Extracts of Vine Tea Improve Diet-Induced Non-Alcoholic Steatohepatitis Through AMPK-LXRα Signaling

Chinese vine tea can improve glucose and lipid metabolic disorders. However, its protective effects in non-alcoholic steatohepatitis (NASH) and its underlying molecular mechanisms remain unclear. Liver X receptor α (LXRα) inhibition and adenosine monophosphate-(AMP)-activated protein kinase (AMPK) activation can enhance control of NASH. AMPK activators have also been shown to inactivate LXRα. Here, the anti-NASH effects of vine tea extract (VTE) dosed at 1 g.100 g−1 diet were investigated using NASH mice challenged with a methionine and choline-deficient l-amino acid diet (MCDD) and a high-fat diet (HFD). Pharmacological mechanisms of VTE were explored using TUNEL staining, AMPK inhibition, Western blot, reporter assays, qRT-PCR analyses, and immunofluorescence. VTE treatment improved fatty liver in HFD-induced mice, while it alleviated the progression of NASH including protecting against liver lipid accumulation, steatosis, endoplasmic reticulum stress, apoptosis, inflammation, and functional injury in MCDD-fed mice. VTE reduced the action of hepatic lipogenic genes, F4/80, pro-inflammatory cytokines, CHOP, and cleaved Caspase-3 expression, while promoting expression of fatty acid oxidation genes CPT1α, ß. VTE also enhanced AMPK and blocked LXRα signaling in mouse livers. In vitro results indicated that VTE increased AMPK phosphorylation and reduced LXRα activity in HepG2 cells. Conversely, the antagonistic effect of VTE on LXRα was decreased through AMPK inhibition. Our data suggests that VTE may improve diet-induced NASH, which involves the pharmacological modulation of the AMPK-LXRα signaling pathway.

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Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

Antioxidants ◽

10.3390/antiox10020334 ◽

2021 ◽

Vol 10 (2) ◽

pp. 334

Author(s):

Aisha Y. Madani ◽

Yasser Majeed ◽

Houari B. Abdesselem ◽

Maha V. Agha ◽

Muneera Vakayil ◽

...

Keyword(s):

Adipose Tissue ◽

Molecular Mechanisms ◽

Adenosine Monophosphate ◽

Human Adipose Tissue ◽

Premature Aging ◽

Guanosine Monophosphate ◽

Negative Regulator ◽

Signal Transducer ◽

Interferon Signaling

Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling—it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.

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Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/163057 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Yan-Fang Xian ◽

Zhi-Xiu Lin ◽

Qing-Qiu Mao ◽

Jian-Nan Chen ◽

Zi-Ren Su ◽

...

Keyword(s):

Signaling Pathway ◽

Pc12 Cells ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Neuroprotective Effect ◽

Protective Action ◽

Protective Effects ◽

Phosphorylated Akt ◽

Induced Apoptosis

The neurotoxicity of amyloid-β(Aβ) has been implicated as a critical cause of Alzheimer’s disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated fromUncaria rhynchophylla,exerts neuroprotective effect againstAβ25–35-induced neurotoxicityin vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN againstAβ25–35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation inAβ25–35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β(p-GSK-3β). Lithium chloride blockedAβ25–35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3βinhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversedAβ25–35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN againstAβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3βsignaling pathway.

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Bioinformatic and experimental findings to indicate anti-cancer targets and mechanisms of calycosin against nasopharyngeal carcinoma

10.21203/rs.2.23332/v1 ◽

2020 ◽

Author(s):

