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Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Chemerin has been found to be associated with pulmonary hypertension (PH). However, the specific role of chemerin in mediating PH development remains unclear. This study aimed to elucidate the regulatory effects and the underlying mechanism of chemerin on PH and to investigate the expression levels of chemerin protein in plasma in PAH patients. In vivo, two animal models of PH were established in rats by monocrotaline (MCT) injection and hypoxia. We found that the expression levels of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), were significantly upregulated in the lungs of PH rats. Primary cultured pulmonary arterial smooth muscle cells [(PASMCs) (isolated from pulmonary arteries of normal healthy rats)] were exposed to hypoxia or treated with recombinant human chemerin, we found that CMKLR1 expression was upregulated in PASMCs in response to hypoxia or chemerin stimulation, whereas the exogenous chemerin significantly promoted the migration and proliferation of PASMCs. Notably, the regulatory effects of chemerin on PASMCs were blunted by PD98059 (a selective ERK1/2 inhibitor). Using enzyme linked immunosorbent assay (ELISA), we found that the protein level of chemerin was also markedly increased in plasma from idiopathic pulmonary arterial hypertension (IPAH) patients compared to that from healthy controls. Moreover, the diagnostic value of chemerin expression in IPAH patients was determined through receiver operating characteristic (ROC) curve analysis and the result revealed that area under ROC curve (AUC) for plasma chemerin was 0.949. Taken together, these results suggest that chemerin exacerbates PH progression by promoting the proliferation and migration of PASMCs via the ERK1/2 signaling pathway, and chemerin is associated with pulmonary hypertension.

Osteoporosis is a condition in which bone mineral density is reduced due to altered bone microstructure, which results in increased skeletal fragility and incidence of various types of fractures. Adipokines such as chemerin, vaspin, omentin-1 and osteoprotegerin are involved in bone remodeling. The current study was designed to determine the changes in circulating chemerin, vaspin, omentin-1, and osteoprotegerin levels after treatment with oral ibandronate 150 mg in postmenopausal osteoporotic females. The present study enrolled 107 postmenopausal osteoporotic females from a tertiary care hospital in Faisalabad, Pakistan, based on stringent inclusion and exclusion criteria. Sixty-six healthy postmenopausal, non-osteoporotic females with no systemic illness were chosen from the general population. The assessment of bone mineral density (BMD) was done using a DEXA scan. Serum levels of chemerin, vaspin, omentin-1 and osteoprotegerin were estimated using commercially available enzyme-linked immunosorbent assay kits. The collected data were analyzed with the Statistical Package for Social Sciences (SPSS) version 24. Following 6 months of ibandronate treatment, there was a significant decrease of 24.24% (p < .033) in serum chemerin levels, as well as a significant increase in serum vaspin levels 343.32% (p < .001) and osteoprotegerin levels 19.57% (p < .001), with no significant change in omentin-1 levels. Thus, an increase in serum chemerin levels and a decrease in serum vaspin and osteoprotegerin levels could be implicated in osteoporosis.

Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Chemerin has been found to be associated with pulmonary hypertension (PH). However, the specific role of chemerin in mediating PH development remains unclear. This study aimed to elucidate the regulatory effects and the underlying mechanism of chemerin on PH and to investigate the expression levels of chemerin protein in plasma in PAH patients. In vivo , two animal models of PH were established in rats by monocrotaline (MCT) injection and hypoxia. We found that the expression levels of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), were significantly upregulated in the lungs of PH rats. Primary cultured pulmonary arterial smooth muscle cells [(PASMCs) (isolated from pulmonary arteries of normal healthy rats)] were exposed to hypoxia or treated with recombinant human chemerin, we found that CMKLR1 expression was upregulated in PASMCs in response to hypoxia or chemerin stimulation, whereas the exogenous chemerin significantly promoted the migration and proliferation of PASMCs. Notably, the regulatory effects of chemerin on PASMCs were blunted by PD98059 (a selective ERK1/2 inhibitor). Using enzyme linked immunosorbent assay (ELISA), we found that the protein level of chemerin was also markedly increased in plasma from idiopathic pulmonary arterial hypertension (IPAH) patients compared to that from healthy controls. Moreover, the diagnostic value of chemerin expression in IPAH patients was determined through receiver operating characteristic (ROC) curve analysis and the result revealed that area under ROC curve (AUC) for plasma chemerin was 0.949. Taken together, these results suggest that chemerin exacerbates PH progression by promoting the proliferation and migration of PASMCs via the ERK1/2 signaling pathway, and chemerin is associated with pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Osteoporosis is a condition in which bone mineral density is reduced due to altered bone microstructure, which results in increased skeletal fragility and incidence of various types of fractures. Adipokines such as chemerin, vaspin, omentin-1 and osteoprotegerin are involved in bone remodeling. The current study was designed to determine the changes in circulating chemerin, vaspin, omentin-1, and osteoprotegerin levels after treatment with oral ibandronate 150 mg in postmenopausal osteoporotic females. The present study enrolled 107 postmenopausal osteoporotic females from a tertiary care hospital in Faisalabad, Pakistan, based on stringent inclusion and exclusion criteria. Sixty-six healthy postmenopausal, non-osteoporotic females with no systemic illness were chosen from the general population. The assessment of bone mineral density (BMD) was done using a DEXA scan. Serum levels of chemerin, vaspin, omentin-1 and osteoprotegerin were estimated using commercially available enzyme-linked immunosorbent assay kits. The collected data were analyzed with the Statistical Package for Social Sciences (SPSS) version 24. Following 6 months of ibandronate treatment, there was a significant decrease of 24.24% (p <.033) in serum chemerin levels, as well as a significant increase in serum vaspin levels 343.32% (p <.001) and osteoprotegerin levels 19.57% (p <.001), with no significant change in omentin-1 levels. Thus, an increase in serum chemerin levels and a decrease in serum vaspin and osteoprotegerin levels could be implicated in osteoporosis. [ABSTRACT FROM AUTHOR]

Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Caryopteris odorata (D. Don) B.L. Robinson (Verbenaceae family) is an aromaric shrub traditionally used to treat diabetes and related pathologies (diabetic foot ulcer), cancer/tumors, wound healing, and inflammation. It is enriched with flavonoids and phenolics like coumarins, quercetin, gallic acid, coumaric acid, stigmasterol, α-tocopherol, and iridoids. C. odorata has been reported as having α-glucosidase, anti-inflammatory, and anti-oxidant properties. Its effectiveness in preventing cardiometabolic syndrome has not yet been assessed. This study aims to investigate the potential efficacy of C. odorata and coumarin for characteristic features of cardiometabolic syndrome (CMS), including obesity, dyslipidemia, hyperglycemia, insulin resistance, and hypertension by using high-refined carbohydrate-high fat-cholesterol (HRCHFC)-loaded feed-fed rats. Chronic administration of C. odorata and coumarin for 6 weeks revealed a marked attenuation in body and organ weights, with a consistent decline in feed intake compared to HRCHFC diet fed rats. The test materials also caused a significant reduction in the blood pressure (systolic, diastolic, and mean) and heart rate of HRCHFC-diet fed rats. Improved glucose tolerance and insulin sensitivity tests were also observed in test material administered rats compare to only HRCHFCdiet fed rats. C. odorata and coumarin-treated animals produced a marked decline in serum FBG, TC, TG, LFTs, and RFTs, while an increase in serum HDL-C levels was noticed. C. odorata and coumarin also significantly modulated inflammatory biomarkers (TNFα, IL-6), adipokines (leptin, adiponectin, and chemerin), and HMG-CoA reductase levels, indicating prominent anti-inflammatory, cholesterol-lowering, and anti-hyperglycemic potential. Administration of C. odorata and coumarin exhibited a marked improvement in oxidative stress markers (CAT, SOD, and MDA). Histopathological analysis of liver, heart, kidney, pancreas, aorta, and fat tissues showed a revival of normal tissue architecture in C. odorata and coumarin-treated rats compared to only HRCHFC-diet fed rats. These results suggest that C. odorata and coumarin possess beneficial effects against the characteristic features of CMS (obesity, insulin resistance, hypertension, and dyslipidemia) in HRCHFC feed-administered rats. These effects were possibly mediated through improved adipokines, glucose tolerance, and insulin sensitivity, the attenuation of HMG-CoA reductase and inflammatory biomarkers, and modulated oxidative stress biomarkers. This study thus demonstrates a rationale for the therapeutic potential of C. odorata and coumarin in CMS. Caryopteris odorata (D. Don) B.L. Robinson (Verbenaceae family) is an aromaric shrub traditionally used to treat diabetes and related pathologies (diabetic foot ulcer), cancer/tumors, wound healing, and inflammation. It is enriched with flavonoids and phenolics like coumarins, quercetin, gallic acid, coumaric acid, stigmasterol, α-tocopherol, and iridoids. C. odorata has been reported as having α-glucosidase, anti-inflammatory, and anti-oxidant properties. Its effectiveness in preventing cardiometabolic syndrome has not yet been assessed. This study aims to investigate the potential efficacy of C. odorata and coumarin for characteristic features of cardiometabolic syndrome (CMS), including obesity, dyslipidemia, hyperglycemia, insulin resistance, and hypertension by using high-refined carbohydrate-high fat-cholesterol (HRCHFC)-loaded feed-fed rats. Chronic administration of C. odorata and coumarin for 6 weeks revealed a marked attenuation in body and organ weights, with a consistent decline in feed intake compared to HRCHFC diet fed rats. The test materials also caused a significant reduction in the blood pressure (systolic, diastolic, and mean) and heart rate of HRCHFC-diet fed rats. Improved glucose tolerance and insulin sensitivity tests were also observed in test material administered rats compare to only HRCHFCdiet fed rats. C. odorata and coumarin-treated animals produced a marked decline in serum FBG, TC, TG, LFTs, and RFTs, while an increase in serum HDL-C levels was noticed. C. odorata and coumarin also significantly modulated inflammatory biomarkers (TNFα, IL-6), adipokines (leptin, adiponectin, and chemerin), and HMG-CoA reductase levels, indicating prominent anti-inflammatory, cholesterol-lowering, and anti-hyperglycemic potential. Administration of C. odorata and coumarin exhibited a marked improvement in oxidative stress markers (CAT, SOD, and MDA). Histopathological analysis of liver, heart, kidney, pancreas, aorta, and fat tissues showed a revival of normal tissue architecture in C. odorata and coumarin-treated rats compared to only HRCHFC-diet fed rats. These results suggest that C. odorata and coumarin possess beneficial effects against the characteristic features of CMS (obesity, insulin resistance, hypertension, and dyslipidemia) in HRCHFC feed-administered rats. These effects were possibly mediated through improved adipokines, glucose tolerance, and insulin sensitivity, the attenuation of HMG-CoA reductase and inflammatory biomarkers, and modulated oxidative stress biomarkers. This study thus demonstrates a rationale for the therapeutic potential of C. odorata and coumarin in CMS. [ABSTRACT FROM AUTHOR]

Medicinal plants play a key role in protection of chronic non-communicable ailments like diabetes, hypertension and dyslipidemia. Berberis brandisiana Ahrendt (Berberidaceae) is traditionally used to treat diabetes, liver problems, wounds, arthritis, infections, swelling and tumors. It is also known to be enriched with multiple phytoconstituents including berbamine, berberine, quercetin, gallic acid, caffeic acid, vanillic acid, benzoic acid, chlorogenic acid, syringic acid, p-coumaric acid, m-coumaric acid and ferulic acid. The efficacy of B. brandisiana has not been established yet in diabetes. This study has been planned to assess the antidiabetic activity of B. brandisiana in high fat diet and streptozotocin (HFD/STZ)-induced diabetes using animals. Administration of aqueous methanolic extract of B. brandisiana (AMEBB) and berbamine (Berb) for 8 weeks caused a dose dependent marked (p < 0.01) rise in serum insulin and HDL levels with a significant decline (p < 0.01) in glucose, triglycerides, glycosylated hemoglobin (HbA1c), cholesterol, LDL, LFTs and RFTs levels when compared with only HFD/STZ-administered rats. AMEBB and Berb also modulated inflammatory biomarkers (TNF-α, IL-6) and adipocytokines (leptin, adiponectin and chemerin). AMEBB (150 mg/kg and 300 mg/kg) and Berb (80 mg/kg and 160 mg/kg) treated rats showed a marked increase (p < 0.001) in catalase levels (Units/mg) in pancreas (42.4 ± 0.24, 47.4 ± 0.51), (38.2 ± 0.583, 48.6 ± 1.03) and liver (52 ± 1.41, 63.2 ± 0.51), (57.2 ± 0.58, 61.6 ± 1.24) and superoxide dismutase levels (Units/mg) in pancreas (34.8 ± 1.46, 38.2 ± 0.58), (33.2 ± 0.80, 40.4 ± 1.96) and liver (31.8 ± 1.52, 36.8 ± 0.96), (30 ± 0.70, 38.4 ± 0.81),respectively while a significant (p < 0.01) decrease in serum melondialdehyde levels (nmol/g) in pancreas (7.34 ± 0.17, 6.22 ± 0.22), (7.34 ± 0.20, 6.34 ± 0.11) and liver (9.08 ± 0.31,8.18 ± 0.29), (9.34 ± 0.10, 8.86 ± 0.24) compared to the data of only HFD/STZ-fed rats. Histopathological studies of pancreas, liver, kidney, heart and aorta revealed restoration of normal tissue architect in AMEBB and Berb treated rats. When mRNA expressions of candidate genes were assessed, AMEBB and Berb showed upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17. These findings suggest that AMEBB and Berb possess antidiabetic activity, possibly due to its effect on oxidative stress, glucose metabolism, inflammatory biomarkers and adipocytokines levels. Further upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17, demonstrated its potential impact on glucose homeostasis, insulin resistance and chronic inflammatory markers. Thus, this study provides support to the medicinal use of B. brandisiana and berbamine in diabetes.

