Pub Date : 2024-01-01DOI: 10.2174/0118761429329635241016054513
Wael A Alanazi, Turki Alharbi, Khalid M Bin Anzan, Musab K Alyahiya, Doaa M El-Nagar, Mohammed M Alanazi, Mohammed M Almutairi, Hussain N Alhamami, Abdullah M Albogami, Mohamed Mohany
Background: Recent research has validated the efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in reducing glucose levels and exerting a nephroprotective role.
Objective: This study aimed to examine the impact of dapagliflozin in preventing sepsis-induced acute kidney injury (AKI) and related consequences. The study used both normal and diabetic rat models to investigate whether the effectiveness of dapagliflozin is influenced by glycemia levels.
Methods: Normal and diabetic Wistar albino rats were treated with dapagliflozin for two weeks and then received a single dose of lipopolysaccharide (LPS). After sepsis induction, skin and deep body temperatures were recorded every two hours. Blood and kidneys were collected for analysis using histological examination and biochemical assays.
Results: Dapagliflozin attenuated the consequences of sepsis through mitigation of LPS-induced hypothermia and AKI in the normal and diabetic septic groups. Dapagliflozin regulated the serum levels of AKI markers, including creatinine and blood urea nitrogen, as well as ion levels. Dapagliflozin attenuated LPS-induced AKI through modulation of renal inflammation and oxidative stress, which showed well-abundant glomeruli. These results indicated the protective effect of dapagliflozin against LPS-induced hypothermia and AKI, which was likely unrelated to its glucose-lowering properties, as evidenced in the non-diabetic septic group.
Conclusion: The outcomes suggest that dapagliflozin has a potential impact in preventing sepsis-induced hypothermia and AKI via modulation of inflammation and oxidative stress, irrespective of glycemic levels.
{"title":"The Role of Dapagliflozin in the Modulation of Hypothermia and Renal Injury Caused by Septic Shock in Euglycemic and Hyperglycemic Rat Models.","authors":"Wael A Alanazi, Turki Alharbi, Khalid M Bin Anzan, Musab K Alyahiya, Doaa M El-Nagar, Mohammed M Alanazi, Mohammed M Almutairi, Hussain N Alhamami, Abdullah M Albogami, Mohamed Mohany","doi":"10.2174/0118761429329635241016054513","DOIUrl":"10.2174/0118761429329635241016054513","url":null,"abstract":"<p><strong>Background: </strong>Recent research has validated the efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in reducing glucose levels and exerting a nephroprotective role.</p><p><strong>Objective: </strong>This study aimed to examine the impact of dapagliflozin in preventing sepsis-induced acute kidney injury (AKI) and related consequences. The study used both normal and diabetic rat models to investigate whether the effectiveness of dapagliflozin is influenced by glycemia levels.</p><p><strong>Methods: </strong>Normal and diabetic Wistar albino rats were treated with dapagliflozin for two weeks and then received a single dose of lipopolysaccharide (LPS). After sepsis induction, skin and deep body temperatures were recorded every two hours. Blood and kidneys were collected for analysis using histological examination and biochemical assays.</p><p><strong>Results: </strong>Dapagliflozin attenuated the consequences of sepsis through mitigation of LPS-induced hypothermia and AKI in the normal and diabetic septic groups. Dapagliflozin regulated the serum levels of AKI markers, including creatinine and blood urea nitrogen, as well as ion levels. Dapagliflozin attenuated LPS-induced AKI through modulation of renal inflammation and oxidative stress, which showed well-abundant glomeruli. These results indicated the protective effect of dapagliflozin against LPS-induced hypothermia and AKI, which was likely unrelated to its glucose-lowering properties, as evidenced in the non-diabetic septic group.</p><p><strong>Conclusion: </strong>The outcomes suggest that dapagliflozin has a potential impact in preventing sepsis-induced hypothermia and AKI via modulation of inflammation and oxidative stress, irrespective of glycemic levels.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":"17 1","pages":"e18761429329635"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-25DOI: 10.2174/0118761429272806231020045840
Ravikant Sharma, M D Abubakar, Priya Bisht, Mahesh Rachamalla, Arun Kumar, Krishna Murti, Velayutham Ravichandiran, Nitesh Kumar
Background: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition.
Aims: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease.
Methods: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus.
Description: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by β-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article.
