Mechanisms and Effect of Coptidis Rhizoma on Obesity-Induced Inflammation: In Silico and In Vivo Approaches

Obesity is characterized as a chronic, low-grade inflammation state accompanied by the infiltration of immune cells into adipose tissue and higher levels of inflammatory cytokines and chemokines. This study aimed to investigate the mechanisms and effects of Coptidis Rhizoma (CR) on obesity and its associated inflammation. First, we applied a network pharmacology strategy to search the target genes and pathways regulated by CR in obesity. Next, we performed in vivo experiments to confirm the antiobesity and anti-inflammatory effects of CR. Mice were assigned to five groups: normal chow (NC), control (high-fat diet (HFD)), HFD + CR 200 mg/kg, HFD + CR 400 mg/kg, and HFD + metformin 200 mg/kg. After 16 weeks of the experimental period, CR administration significantly reduced the weight of the body, epididymal fat, and liver; it also decreased insulin resistance, as well as the area under the curve of glucose in the oral glucose tolerance test and triglyceride in the oral fat tolerance test. We observed a decrease in adipose tissue macrophages (ATMs) and inflammatory M1 ATMs, as well as an increase in anti-inflammatory M2 ATMs. Gene expression levels of inflammatory cytokines and chemokines, including tumor necrosis factor-α, F4/80, and C-C motif chemokine (CCL)-2, CCL4, and CCL5, were suppressed in adipose tissue in the CR groups than levels in the control group. Additionally, histological analyses suggested decreased fat accumulation in the epididymal fat pad and liver in the CR groups than that in the control group. Taken together, these results suggest that CR has a therapeutic effect on obesity-induced inflammation, and it functions through the inhibition of macrophage-mediated inflammation in adipose tissue.

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Nobiletin exerts anti-diabetic and anti-inflammatory effects in an in vitro human model and in vivo murine model of gestational diabetes

Clinical Science ◽

10.1042/cs20191099 ◽

2020 ◽

Vol 134 (6) ◽

pp. 571-592 ◽

Cited By ~ 5

Author(s):

Caitlyn Nguyen-Ngo ◽

Carlos Salomon ◽

Stephanie Quak ◽

Andrew Lai ◽

Jane C Willcox ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Metabolism ◽

Gestational Diabetes ◽

Mrna Expression ◽

Inflammatory Cytokines ◽

Cytokines And Chemokines ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.

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Puerarin Attenuates Obesity-Induced Inflammation and Dyslipidemia by Regulating Macrophages and TNF-Alpha in Obese Mice

Biomedicines ◽

10.3390/biomedicines10010175 ◽

2022 ◽

Vol 10 (1) ◽

pp. 175

Author(s):

Ji-Won Noh ◽

Hee-Kwon Yang ◽

Min-Soo Jun ◽

Byung-Cheol Lee

Keyword(s):

Adipose Tissue ◽

In Silico ◽

Tolerance Test ◽

Low Grade ◽

Adipocyte Size ◽

Metabolic Complications ◽

Immunological Mechanisms ◽

Tnf Α ◽

Test Serum

Obesity causes low-grade inflammation that results in dyslipidemia and insulin resistance. We evaluated the effect of puerarin on obesity and metabolic complications both in silico and in vivo and investigated the underlying immunological mechanisms. Twenty C57BL/6 mice were divided into four groups: normal chow, control (HFD), HFD + puerarin (PUE) 200 mg/kg, and HFD + atorvastatin (ATO) 10 mg/kg groups. We examined bodyweight, oral glucose tolerance test, serum insulin, oral fat tolerance test, serum lipids, and adipocyte size. We also analyzed the percentage of total, M1, and M2 adipose tissue macrophages (ATMs) and the expression of F4/80, tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4. In silico, we identified the treatment-targeted genes of puerarin and simulated molecular docking with puerarin and TNF, M1, and M2 macrophages based on functionally enriched pathways. Puerarin did not significantly change bodyweight but significantly improved fat pad weight, adipocyte size, fat area in the liver, free fatty acids, triglycerides, total cholesterol, and HDL-cholesterol in vivo. In addition, puerarin significantly decreased the ATM population and TNF-α expression. Therefore, puerarin is a potential anti-obesity treatment based on its anti-inflammatory effects in adipose tissue.