Caryopteris odorata (D. Don) B.L. Robinson (Verbenaceae family) is an aromaric shrub traditionally used to treat diabetes and related pathologies (diabetic foot ulcer), cancer/tumors, wound healing, and inflammation. It is enriched with flavonoids and phenolics like coumarins, quercetin, gallic acid, coumaric acid, stigmasterol, α-tocopherol, and iridoids. C. odorata has been reported as having α-glucosidase, anti-inflammatory, and anti-oxidant properties. Its effectiveness in preventing cardiometabolic syndrome has not yet been assessed. This study aims to investigate the potential efficacy of C. odorata and coumarin for characteristic features of cardiometabolic syndrome (CMS), including obesity, dyslipidemia, hyperglycemia, insulin resistance, and hypertension by using high-refined carbohydrate-high fat-cholesterol (HRCHFC)-loaded feed-fed rats. Chronic administration of C. odorata and coumarin for 6 weeks revealed a marked attenuation in body and organ weights, with a consistent decline in feed intake compared to HRCHFC diet fed rats. The test materials also caused a significant reduction in the blood pressure (systolic, diastolic, and mean) and heart rate of HRCHFC-diet fed rats. Improved glucose tolerance and insulin sensitivity tests were also observed in test material administered rats compare to only HRCHFC-diet fed rats. C. odorata and coumarin-treated animals produced a marked decline in serum FBG, TC, TG, LFTs, and RFTs, while an increase in serum HDL-C levels was noticed. C. odorata and coumarin also significantly modulated inflammatory biomarkers (TNFα, IL-6), adipokines (leptin, adiponectin, and chemerin), and HMG-CoA reductase levels, indicating prominent anti-inflammatory, cholesterol-lowering, and anti-hyperglycemic potential. Administration of C. odorata and coumarin exhibited a marked improvement in oxidative stress markers (CAT, SOD, and MDA). Histopathological analysis of liver, heart, kidney, pancreas, aorta, and fat tissues showed a revival of normal tissue architecture in C. odorata and coumarin-treated rats compared to only HRCHFC-diet fed rats. These results suggest that C. odorata and coumarin possess beneficial effects against the characteristic features of CMS (obesity, insulin resistance, hypertension, and dyslipidemia) in HRCHFC feed-administered rats. These effects were possibly mediated through improved adipokines, glucose tolerance, and insulin sensitivity, the attenuation of HMG-CoA reductase and inflammatory biomarkers, and modulated oxidative stress biomarkers. This study thus demonstrates a rationale for the therapeutic potential of C. odorata and coumarin in CMS.

Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM. [ABSTRACT FROM AUTHOR]

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that 'just' lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes – such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with an elevated risk of respiratory infections and inflammatory lung diseases. The objective was to investigate (i) the effects of adipokines (adiponectin (APN), leptin, chemerin, and visfatin) on the production of cytokines by unstimulated and poly(I:C)- and TNF-α-activated human primary bronchial epithelial cells (hBECs), (ii) the cells' expression of the APN receptors (AdipoR1 and AdipoR2), and (iii) the cells' production of APN. Methods: The hBECs were isolated from patients undergoing surgery for lung carcinoma. The cells were then cultured with human recombinant adipokines in the absence or presence of TNF-α or poly(I:C) for 24 h. Supernatant levels of cytokines (IL-6, CCL2, CCL5, CCL20, CXCL1, CXCL8) and APN were measured using ELISAs. The mRNA levels of AdipoR1 and AdipoR2 in hBECs were determined using a real-time quantitative PCR. Results: Of the four adipokines tested, only APN significantly influenced the basal production and the TNF-α poly(I:C)-induced production of cytokines by hBECs. APN (3-30 µg.ml-1) was associated with greater basal production of IL-6, CCL20, and CXCL8, lower basal production of CCL2 and CXCL1 and no difference in CCL5 production. APN inhibited the poly(I:C)-induced production of these five cytokines and the TNF-α-induced production of CCL2 and CXCL1. AdipoR1 and AdipoR2 were both expressed in hBECs. In contrast to human bronchial explants, isolated hBECs did not produce APN. Conclusions: The APN concentrations are abnormally low in obese individuals, and this fall may contribute to the susceptibility to viral lung infections and the severity of these infections in obese individuals. [ABSTRACT FROM AUTHOR]

Metabolic syndrome refers to the pathological state of metabolic disorder of protein, fat, carbohydrate, and other substances in the human body. It is a syndrome composed of a group of complex metabolic disorders, whose pathogenesis includes multiple genetic and acquired entities falling under the category of insulin resistance and chronic low-grade inflammationand. It is a risk factor for increased prevalence and mortality from diabetes and cardiovascular disease. Cardiovascular diseases are the predominant cause of morbidity and mortality globally, thus it is imperative to investigate the impact of metabolic syndrome on alleviating this substantial disease burden. Despite the increasing number of scientists dedicating themselves to researching metabolic syndrome in recent decades, numerous aspects of this condition remain incompletely understood, leaving many questions unanswered. In this review, we present an epidemiological analysis of MetS, explore both traditional and novel pathogenesis, examine the pathophysiological repercussions of metabolic syndrome, summarize research advances, and elucidate the mechanisms underlying corresponding treatment approaches. [ABSTRACT FROM AUTHOR]

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.

