy density of 2600 Wh kg(-1). The widely used slurry made electrodes of Li-S batteries are plagued by the serious shuttle effect and insulating nature of sulfur. Herein, a reduced graphene oxide coated porous carbon nanofiber flexible paper (rGO@S-PCNP) was fabricated and directly used as an additive-free cathode for Li-S batteries. The results show that the rGO@S-PCNP is certified to be effective at relieving the shuttle effect and improving the conductivity, thus achieving high electrochemical performance. The rGO@S-PCNP composite with a sulfur content of 58.4 wt% delivers a high discharge capacity of 623.7 mA h g(-1) after 200 cycles at 0.1 C (1 C = 1675 mA g(-1)) with the average Coulombic efficiency of 97.1%. The excellent cyclability and high Coulombic efficiency indicate that the as-prepared rGO@S-PCNP composite paper can be a promising cathode for lithium-sulfur batteries, and is envisioned to have great potential in high energy density flexible power devices. This facile strategy brings great significance for large-scale industrial fabrication of flexible lithium-sulfur batteries.
Phillyrin: an adipose triglyceride lipase inhibitor supported by molecular docking, dynamics simulation, and pharmacological validation

Zhou C, Yan L, Xu J, Hamezah HS, Wang T, Du F, et al.

J Mol Model, 2024 Feb 13;30(3):68.
PMID: 38347278 DOI: 10.1007/s00894-024-05875-7

CONTEXT: Adipose triglyceride lipase (ATGL), a key enzyme responsible for lipolysis, catalyzes the first step of lipolysis and converts triglycerides to diacylglycerols and free fatty acids (FFA). Our previous work suggested that phillyrin treatment improves insulin resistance in HFD-fed mice, which was associated with ATGL inhibition. In this study, using docking simulation, we explored the binding pose of phillyrin and atglistatin (a mouse ATGL inhibitor) to ATGL in mouse. From the docking results, the interactions with Ser47 and Asp166 were speculated to have caused phillyrin to inhibit ATGL in mice. Further, molecular dynamics simulation of 100 ns and MM-GBSA were conducted for the protein-ligand complex, which indicated that the system was stable and that phillyrin displayed a better affinity to ATGL than did atglistatin throughout the simulation period. Moreover, the results of pharmacological validation were consistent with those of the in silico simulations. In summary, our study illustrates the potential of molecular docking to accurately predict the binding protein produced by AlphaFold and suggests that phillyrin is a potential small molecule that targets and inhibits ATGL enzymatic activity.
METHODS: The ATGL-predicted protein structure, verified by PROCHECK, was determined using AlphaFold. Molecular docking, molecular dynamics simulation, and prime molecular mechanic-generalized born surface area were performed using LigPrep, Desmond, and prime MM-GBSA modules of Schrödinger software release 2021-2, respectively. For pharmacological validation, immunoblotting was performed to assess ATGL protein expression. The fluorescence intensity and glycerol concentration were quantified to evaluate the efficiency of phillyrin in inhibiting ATGL.
Fulltext Efficacy of Forsythia suspensa (Thunb.) Vahl on mouse and rat models of inflammation-related diseases: a meta-analysis

Zhou C, Xia Q, Hamezah HS, Fan Z, Tong X, Han R

Front Pharmacol, 2024;15:1288584.
PMID: 38500762 DOI: 10.3389/fphar.2024.1288584

Objective: To evaluate the efficacy of the fruits of the medicinal plant Forsythia suspensa (Thunb.) Vahl (FS), in treating inflammation-associated diseases through a meta-analysis of animal models, and also probe deeply into the signaling pathways underlying the progression of inflammation. Materials and methods: All data analyses were performed using Review Manager 5.3 and the results are presented as flow diagrams, risk-of-bias summaries, forest plots, and funnel plots. Summary estimates were calculated using a random- or fixed-effect model, depending on the value of I2. Results: Of the 710 records identified in the initial search, 11 were selected for the final meta-analysis. Each study extracted data from the model and treatment groups for analysis, and the results showed that FS alleviated the inflammatory cytokine levels in serum; oxidant indicator: reactive oxygen species; enzymes of liver function; endotoxin and regulatory cells in blood; and improved the antioxidant enzyme superoxide dismutase. Conclusion: FS effectively reversed the change in acute or chronic inflammation indicators in animal models, and the regulation of multiple channel proteins in inflammatory signaling pathways suggests that FS is a good potential drug for inflammatory disease drug therapy.
Fulltext An insight review on the neuropharmacological effects, mechanisms of action, pharmacokinetics and toxicity of mitragynine

Annuar NAK, Azlan UK, Mediani A, Tong X, Han R, Al-Olayan E, et al.