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Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22179208 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9208

Author(s):

Vilim Molnar ◽

Vid Matišić ◽

Ivan Kodvanj ◽

Roko Bjelica ◽

Željko Jeleč ◽

...

Keyword(s):

Complex Network ◽

Inflammatory Cytokines ◽

Cell Communication ◽

Low Grade ◽

Joint Cartilage ◽

Common Cause ◽

Degenerative Process ◽

Cytokines And Chemokines ◽

Anti Inflammatory ◽

Low Grade Inflammation

Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.

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Evaluating the effect of rice (Oryza sativa L.: SRNC05053-6-2) crude extract on psoriasis using in vitro and in vivo models

Scientific Reports ◽

10.1038/s41598-020-74634-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sumate Ampawong ◽

Kanchana Kengkoom ◽

Passanesh Sukphopetch ◽

Pornanong Aramwit ◽

Watcharamat Muangkaew ◽

...

Keyword(s):

Oryza Sativa ◽

Inflammatory Cytokines ◽

Crude Extract ◽

Oryza Sativa L ◽

Therapeutic Effects ◽

In Vivo Models ◽

Cytokines And Chemokines ◽

Anti Inflammatory

Abstract Psoriasis is mainly caused because of inappropriate immune responses in the epidermis. Rice (Oryza sativa L.: SRNC05053-6-2) consists of anthocyanin, which exhibits strong antioxidative and anti-inflammatory properties. This study aimed to evaluate the role of this black-coloured rice crude extract in alleviating the symptoms of psoriasis using human psoriatic artificial skin and an imiquimod-induced rat psoriasis model. Psoriasis-related genes, cytokines and chemokines were examined; in addition, the antioxidative and anti-inflammatory properties and the immunohistopathological features of this condition were studied. The results showed that the rice extract reduced the severity of psoriasis by (1) decreasing the epidermal thickness, acanthosis, hyperkeratosis, epidermal inflammation and degree of apoptosis induction via caspase-3, (2) increasing the expression levels of anti-inflammatory cytokines (IL-10 and TGF-β), (3) reducing the levels of pro-inflammatory cytokines (IL-6, IL-8, IL-20, IL-22 and TNF-α), chemokines (CCL-20) and anti-microbial peptides (psoriasin and β-defensin), (4) enhancing the antioxidative property (Nrf-2), (5) downregulating the levels of psoriasis-associated genes (psoriasin, β-defensin, koebnerisin 15L and koebnerisin 15S) and (6) upregulating the levels of psoriasis-improving genes (caspase-14, involucrin and filaggrin). Thus, the extract appears to exert therapeutic effects on psoriasis through its antioxidative and immunomodulatory properties.

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Obesity-Associated Inflammation: Does Curcumin Exert a Beneficial Role?

Nutrients ◽

10.3390/nu13031021 ◽

2021 ◽

Vol 13 (3) ◽

pp. 1021

Author(s):

Rosaria Varì ◽

Beatrice Scazzocchio ◽

Annalisa Silenzi ◽

Claudio Giovannini ◽

Roberta Masella

Keyword(s):

Adipose Tissue ◽

Inflammatory Response ◽

Chronic Diseases ◽

Immune Cells ◽

Molecular Mechanisms ◽

Curcuma Longa ◽

Low Grade ◽

Obese People ◽

Cytokines And Chemokines ◽

Anti Inflammatory

Curcumin is a lipophilic polyphenol, isolated from the plant turmeric of Curcuma longa. Curcuma longa has always been used in traditional medicine in Asian countries because it is believed to have numerous health benefits. Nowadays it is widely used as spice component and in emerging nutraceutical food worldwide. Numerous studies have shown that curcumin possesses, among others, potential anti-inflammatory properties. Obesity represents a main risk factor for several chronic diseases, including type 2 diabetes, cardiovascular disease, and some types of cancer. The establishment of a low-grade chronic inflammation, both systemically and locally in adipose tissue, occurring in obesity most likely represents a main factor in the pathogenesis of chronic diseases. The molecular mechanisms responsible for the onset of the obesity-associated inflammation are different from those involved in the classic inflammatory response caused by infections and involves different signaling pathways. The inflammatory process in obese people is triggered by an inadequate intake of nutrients that produces quantitative and qualitative alterations of adipose tissue lipid content, as well as of various molecules that act as endogenous ligands to activate immune cells. In particular, dysfunctional adipocytes secrete inflammatory cytokines and chemokines, the adipocytokines, able to recruit immune cells into adipose tissue, amplifying the inflammatory response also at systemic level. This review summarizes the most recent studies focused at elucidating the molecular targets of curcumin activity responsible for its anti-inflammatory properties in obesity-associated inflammation and related pathologies.