NOD-like receptor protein 3 (NLRP3) inflammasome is an intracellular sensing protein complex that possesses NACHT, leucine-rich repeat, and pyrin domain, playing a crucial role in innate immunity. Activation of the NLRP3 inflammasome leads to the production of pro-inflammatory cellular contents, such as interleukin (IL)-1γ and IL-18, and induction of inflammatory cell death known as pyroptosis, thereby amplifying or sustaining inflammation. While a balanced inflammatory response is beneficial for resolving damage and promoting tissue healing, excessive activation of the NLRP3 inflammasome and pyroptosis can have harmful effects. The involvement of the NLRP3 inflammasome has been observed in various cardiovascular diseases (CVD). Indeed, the NLRP3 inflammasome and its associated pyroptosis are closely linked to key cardiovascular risk factors including hyperlipidemia, diabetes, hypertension, obesity, and hyperhomocysteinemia. Exercise compared with medicine is a highly effective measure for both preventing and treating CVD. Interestingly, emerging evidence suggests that exercise improves CVD and inhibits the activity of NLRP3 inflammasome and pyroptosis. In this review, the activation mechanisms of the NLRP3 inflammasome and its pathogenic role in CVD are critically discussed. Importantly, the purpose is to emphasize the crucial role of exercise in managing CVD by suppressing NLRP3 inflammasome activity and proposes it as the foundation for developing novel treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: Some studies have proved that polyethylene glycol loxenatide (PEGLoxe) has significant effects on controlling blood glucose and body weight in patients with type 2 diabetes mellitus (T2DM), but there is still some controversy over the improvement of blood lipid profiles (BLP) and blood pressure (BP), and more evidences are needed to verify such effects. Therefore, this study was conducted to provide a comprehensive evaluation of the efficacy of PEG-Loxe in improving blood glucose (BG), BLP, BP, body mass index (BMI), and body weight (BW) in patients with T2DM for clinical reference. Methods: Randomized controlled trials (RCT) in which PEG-Loxe was applied to treat T2DM were retrieved by searching PubMed, Cochrane Library, Embase, Medline, Scopus, Web of Science, China National Knowledge Infrastructure, China Scientific Journal, Wanfang Data, and SinoMed databases. Outcome measures included BG, BLP, BP, BMI, and BW. RevMan 5.3 software was used to perform data analysis. Results: Eighteen trials were identified involving 2,166 patients. In experimental group 1,260 patients received PEG-Loxe alone or with other hypoglycemic agents, while in control group 906 patients received placebo or other hypoglycemic agents. In the overall analysis, PEG-Loxe significantly reduced the levels of glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-h postprandial blood glucose (2-h PBG), BMI, and BW compared with control group. However, it had no obvious effect on total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Conclusion: PEG-Loxe has better hypoglycemic effects compared with placebo in patients with T2DM, but could not significantly improved TG, LDL-C, HDL-C, SBP, and DBP. And the combination of conventional hypoglycemic drugs (CHD) and PEG-Loxe could more effectively improve the levels of HbA1c, FPG, 2-h PBG, TC, TG, BMI, and BW compared with CHD in T2DM patients. [ABSTRACT FROM AUTHOR]

Ferroptosis, a recently identified form of non-apoptotic cell death, is distinguished by its dependence on iron-triggered lipid peroxidation and accumulation of iron. It has been linked to various disorders, including the development of tumours. Interestingly, ferroptosis appears to exhibit a dual role in the context of tumour growth. This article provides a thorough exploration of the inherent ambivalence within ferroptosis, encompassing both its facilitation and inhibition of tumorous proliferation. It examines potential therapeutic targets associated with ferroptosis, the susceptibility of cancerous cells to ferroptosis, strategies to enhance the efficacy of existing cancer treatments, the interaction between ferroptosis and the immune response to tumours, and the fundamental mechanisms governing ferroptosis-induced tumour progression. A comprehensive understanding of how ferroptosis contributes to tumour biology and the strategic management of its dual nature are crucial for maximizing its therapeutic potential. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing approximately 85% of cases. The diagnosis is often made in the middle and late stages, necessitating systemic treatment as the primary therapeutic option. Despite sorafenib being the established standard of care for advanced HCC in the past decade, the efficacy of systemic therapy remains unsatisfactory, highlighting the need for novel treatment modalities. Recent breakthroughs in immunotherapy have shown promise in HCC treatment, particularly with immune checkpoint inhibitors (ICIs). However, the response rate to ICIs is currently limited to approximately 15%-20% of HCC patients. Recently, ICIs demonstrated greater efficacy in "hot" tumors, highlighting the urgency to devise more effective approaches to transform "cold" tumors into "hot" tumors, thereby enhancing the therapeutic potential of ICIs. This review presented an updated summary of the factors influencing the effectiveness of immunotherapy in HCC treatment, identified potential combination therapies that may improve patient response rates to ICIs, and offered an overview of ongoing clinical trials focusing on ICI-based combination therapy. [ABSTRACT FROM AUTHOR]

Obesity is fast growing as a global pandemic and is associated with numerous comorbidities like cardiovascular disease, hypertension, diabetes, gastroesophageal reflux disease, sleep disorders, nephropathy, neuropathy, as well as asthma. Studies stated that obese asthmatic subjects suffer from an increased risk of asthma, and encounter severe symptoms due to a number of pathophysiology. It is very vital to understand the copious relationship between obesity and asthma, however, a clear and pinpoint pathogenesis underlying the association between obesity and asthma is scarce. There is a plethora of obesity-asthma etiologies reported viz., increased circulating pro-inflammatory adipokines like leptin, resistin, and decreased antiinflammatory adipokines like adiponectin, depletion of ROS controller Nrf2/HO- 1 axis, nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3 (NLRP3) associated macrophage polarization, hypertrophy of WAT, activation of Notch signaling pathway, and dysregulated melanocortin pathway reported, however, there is a very limited number of reports that interrelates these pathophysiologies. Due to the underlying complex pathophysiologies exaggerated by obese conditions, obese asthmatics respond poorly to anti-asthmatic drugs. The poor response towards anti-asthmatic drugs may be due to the anti-asthmatics approach only that ignores the anti-obesity target. So, aiming only at the conventional antiasthmatic targets in obese-asthmatics may prove to be futile until and unless treatment is directed towards ameliorating obesity pathogenesis for a holistic approach towards amelioration of obesity-associated asthma. Herbal medicines for obesity as well as obesity-associated comorbidities are fast becoming safer and more effective alternatives to conventional drugs due to their multitargeted approach with fewer adverse effects. Although, herbal medicines are widely used for obesity-associated comorbidities, however, a limited number of herbal medicines have been scientifically validated and reported against obesity-associated asthma. Notable among them are quercetin, curcumin, geraniol, resveratrol, ß-Caryophyllene, celastrol, tomatidine to name a few. In view of this, there is a dire need for a comprehensive review that may summarize the role of bioactive phytoconstituents from different sources like plants, marine as well as essential oils in terms of their therapeutic mechanisms. So, this review aims to critically discuss the therapeutic role of herbal medicine in the form of bioactive phytoconstituents against obesity-associated asthma available in the scientific literature to date. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) refers to the aging and degenerative diseases of intervertebral disc components such as nucleus pulposus, annulus fibrosus, and cartilage endplate, and is the main cause of chronic low back pain. Over the past few years, many researchers around the world concerned that the degeneration of nucleus pulposus (NP) cells plays the main role in IVDD. The degeneration of NP cells is caused by a series of pathological processes, including oxidative stress, inflammatory response, apoptosis, abnormal proliferation, and autophagy. Interestingly, many studies have found a close relationship between the senescence of NP cells and the progression of NP degeneration. The classical aging pathways also have been confirmed to be involved in the pathological process of IVDD. Moreover, several anti-aging drugs have been used to treat IVDD by inhibiting NP cells senescence, such as proanthocyanidins, resveratrol and bone morphogenetic protein 2. Therefore, this article will systematically list and discuss aging, cell senescence, the pathogenesis and targeted therapies of IVDD, in order to provide new ideas for the treatment of IVDD in the future. [ABSTRACT FROM AUTHOR]