Biomed Pharmacother, 2024 Feb;171:116134.
PMID: 38219389 DOI: 10.1016/j.biopha.2024.116134

Mitragynine is one of the main psychoactive alkaloids in Mitragyna speciosa Korth. (kratom). It has opium-like effects by acting on μ-, δ-, and κ-opioid receptors in the brain. The compound also interacts with other receptors, such as adrenergic and serotonergic receptors and neuronal Ca2+ channels in the central nervous system to have its neuropharmacological effects. Mitragynine has the potential to treat diseases related to neurodegeneration such as Alzheimer's disease and Parkinson's disease, as its modulation on the opioid receptors has been reported extensively. This review aimed to provide an up-to-date and critical overview on the neuropharmacological effects, mechanisms of action, pharmacokinetics and safety of mitragynine as a prospective psychotropic agent. Its multiple neuropharmacological effects on the brain include antinociceptive, anti-inflammatory, antidepressant, sedative, stimulant, cognitive, and anxiolytic activities. The potential of mitragynine to manage opioid withdrawal symptoms related to opioid dependence, its pharmacokinetics and toxic effects were also discussed. The interaction of mitragynine with various receptors in the brain produce diverse neuropharmacological effects, which have beneficial properties in neurological disorders. However, further studies need to be carried out on mitragynine to uncover its complex mechanisms of action, pharmacokinetics, pharmacodynamic profiles, addictive potential, and safe dosage to prevent harmful side effects.
Fulltext Modelling the Public Health Burden of Herpes Zoster and the Impact of Adjuvanted Recombinant Zoster Vaccine in Five Selected Countries in Southeast Asia

Han R, San Martin P, Ahmed N, Guzman-Holst A, Mohy A, Pinto T, et al.

Infect Dis Ther, 2024 Apr;13(4):761-778.
PMID: 38493411 DOI: 10.1007/s40121-024-00945-y

INTRODUCTION: Herpes zoster (HZ) can cause substantial patient morbidity and lead to large healthcare costs. However, the disease burden of HZ in Southeast Asia may be underestimated. This study aimed to estimate the public health burden of HZ and the impact of vaccinating adults aged ≥ 50 years old in five Southeast Asian countries (Indonesia, Malaysia, Philippines, Thailand, and Vietnam), with adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination.
METHODS: For each country, we adapted a static multicohort Markov model developed with a 1-year cycle length and lifetime horizon. Demographics were obtained from the World Health Organization, HZ incidence from a worldwide meta-regression reporting Asian-specific values, proportions of postherpetic neuralgia (PHN) and non-PHN complications from local/regional studies, and vaccine efficacy from a long-term follow-up trial. First-dose coverage and second-dose compliance were assumed to be 30% and 70%, respectively. A one-way deterministic sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness and uncertainty of inputs for each country.
RESULTS: Without RZV, it was estimated that there would be a total of approximately 10 million HZ cases, 2.1 million PHN cases, and 1.4 million non-PHN complications in individuals aged ≥ 50 years included in the model. Introducing RZV under 30% coverage could avoid approximately 2.2 million (22%) HZ cases, almost 500,000 (21%) PHN cases, and around 300,000 (22%) non-PHN complications. OWSA showed that first-dose coverage and initial HZ incidence had the largest impact on the estimated number of HZ cases avoided. The number needed to vaccinate ranged from 15 to 21 to prevent one case of HZ and from 68 to 104 to prevent one case of PHN across each country.
CONCLUSIONS: This study demonstrated that there is substantial HZ disease burden in older adults for the five selected countries in Southeast Asia, negatively impacting national healthcare systems. Introducing RZV could potentially reduce this burden. A graphical abstract is available with this article.