Fangxian Liu ◽

Qijin Pan ◽

Liangliang Wang ◽

Shijiang Yi ◽

Peng Liu ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Cell Number ◽

Network Pharmacology ◽

Tunel Staining ◽

Pharmacological Targets ◽

Experimental Findings

Abstract Background: Calycosin is a naturally-occurring phytoestrogen that reportedly exerts anti- nasopharyngeal carcinoma (NPC) effects. Nevertheless, the molecular mechanisms for anti-NPC using calycosin remain unrevealed. Methods: Thus, a network pharmacology was used to uncover anti-NPC pharmacological targets and mechanisms of calycosin. Additionally, validated experiments were conducted to validate the bioinformatic findings of calycosin for treating NPC. Results: As results, bioinformatic assays showed that the predictive pharmacological targets of calycosin against NPC were TP53, MAPK14, CASP8, MAPK3, CASP3, RIPK1, JUN, ESR1, respectively. And the top 20 biological processes and pharmacological mechanisms of calycosin against NPC were identified accordingly. In clinical data, NPC samples showed positive expression of MAPK14, reduced TP53, CASP8 expressions. In studies in vitro and in vivo, calycosin-dosed NPC cells resulted in reduced cell proliferation, promoted cell apoptosis. In TUNEL staining, calycosin exhibited elevated apoptotic cell number. And immunostaining assays resulted in increased TP53, CASP8 positive cells, and reduced MAPK14 expressions in calycosin-dosed NPC cells and tumor-bearing nude mice. Conclusion: Altogether, these bioinformatic findings reveal optimal pharmacological targets and mechanisms of calycosin against NPC, following with representative identification of human and preclinical experiments. Notably, some of original biotargets may be potentially used to treat NPC.

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Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression

Scientific Reports ◽

10.1038/s41598-020-75288-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Minyoung Lee ◽

Eugene Shin ◽

Jaehyun Bae ◽

Yongin Cho ◽

Ji-Yeon Lee ◽

...

Keyword(s):

Molecular Mechanisms ◽

Dipeptidyl Peptidase ◽

Trail Receptor ◽

Dipeptidyl Peptidase 4 ◽

Alcoholic Steatohepatitis ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Group 2 ◽

Induced Apoptosis

Abstract Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

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Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9480945 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11

Author(s):

Hai-tao Xiao ◽

Jiao Peng ◽

Bo Wen ◽

Dong-dong Hu ◽

Xiao-peng Hu ◽

...

Keyword(s):

Oxidative Stress ◽

Chinese Medicine ◽

Th17 Cells ◽

Molecular Mechanisms ◽

Activity Index ◽

Disease Activity Index ◽

Protective Effects ◽

Mesenteric Lymph Nodes ◽

Indigo Naturalis

Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.

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Estrogens and progestins: molecular effects on brain cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2010.078 ◽

2010 ◽

Vol 4 (3) ◽

Author(s):

Paolo Mannella ◽

Tommaso Simoncini ◽

Andrea Riccardo Genazzani

Keyword(s):

Sex Steroids ◽

Molecular Mechanisms ◽

Neural Cells ◽

Protective Effects ◽

Complete Knowledge ◽

Molecular Effects ◽

In Vivo Effects ◽

The Brain

AbstractSex steroids are known to regulate brain function and their role is so important that several diseases are strictly correlated with the onset of menopause when estrogen-progesterone deficiency makes neural cells much more vulnerable to toxic stimuli. Although in the past years several scientists have focused their studies on in vitro and in vivo effects of sex steroids on the brain, we are still far from complete knowledge. Indeed, contrasting results from large clinical trials have made the entire issue much more complicated. Currently we know that protective effects exerted by sex steroids depend on several factors among which the dose, the health of the cells and the type of molecule being used. In this review, we present an overview of the direct and indirect effects of estrogen and progesterone on the brain with specific focus on the molecular mechanisms by which these molecules act on neural cells.

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The Antioxidant Mechanisms Underlying the Aged Garlic Extract- and S-Allylcysteine-Induced Protection

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/907162 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 103

Author(s):

Ana L. Colín-González ◽

Ricardo A. Santana ◽

Carlos A. Silva-Islas ◽

Maria E. Chánez-Cárdenas ◽

Abel Santamaría ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Original Data ◽

Garlic Extract ◽

Protective Effects ◽

Aged Garlic Extract ◽

Antioxidant Mechanisms ◽

Aged Garlic

Aged garlic extract (AGE) is an odorless garlic preparation containing S-allylcysteine (SAC) as its most abundant compound. A large number of studies have demonstrated the antioxidant activity of AGE and SAC in bothin vivo—in diverse experimental animal models associated to oxidative stress—andin vitroconditions—using several methods to scavenge reactive oxygen species or to induce oxidative damage. Derived from these experiments, the protective effects of AGE and SAC have been associated with the prevention or amelioration of oxidative stress. In this work, we reviewed different antioxidant mechanisms (scavenging of free radicals and prooxidant species, induction of antioxidant enzymes, activation of Nrf2 factor, inhibition of prooxidant enzymes, and chelating effects) involved in the protective actions of AGE and SAC, thereby emphasizing their potential use as therapeutic agents. In addition, we highlight the ability of SAC to activate Nrf2 factor—a master regulator of the cellular redox state. Here, we include original data showing the ability of SAC to activate Nrf2 factor in cerebral cortex. Therefore, we conclude that the therapeutic properties of these molecules comprise cellular and molecular mechanisms at different levels.