Background/aim: Hypertensive nephropathy (HN) is a common complication of hypertension. Traditional Chinese medicine has long been used in the clinical treatment of Hypertensive nephropathy. However, botanical drug prescriptions have not been summarized. The purpose of this study is to develop a prescription for improving hypertensive nephropathy, explore the evidence related to clinical application of the prescription, and verify its molecular mechanism of action. Methods: In this study, based on the electronic medical record data on Hypertensive nephropathy, the core botanical drugs and patients' symptoms were mined using the hierarchical network extraction and fast unfolding algorithm, and the protein interaction network between botanical drugs and Hypertensive nephropathy was established. The K-nearest neighbors (KNN) model was used to analyze the clinical and biological characteristics of botanical drug compounds to determine the effective compounds. Hierarchical clustering was used to screen for effective botanical drugs. The clinical efficacy of botanical drugs was verified by a retrospective cohort. Animal experiments were performed at the target and pathway levels to analyze the mechanism. Results: A total of 14 botanical drugs and five symptom communities were obtained from real-world clinical data. In total, 76 effective compounds were obtained using the K-nearest neighbors model, and seven botanical drugs were identified as Gao Shen Formula by hierarchical clustering. Compared with the classical model, the Area under the curve (AUC) value of the K-nearest neighbors model was the best; retrospective cohort verification showed that Gao Shen Formula reduced serum creatinine levels and Chronic kidney disease (CKD) stage [OR = 2.561, 95% CI (1.025-6.406), p < 0.05]. With respect to target and pathway enrichment, Gao Shen Formula acts on inflammatory factors such as TNF-α, IL-1β, and IL-6 and regulates the NF-κB signaling pathway and downstream glucose and lipid metabolic pathways. Conclusion: In the retrospective cohort, we observed that the clinical application of Gao Shen Formula alleviates the decrease in renal function in patients with hypertensive nephropathy. It is speculated that Gao Shen Formula acts by reducing inflammatory reactions, inhibiting renal damage caused by excessive activation of the renin-angiotensin-aldosterone system, and regulating energy metabolism. [ABSTRACT FROM AUTHOR]

Acquired brain injury (ABI) is the most common disease of the nervous system, involving complex pathological processes, which often leads to a series of nervous system disorders. The structural destruction and dysfunction of the Neurovascular Unit (NVU) are prominent features of ABI. Therefore, understanding the molecular mechanism underlying NVU destruction and its reconstruction is the key to the treatment of ABI. SUMOylation is a protein post-translational modification (PTM), which can degrade and stabilize the substrate dynamically, thus playing an important role in regulating protein expression and biological signal transduction. Understanding the regulatory mechanism of SUMOylation can clarify the molecular mechanism of the occurrence and development of neurovascular dysfunction after ABI and is expected to provide a theoretical basis for the development of potential treatment strategies. This article reviews the role of SUMOylation in vascular events related to ABI, including NVU dysfunction and vascular remodeling, and puts forward therapeutic prospects. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common digestive malignancies. HCC It ranges as the fifth most common cause of cancer mortality worldwide. While The prognosis of metastatic or advanced HCC is still quite poor. Recently, locoregional treatment, especially local ablation therapies, plays an important role in the treatment of HCC. Radiofrequency ablation (RFA) and high-intensity focused ultrasound (HIFU) ablation are the most common-used methods effective and feasible for treating HCC. However, the molecular mechanisms underlying the actions of ablation in the treatments for HCC and the HCC recurrence after ablation still are poorly understood. Hypoxia-inducible factor (HIF), the key gene switch for adaptive responses to hypoxia, has been found to play an essential role in the rapid aggressive recurrence of HCC after ablation treatment. In this review, we summarized the current evidence of the roles of HIF in the treatment of HCC with ablation. Fifteen relevant studies were included and further analyzed. Among them, three clinical studies suggested that HIF-1α might serve as a crucial role in the RAF treatment of HCC or the local recurrence of HCC after RFA. The remainder included experimental studies demonstrated that HIF-1, 2α might target the different molecules (e.g., BNIP3, CA-IX, and arginase-1) and signaling cascades (e.g., VEGFA/EphA2 pathway), constituting a complex network that promoted HCC invasion and metastasis after ablation. Currently, the inhibitors of HIF have been developed, providing important proof of targeting HIF for the prevention of HCC recurrence after IRFA and HIFU ablation. Further confirmation by prospective clinical and in-depth experimental studies is still warranted to illustrate the effects of HIF in HCC recurrence followed ablation treatment in the future. [ABSTRACT FROM AUTHOR]