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Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice

Journal of Endocrinology ◽

10.1530/joe-14-0069 ◽

2014 ◽

Vol 222 (2) ◽

pp. 201-215 ◽

Cited By ~ 52

Author(s):

Jillian L Rourke ◽

Shanmugam Muruganandan ◽

Helen J Dranse ◽

Nichole M McMullen ◽

Christopher J Sinal

Keyword(s):

Adipose Tissue ◽

Glucose Homeostasis ◽

Stromal Vascular Fraction ◽

Tolerance Test ◽

Glucose Levels ◽

Brown Adipose ◽

Elevated Glucose ◽

And Function ◽

G Protein Coupled

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

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N-palmitoyl-D-glucosamine, A Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22031491 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1491 ◽

Cited By ~ 1

Author(s):

Monica Iannotta ◽

Carmela Belardo ◽

Maria Consiglia Trotta ◽

Fabio Arturo Iannotti ◽

Rosa Maria Vitale ◽

...

Keyword(s):

Sciatic Nerve ◽

Inflammatory Cytokines ◽

Lipid A ◽

Saturated Fatty Acids ◽

Structural Similarity ◽

Antagonistic Activity ◽

Critical Function ◽

Anti Inflammatory

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.

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SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF NEW NAPROXEN ANALOGUES HAVING 1, 2, 4-TRIAZOLE-3-THIOL

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2017v9i7.18273 ◽

2017 ◽

Vol 9 (7) ◽

pp. 66

Author(s):

Monther F. Mahdi ◽

Noor H. Naser ◽

Nethal H. Hammud

Keyword(s):

Aromatic Aldehydes ◽

Heterocyclic Ring ◽

Inflammatory Activity ◽

Control Group ◽

Paw Edema ◽

Dose Equivalent ◽

Edema Model ◽

Anti Inflammatory ◽

Derivatives Of

Objective: The objective of this search was to synthesize a new naproxen analogues having a 1,2,4-triazole-3-thiol heterocyclic ring, and preliminary pharmacological assessment of the anti-inflammatory activity of the synthesized compounds. Methods: The synthesis of naproxen analogues that having 1,2,4-triazole-3-thiol heterocyclic ring occur through esterification of naproxen, and then its reaction with hydrazine hydrate, and carbon disulfide, finally different aromatic aldehydes reacted with triazole derivatives of naproxen containing amino group to produce schiff bases.Results: In vivo acute anti-inflammatory activity of the synthesize compounds (Va-Vd) was evaluated in rats using egg-white induced edema model of inflammation in a dose equivalent to (50 mg/kg) of naproxen. All tested compounds were produced a significant reduction in paw edema with respect to the effect of propylene glycol 50% v/v (control group). Compound Vd produced superior anti-inflammatory activity compared to naproxen.Conclusion: The results obtained in this work give evidence about the valid synthesis of 1,2,4 triazole-3-thiol derivatives of naproxen, which reacted with different aldehydes to yield several schiff bases. The incorporation of benzaldehyde possess para-electron donating group (para-hydroxyl benzaldehyde) will increase the anti-inflammatory activity of naproxen.

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Decreased TLR3 in Hyperplastic Adipose Tissue, Blood and Inflamed Adipocytes is Related to Metabolic Inflammation

Cellular Physiology and Biochemistry ◽

10.1159/000495487 ◽

2018 ◽

Vol 51 (3) ◽

pp. 1051-1068 ◽

Cited By ~ 7

Author(s):

Jèssica Latorre ◽

José M. Moreno-Navarrete ◽

Mónica Sabater ◽

Maria Buxo ◽

José I. Rodriguez-Hermosa ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Inflammation ◽