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Human primary astrocytes increase basal fatty acid oxidation following recurrent low glucose to maintain intracellular nucleotide levels

10.1101/271981 ◽

2018 ◽

Cited By ~ 1

Author(s):

Paul G Weightman Potter ◽

Julia M. Vlachaki Walker ◽

Josephine L Robb ◽

John K. Chilton ◽

Ritchie Williamson ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Molecular Mechanisms ◽

Coupling Efficiency ◽

Acid Oxidation ◽

Major Barrier ◽

Specificity And Sensitivity ◽

Low Glucose ◽

Primary Astrocytes

ABSTRACTHypoglycemia is a major barrier to good glucose control in type 1 diabetes and frequent exposure to hypoglycemia can impair awareness to subsequent bouts of hypoglycemia. The neural changes that occur to reduce a person’s awareness of hypoglycemia are poorly defined. Moreover, the molecular mechanisms by which glial cells contribute to hypoglycemia sensing and glucose counterregulation require further investigation. To test whether glia, specifically astrocytes, could detect changes in glucose, we utilized human primary astrocytes (HPA) and U373 astrocytoma cells and exposed them to recurrent low glucose (RLG) in vitro. This allowed measurement, with high specificity and sensitivity, of changes in cellular metabolism following RLG. We report that the AMP-activated protein kinase (AMPK) is activated over a pathophysiologically-relevant glucose concentration range. We observed an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and hallmarks of mitochondrial stress including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG, nor were glucose uptake or glycogen levels. Taken together, these data indicate that astrocyte mitochondria are dysfunctional following recurrent low glucose exposure, which could have implications for hypoglycemia glucose counterregulation and/or hypoglycemia awareness.

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Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis

10.2337/figshare.12771341.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Chiara Ruocco ◽

Maurizio Ragni ◽

Fabio Rossi ◽

Pierluigi Carullo ◽

...

Keyword(s):

Amino Acids ◽

Energy Metabolism ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Essential Amino Acids ◽

Brown Fat ◽

Acid Oxidation ◽

White Fat

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance, as such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, <a>we show that a designer protein-deprived diet enriched in free essential amino acids can i) promote the brown fat thermogenic program and fatty acid oxidation, ii) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, iii) change the gut microbiota composition, and iv) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy lifespan. </a>These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by <i>in vitro</i> experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

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Present Status, Limitations and Future Directions of Treatment Strategies Using Fucoidan-Based Therapies in Bladder Cancer

Cancers ◽

10.3390/cancers12123776 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3776

Author(s):

Yasuyoshi Miyata ◽

Tomohiro Matsuo ◽

Kojiro Ohba ◽

Kensuke Mitsunari ◽

Yuta Mukae ◽

...

Keyword(s):

Bladder Cancer ◽

Adverse Events ◽

Molecular Mechanisms ◽

Immune Therapy ◽

Treatment Strategies ◽

Chemotherapeutic Agents ◽

Protective Effects ◽

Future Directions ◽

Anti Cancer

Bladder cancer (BC) is a common urological cancer, with poor prognosis for advanced/metastatic stages. Various intensive treatments, including radical cystectomy, chemotherapy, immune therapy, and radiotherapy are commonly used for these patients. However, these treatments often cause complications and adverse events. Therefore, researchers are exploring the efficacy of natural product-based treatment strategies in BC patients. Fucoidan, derived from marine brown algae, is recognized as a multi-functional and safe substrate, and has been reported to have anti-cancer effects in various types of malignancies. Additionally, in vivo and in vitro studies have reported the protective effects of fucoidan against cancer-related cachexia and chemotherapeutic agent-induced adverse events. In this review, we have introduced the anti-cancer effects of fucoidan extracts in BC and highlighted its molecular mechanisms. We have also shown the anti-cancer effects of fucoidan therapy with conventional chemotherapeutic agents and new treatment strategies using fucoidan-based nanoparticles in various malignancies. Moreover, apart from the improvement of anti-cancer effects by fucoidan, its protective effects against cancer-related disorders and cisplatin-induced toxicities have been introduced. However, the available information is insufficient to conclude the clinical usefulness of fucoidan-based treatments in BC patients. Therefore, we have indicated the aspects that need to be considered regarding fucoidan-based treatments and future directions for the treatment of BC.

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