The immune system plays a crucial role in regulating osteoclast formation and function and has significance for the occurrence and development of immunemediated bone diseases. Kidney-tonifying Chinese herbs, based on the theory of traditional Chinese medicine (TCM) to unify the kidney and strengthen the bone, have been widely used in the prevention and treatment of bone diseases. The common botanical drugs are tonifying kidney-yang and nourishing kidney-yin herbs, which are divided into two parts: one is the compound prescription of TCM, and the other is the single preparation of TCM and its active ingredients. These botanical drugs regulate osteoclastogenesis directly and indirectly by immune cells, however, we have limited information on the differences between the two botanical drugs in osteoimmunology. In this review, the mechanism by which kidney-tonifying Chinese herbs inhibiting osteoclastogenesis was investigated, emphasizing the immune response. The differences in the mechanism of action between tonifying kidney-yang herbs and nourishing kidney-yin herbs were analysed, and the therapeutic value for immune-mediated bone diseases was evaluated. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids in cells. PUFAs regulate cellular function through the formation of derived lipid mediators termed eicosanoids. The oxygenation of 20-carbon PUFAs via the oxygenases cyclooxygenases, lipoxygenases, or cytochrome P450, generates a class of classical eicosanoids including prostaglandins, thromboxanes and leukotrienes, and also the more recently identified hydroxy-, hydroperoxy-, epoxy- and oxo-eicosanoids, and the specialized pro-resolving (lipid) mediators. These eicosanoids play a critical role in the regulation of inflammation in the blood and the vessel. While arachidonic acidderived eicosanoids are extensively studied due to their pro-inflammatory effects and therefore involvement in the pathogenesis of inflammatory diseases such as atherosclerosis, diabetes mellitus, hypertension, and the coronavirus disease 2019; in recent years, several eicosanoids have been reported to attenuate exacerbated inflammatory responses and participate in the resolution of inflammation. This review focused on elucidating the biosynthesis and the mechanistic signaling of eicosanoids in inflammation, as well as the pro-inflammatory and anti-inflammatory effects of these eicosanoids in the blood and the vascular wall. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress (OS) is associated with ferroptosis. Coenzyme Q10 (CoQ10), as an adjuvant treatment, has shown to be beneficial against OS. However, the efficacy of CoQ10 as a therapeutic agent against OS has not been promptly updated and systematically investigated. Methods: A systematic literature search was performed using the Medline, EMBASE, Web of science, Cochrane Central Register of Controlled Trials, CNKI, CBM, Science direct and clinical trial. gov to identify randomized clinical trials evaluating the efficacy of CoQ10 supplementation on OS parameters. Standard mean differences and 95% confidence intervals were calculated for net changes in OS parameters using a random-effects model. Results: Twenty-one randomized clinical studies met the eligibility criteria to be included in the meta-analysis. Overall, CoQ10 supplementation increased the levels of antioxidant enzymes [including superoxide dismutase (SOD) (SMD = 0.63; 95% CI: 0.38 to 0.88; p < 0.001), catalase (CAT) (SMD = 0.44; 95% CI:0.16 to 0.72; p = 0.002)] significantly and the levels of malondialdehyde (MDA) (SMD = -0.68; 95% CI: 0.93 to -0.43; p < 0.001) was decreased considerably. However, significant associations were not observed between this supplement and total antioxidant capacity (TAC), glutathione peroxidase (GPx) activity. Conclusion: CoQ10 can improve OS as indicated by statistical significance in CAT and MDA concentrations, as well as SOD activity. Future studies focusing on long-term results and specific valuation of OS parameters are required to confirm the efficacy of CoQ10 on OS. We also believe that with the further research on ferroptosis, CoQ10 will gain more attention. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a rare, recurrent, and intractable inflammation obstruction of the stomach tract, usually accompanied by inflammation of cell proliferation and inflammation of the colon and carries a particular cause of inflammation. The clinical use of drugs in western countries affects IBD treatment, but various adverse effects and high prices limit their application. For these reasons, Traditional Chinese Medicine (TCM) is more advantageous in treating IBD. This paper reviews the mechanism and research status of TCM and natural products in IBD treatment by analyzing the relevant literature to provide a scientific and theoretical basis for IBD treatment. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy and safety of Chinese herbal medicine (CHM) for type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD) with current evidence. Methods: This study was registered in PROSPERO as CRD42021271488. A literature search was conducted in eight electronic databases from inception to December 2021. The primary outcomes were lipid indices and liver functions, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine transaminase (ALT), and aspartate transaminase (AST). Review Manager 5.2 and Stata v14.0 were applied for analysis. Results: The research enrolled 18 RCTs with 1,463 participants. Results showed CHM combined with western medicine (WM) was more effective than WM alone in TG (weighted mean differences (WMD) = −0.35.95% confidence interval (CI) [−0.51, −0.19], p < 0.0001), TC (WMD = −0.58.95%CI [−0.80, −0.36], p < 0.00001), LDL-C (WMD = −0.37, 95%CI [−0.47, −0.26], p < 0.00001), HDL-C (WMD = 0.20, 95%CI [0.10, 0.29], p < 0.0001), ALT (WMD = −4.99, 95%CI [−6.64, −3.33], p < 0.00001), AST (WMD = −4.76, 95%CI [−6.35, −3.16], p < 0.00001), homeostatic model assessment of insulin resistance (WMD = −1.01, 95%CI [−1.22, −0.79], p < 0.00001), fasting blood glucose (WMD = −0.87, 95%CI [−1.13, −0.61], p < 0.00001), 2-h postprandial glucose (WMD = −1.45.95%CI [−2.00, −0.91], p < 0.00001), body mass index (WMD = −0.73.95%CI [−1.35, −0.12], p = 0.02), and overall effective rate (risk ratio (RR) = 1.37.95%CI [1.29, 1.46], p < 0.00001). Conclusion: The CHM in combination with WM seems to be more beneficial in T2DM with NAFLD patients in improving lipid and glucose metabolism, liver function, and insulin resistance as well as improving overall efficiency and reducing body weight. Given the poor quality of reports from these studies and uncertain evidence, these findings should be interpreted cautiously. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display%5frecord.php?ID=CRD42021271488, identifier CRD42021271488. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) caused by intervertebral disc degeneration (IVDD) is accredited to the release of inflammatory cytokines followed by biomechanical and structural deterioration. In our study, we used a plant-derived medicine, curcumenol, to treat IVDD. A cell viability test was carried out to evaluate the possibility of using curcumenol. RNA-seq was used to determine relative pathways involved with curcumenol addition. Using TNFα as a trigger of inflammation, the activation of the NF-κB signaling pathway and expression of the MMP family were determined by qPCR and western blotting. Nucleus pulposus (NP) cells and the rats' primary NP cells were cultured. The catabolism status was evaluated by an ex vivo model. A lumbar instability mouse model was carried out to show the effects of curcumenol in vivo. In general, RNA-seq revealed that multiple signaling pathways changed with curcumenol addition, especially the TNFα/NF-κB pathway. So, the NP cells and primary NP cells were induced to suffer inflammation with the activated TNFα/NF-κB signaling pathway and increased expression of the MMP family, such as MMP3, MMP9, and MMP13, which would be mitigated by curcumenol. Owing to the protective effects of curcumenol, the height loss and osteophyte formation of the disc could be prevented in the lumbar instability mouse model in vivo. [ABSTRACT FROM AUTHOR]

Methods: Articles on inflammatory tumor microenvironment were retrieved from the Web of Science Core Collection, and the characteristics of the articles were analyzed by CiteSpace software. Background: The inflammatory tumor microenvironment is an essential feature of the tumor microenvironment. The way in which it promotes or inhibits tumor progression plays an important role in the outcome of a tumor treatment. This research aims to explore a scientific collaboration network, describe evolution of hotspots, and predict future trends through bibliometric analysis. Results: A total of 3,534 papers published by 390 institutions in 81 countries/regions were screened, and the annual quantity has been increasing rapidly in the past decades. United States was the leading country and has the most productive institutions in this field. The research topics were mainly focused on inflammation and immunity mediated by crucial factors as well as the mechanisms of angiogenesis. Additionally, the development and application of nanoparticles is currently a novel research frontier with bright prospect. Conclusion: The present scientometric study provides an overview of inflammatory tumor microenvironment research over the previous decades using quantitative and qualitative methods, and the findings of this study can provide references for researchers focusing on tumor treatment. [ABSTRACT FROM AUTHOR]