Fat Depots ◽

Acute Surgery ◽

Obese Subjects ◽

Anti Inflammatory ◽

The Impact

Background/Aims: Obesity is characterized by the immune activation that eventually dampens insulin sensitivity and changes metabolism. This study explores the impact of different inflammatory/ anti-inflammatory paradigms on the expression of toll-like receptors (TLR) found in adipocyte cultures, adipose tissue, and blood. Methods: We evaluated by real time PCR the impact of acute surgery stress in vivo (adipose tissue) and macrophages (MCM) in vitro (adipocytes). Weight loss was chosen as an anti-inflammatory model, so TLR were analyzed in fat samples collected before and after bariatric surgery-induced weight loss. Associations with inflammatory and metabolic parameters were analyzed in non-obese and obese subjects, in parallel with gene expression measures taken in blood and isolated adipocytes/ stromal-vascular cells (SVC). Treatments with an agonist of TLR3 were conducted in human adipocyte cultures under normal conditions and upon conditions that simulated the chronic low-grade inflammatory state of obesity. Results: Surgery stress raised TLR1 and TLR8 in subcutaneous (SAT), and TLR2 in SAT and visceral (VAT) adipose tissue, while decreasing VAT TLR3 and TLR4. MCM led to increased TLR2 and diminished TLR3, TLR4, and TLR5 expressions in human adipocytes. The anti-inflammatory impact of weight loss was concomitant with decreased TLR1, TLR3, and TLR8 in SAT. Cross-sectional associations confirmed increased V/ SAT TLR1 and TLR8, and decreased TLR3 in obese patients, as compared with non-obese subjects. As expected, TLR were predominant in SVC and adipocyte precursor cells, even though expression of all of them but TLR8 (very low levels) was also found in ex vivo isolated and in vitro differentiated adipocytes. Among SVC, CD14+ macrophages showed increased TLR1, TLR2, and TLR7, but decreased TLR3 mRNA. The opposite patterns shown for TLR2 and TLR3 in V/ SAT, SVC, and inflamed adipocytes were observed in blood as well, being TLR3 more likely linked to lymphocyte instead of neutrophil counts. On the other hand, decreased TLR3 in adipocytes challenged with MCM dampened lipogenesis and the inflammatory response to Poly(I:C). Conclusion: Functional variations in the expression of TLR found in blood and hypertrophied fat depots, namely decreased TLR3 in lymphocytes and inflamed adipocytes, are linked to metabolic inflammation.

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Pro- and Anti-Inflammatory Cytokines in the First Trimester—Comparison of Missed Miscarriage and Normal Pregnancy

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168538 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8538

Author(s):

Maciej Kwiatek ◽

Tomasz Gęca ◽

Anna Kwaśniewska

Keyword(s):

Immune Response ◽

Inflammatory Cytokines ◽

First Trimester ◽

Normal Pregnancy ◽

Control Group ◽

Study Group ◽

Tnf Α ◽

Cytokine Levels ◽

Anti Inflammatory ◽

Tgf Β1

The advantage in response of Th2 over Th1 is observed in normal pregnancy in peripheral blood. A disturbance of this balance can lead to symptoms of miscarriage and pregnancy loss. The aim of this study was to evaluate the pro- and anti-inflammatory cytokines in sera of women who were diagnosed with missed miscarriage in the first trimester and to compare this systemic immune response to the response in women with normal pregnancy. The study group consisted of 61 patients diagnosed with missed miscarriage. In total, 19 healthy women with uncomplicated first trimester created the control group. Cytokines were determined in the maternal serum by ELISA. The analysis included INF-γ, TNF-α, Il-1β, Il-4, Il-5, Il-6, Il-9, Il-10, Il-13 and TGF-β1. Th1 cytokine levels in the study group reached slightly higher values for INF-γ, Il-1β and slightly lower for IL-6 and TNF-α. In turn, Th2 cytokine levels in the study group were slightly higher (Il-9, Il-13), significantly higher (Il4, p = 0.015; Il-5, p = 0.0003) or showed no differences with the control group (Il-10). Slightly lower concentration involved only TGF-β1. Analysis of the correlation between levels of pro- and anti-inflammatory cytokines resulted in some discrepancies, without showing predominance of a specific immune response. The results did not confirm that women with missed miscarriage had an advantage in any type of immune response in comparison to women with normal pregnancy.

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