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is mainly caused by joint inflammation. RA significantly increases the probability of cardiovascular disease. Although the progress of RA has been well controlled recently, the mortality of patients with RA complicated with cardiovascular disease is 1.5–3 times higher than that of patients with RA alone. The number of people with atherosclerosis in patients with RA is much higher than that in the general population, and atherosclerotic lesions develop more rapidly in patients with RA, which has become one of the primary factors resulting in the death of patients with RA. The rapid development of atherosclerosis in RA is induced by inflammation-related factors. Recent studies have reported that the expression of IL-17 is significantly upregulated in patients with RA and atherosclerosis. Simultaneously, there is evidence that IL-17 can regulate the proliferation, migration, and apoptosis of vascular endothelial cells and vascular smooth muscle cells through various ways and promote the secretion of several cytokines leading to the occurrence and development of atherosclerosis. Presently, there is no clear prevention or treatment plan for atherosclerosis in patients with RA. Therefore, this paper explores the mechanism of IL-17 in RA complicated with atherosclerosis and shows the reasons for the high incidence of atherosclerosis in patients with RA. It is hoped that the occurrence and development of atherosclerosis in patients with RA can be diagnosed or prevented in time in the early stage of lesions, and the prevention and treatment of cardiovascular complications in patients with RA can be enhanced to reduce mortality. [ABSTRACT FROM AUTHOR]

Forkhead box (Fox) family, an evolutionarily conserved family of transcription factors carrying the "Forkhead" motif, plays an indispensable role in human health and disease. Fox family genes are involved in cell differentiation, proliferation and apoptosis, embryonic development, aging, glucose and lipid metabolism, and immune regulation. The regulatory role of the Fox family in the context of bone metabolism and orthopedic diseases is an emerging research hotspot. In this review, we highlight the major molecular mechanisms underlying the regulatory role of Fox factors in bone metabolism, bone development, bone homeostasis, and bone diseases associated with inhibition or upregulation of Fox factors. In addition, we discuss the emerging evidence in the realm of Fox factor-based therapeutics. [ABSTRACT FROM AUTHOR]

Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases. [ABSTRACT FROM AUTHOR]

Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)—i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the "resolution of inflammation"–has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) is a unique fat depot with local and systemic impacts. PVATs are anatomically, developmentally, and functionally different from classical adipose tissues and they are also different from each other. PVAT adipocytes originate from different progenitors and precursors. They can produce and secrete a wide range of autocrine and paracrine factors, many of which are vasoactive modulators. In the context of obesity-associated low-grade inflammation, these phenotypic and functional differences become more evident. In this review, we focus on the recent findings of PVAT's heterogeneity by comparing commonly studied adipose tissues around the thoracic aorta (tPVAT), abdominal aorta (aPVAT), and mesenteric artery (mPVAT). Distinct origins and developmental trajectory of PVAT adipocyte potentially contribute to regional heterogeneity. Regional differences also exist in ways how PVAT communicates with its neighboring vasculature by producing specific adipokines, vascular tone regulators, and extracellular vesicles in a given microenvironment. These insights may inspire new therapeutic strategies targeting the PVAT. [ABSTRACT FROM AUTHOR]

Medicinal plants play a key role in protection of chronic non-communicable ailments like diabetes, hypertension and dyslipidemia. Berberis brandisiana Ahrendt (Berberidaceae) is traditionally used to treat diabetes, liver problems, wounds, arthritis, infections, swelling and tumors. It is also known to be enriched with multiple phytoconstituents including berbamine, berberine, quercetin, gallic acid, caffeic acid, vanillic acid, benzoic acid, chlorogenic acid, syringic acid, p -coumaric acid, m -coumaric acid and ferulic acid. The efficacy of B. brandisiana has not been established yet in diabetes. This study has been planned to assess the antidiabetic activity of B. brandisiana in high fat diet and streptozotocin (HFD/STZ)-induced diabetes using animals. Administration of aqueous methanolic extract of B. brandisiana (AMEBB) and berbamine (Berb) for 8 weeks caused a dose dependent marked ( p < 0.01) rise in serum insulin and HDL levels with a significant decline ( p < 0.01) in glucose, triglycerides, glycosylated hemoglobin (HbA1c), cholesterol, LDL, LFTs and RFTs levels when compared with only HFD/STZ-administered rats. AMEBB and Berb also modulated inflammatory biomarkers (TNF-α, IL-6) and adipocytokines (leptin, adiponectin and chemerin). AMEBB (150 mg/kg and 300 mg/kg) and Berb (80 mg/kg and 160 mg/kg) treated rats showed a marked increase ( p < 0.001) in catalase levels (Units/mg) in pancreas (42.4 ± 0.24, 47.4 ± 0.51), (38.2 ± 0.583, 48.6 ± 1.03) and liver (52 ± 1.41, 63.2 ± 0.51), (57.2 ± 0.58, 61.6 ± 1.24) and superoxide dismutase levels (Units/mg) in pancreas (34.8 ± 1.46, 38.2 ± 0.58), (33.2 ± 0.80, 40.4 ± 1.96) and liver (31.8 ± 1.52, 36.8 ± 0.96), (30 ± 0.70, 38.4 ± 0.81),respectively while a significant ( p < 0.01) decrease in serum melondialdehyde levels (nmol/g) in pancreas (7.34 ± 0.17, 6.22 ± 0.22), (7.34 ± 0.20, 6.34 ± 0.11) and liver (9.08 ± 0.31,8.18 ± 0.29), (9.34 ± 0.10, 8.86 ± 0.24) compared to the data of only HFD/STZ-fed rats. Histopathological studies of pancreas, liver, kidney, heart and aorta revealed restoration of normal tissue architect in AMEBB and Berb treated rats. When mRNA expressions of candidate genes were assessed, AMEBB and Berb showed upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17. These findings suggest that AMEBB and Berb possess antidiabetic activity, possibly due to its effect on oxidative stress, glucose metabolism, inflammatory biomarkers and adipocytokines levels. Further upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17, demonstrated its potential impact on glucose homeostasis, insulin resistance and chronic inflammatory markers. Thus, this study provides support to the medicinal use of B. brandisiana and berbamine in diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mehdi, Mehmood, Ahmed and Ashfaq.)

Objective: The aim of this study was to eluc\idate the preventive and therapeutic effects and the underlying mechanisms of Huoxue Huatan Decoction (HXHT) on myocardial ischemia/reperfusion (I/R) injury in hyperlipidemic rats. Methods: An I/R model was established in hyperlipidemic Wistar rats. After 4–8 weeks of HXHT treatment, the physical signs of rats were observed. Lipid metabolism, myocardial enzyme spectrum, cardiac function, myocardial histomorphology, and mitochondrial biosynthesis were investigated by a biochemical method, ultrasonography, electron microscopy, pathological examination, real-time PCR, and Western blot. Results: HXHT can affect lipid metabolism at different time points and significantly reduce the levels of cholesterol (CHO), triglyceride (TG), high-density lipid-cholesterol (HDL-C), and low-density lipid-cholesterol (LDL-C) in hyperlipidemic rats (P < 0.05 or P < 0.01); it can significantly reduce the levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), reduce the myocardial infarct size and myocardial ischemic area, and improve cardiac function. The results of myocardial histomorphology showed that HXHT could protect myocardial cells, relieve swelling, reduce the number of cardiac lipid droplets, and improve myocardial mitochondrial function. HXHT could significantly increase the levels of total superoxide dismutase (T-SOD) and succinate dehydrogenase (SDH) (P < 0.05 or P < 0.01), increase CuZn-superoxide dismutase (CuZn-SOD) and glutathione-peroxidase (GSH-Px) levels, and decrease the levels of malondialdehyde (MDA) (P < 0.05); it could increase the mRNA and protein expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (mtTFA) (P < 0.05 or P < 0.01), and increase the synthesis of mitochondrial DNA (mtDNA) (P < 0.01). Conclusion: HXHT can reduce myocardial I/R injury in hyperlipidemic rats. The protective mechanisms may involve a reduction in blood lipids, enhancement of PGC-1α–PPARα pathway activity, and, subsequently, an increase in fatty acid β-oxidation, which may provide the required input for mitochondrial energy metabolism. HXHT can additionally enhance PGC-1α–NRF1–mtTFA pathway activity and, subsequently, increase the antioxidant capacity, promote mtDNA synthesis, and reduce mitochondrial damage. The two pathways use PGC-1α as the intersection point to protect mitochondrial structure and function, reduce I/R-induced injury, and improve cardiac function. [ABSTRACT FROM AUTHOR]

Background: Salvianolate, a compound mainly composed of salvia magnesium acetate, is extracted from the Chinese herb Salvia miltiorrhiza. Because of its biological activity, easy quality control and certain efficacy, salvianolate is widely used in treating ischemic cardiocerebral vascular disease, liver damage, renal injury, diabetes, and its complications. Particularly, it has potential protective effects on diabetic nephropathy (DN). Objective: This meta-analysis aimed to evaluate the efficacy and safety of salvianolate when combined with western medicine in patients affected with DN. Methods: We searched Pubmed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data knowledge service platform (Wanfang Data), Chinese Scientific Journal Database (VIP), and China Biology Medicine Disc (SinoMed) for randomized controlled trials (RCTs) of salvianolate in combination with western medicine on DN, including results from the foundation of each database until November 30, 2019. Two reviewers independently performed literature screening, data extraction, and quality evaluation. This meta-analysis was carried out using RevMan5.3 software. Results: From the 12 RCTs, 1,030 patients from China were involved. Compared with single-use western medicine, the combination of salvianolate and western medicine for the treatment of DN could reduce levels of serum creatinine (Scr) [MD=−16.53, 95% CI (−28.79, −4.27), P =0.008], blood urea nitrogen (BUN) [MD=−1.40, 95% CI (−2.17, −0.62), P =0.0004], urinary albumin excretion rate (UARE) [SMD=−1.84, 95% CI (−2.70, −0.98), P < 0.0001], 24-hour urinary protein (24h Upro) [MD=–0.37, 95% CI (–0.47, –0.26), P < 0.00001], albumin-to-creatinine ratio (ACR) [SMD=–1.43, 95% CI (–2.64, –0.23), P =0.02], hypersensitive C-reactive protein (hs-CRP) [MD=−5.69, 95% CI (−7.09, −4.29), P < 0.00001], interleukin-6 (IL-6) [MD=−12.53, 95% CI (−18.55, −6.52), P < 0.0001], malondialdehyde (MDA) [SMD=−2.05, 95% CI (−3.67, −0.43), P =0.01], as well as improve clinical efficacy [RR=1.21, 95% CI (1.12,1.31), P < 0.00001], and increase superoxide dismutase (SOD) levels [SMD=1.12, 95% CI (0.86,1.38), P < 0.00001]. No increase in the occurrence of serious adverse events were observed in the treatment group compared with the control group. Conclusion: This study indicated that salvianolate combined with western medicine contributes to protecting renal function, inhibiting inflammation, and exhibiting anti-oxidative properties, thereby improving clinical efficacy. Thus, salvianolate can be considered as a potential complementary therapy for DN patients. However, due to the low quality of methodology and small sample sizes, more rigorous and larger trials are essential to validate our results. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARβ/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment. [ABSTRACT FROM AUTHOR]

Bilobalide, a unique Ginkgo biloba constituent has attracted significant interest as a novel therapeutic option for neuronal protection. However, there is paucity of data on its effect on colitis. This work sought to evaluate the effect of bilobalide on macrophage polarization in vitro and dextran sulfate sodium (DSS) induced colitis in vivo. Through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and annexin V/PI assay, it was shown that bilobalide has no significant toxicity on macrophage. Lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) induced macrophage activation and polarization were significantly suppressed by bilobalide as indicated by reduced expression of cytokine, major histocompatibility complex II (MHC-II), and CD11c. Pertinently, the signaling pathway study showed that the phosphorylation of p65 and its nuclear translocation were decreased while STAT1 was not affected. In DSS-treated mice, administration (i.g) of three doses of bilobalide na\mely 1.25 mg/kg (low dose group), 2.5 mg/kg (medium dose group), and 5 mg/kg (high dose group) was performed daily starting from day 1 to day 10. Medium and high dose bilobalide markedly reduced the inflammation of colitis proved via elevation of bodyweight, decrement in disease activity index (DAI), alleviation of colon damage as well as reduction in activity of colon tissue myeloperoxidase activity. In accordance with the in vitro results, the levels of inflammatory cytokines such as interleukin 6 (IL-6), IL-1β, and tumor necrosis factor (TNF-α) in serum as well as messenger RNA (mRNA) expression in colon were obviously reduced in the bilobalide treated groups. Also, factor nuclear factor kappa B (NF-κB) signaling pathway was decreased significantly by bilobalide treatment. Collectively, these results indicated that administration of bilobalide improved experimental colitis via inhibition of M1 macrophage polarization through the NF-κB signaling pathway. Thus, bilobalide could act as a potential drug for the treatment of inflammatory bowel disease (IBD) in the not-too-distant future. [ABSTRACT FROM AUTHOR]