Conclusion: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.
{"title":"Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease.","authors":"Ravikant Sharma, M D Abubakar, Priya Bisht, Mahesh Rachamalla, Arun Kumar, Krishna Murti, Velayutham Ravichandiran, Nitesh Kumar","doi":"10.2174/0118761429272806231020045840","DOIUrl":"https://doi.org/10.2174/0118761429272806231020045840","url":null,"abstract":"<p><strong>Background: </strong>Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition.</p><p><strong>Aims: </strong>Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease.</p><p><strong>Methods: </strong>The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus.</p><p><strong>Description: </strong>According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by β-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article.</p><p><strong>Conclusion: </strong>A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Activation of microglia and astrocytes has been observed in Alzheimer's disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.
Objective: We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.
Methods: After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.
Results: In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.
Conclusion: These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.
{"title":"All-trans Retinoic Acid Increased Transglutaminase 2 Expressions in BV-2 Cells and Cultured Astrocytes.","authors":"Katsura Takano-Kawabe, Tatsuhiko Izumo, Tomoki Minamihata Minamihata, Mitsuaki Moriyama","doi":"10.2174/0118761429254388230922112915","DOIUrl":"https://doi.org/10.2174/0118761429254388230922112915","url":null,"abstract":"<p><strong>Background: </strong>Activation of microglia and astrocytes has been observed in Alzheimer's disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.</p><p><strong>Objective: </strong>We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.</p><p><strong>Methods: </strong>After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.</p><p><strong>Results: </strong>In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.</p><p><strong>Conclusion: </strong>These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-23DOI: 10.2174/0118761429261105231011101200
Georgios Papaetis
Almost 20-40% of all patients suffering from diabetes mellitus experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). The implication of several pathophysiological mechanisms (hemodynamic, tubular, metabolic and inflammatory) in the pathogenesis of diabetic kidney disease generates an urgent need to develop multitarget therapeutic strategies to face its development and progression. SGLT2 inhibitors are undoubtedly a practice-changing drug class for individuals who experience type 2 diabetes and diabetic kidney disease. In vitro studies, exploratory research, sub-analyses of large randomized controlled trials, and investigation of several biomarkers have demonstrated that SGLT2 inhibitors achieved multiple beneficial activities, targeting several renal cellular and molecular pathways independent of their antihyperglycemic activity. These mainly include the reduction in intraglomerular pressure through the restoration of TGF, impacts on the renin-angiotensin-aldosterone system, improvement of renal hypoxia, adaptive metabolic alterations in substrate use/energy expenditure, improvement of mitochondrial dysfunction, and reduction of inflammation, oxidative stress and fibrosis. This manuscript thoroughly investigates the possible mechanisms that underlie their salutary renal effects in patients with diabetes, focusing on several pathways involved and the interplay between them. It also explores their upcoming role in ameliorating the evolution of chronic kidney disease in patients with diabetes.
{"title":"SGLT2 Inhibitors and Diabetic Kidney Disease: Targeting Multiple and Interrelated Signaling Pathways for Renal Protection.","authors":"Georgios Papaetis","doi":"10.2174/0118761429261105231011101200","DOIUrl":"https://doi.org/10.2174/0118761429261105231011101200","url":null,"abstract":"<p><p>Almost 20-40% of all patients suffering from diabetes mellitus experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). The implication of several pathophysiological mechanisms (hemodynamic, tubular, metabolic and inflammatory) in the pathogenesis of diabetic kidney disease generates an urgent need to develop multitarget therapeutic strategies to face its development and progression. SGLT2 inhibitors are undoubtedly a practice-changing drug class for individuals who experience type 2 diabetes and diabetic kidney disease. In vitro studies, exploratory research, sub-analyses of large randomized controlled trials, and investigation of several biomarkers have demonstrated that SGLT2 inhibitors achieved multiple beneficial activities, targeting several renal cellular and molecular pathways independent of their antihyperglycemic activity. These mainly include the reduction in intraglomerular pressure through the restoration of TGF, impacts on the renin-angiotensin-aldosterone system, improvement of renal hypoxia, adaptive metabolic alterations in substrate use/energy expenditure, improvement of mitochondrial dysfunction, and reduction of inflammation, oxidative stress and fibrosis. This manuscript thoroughly investigates the possible mechanisms that underlie their salutary renal effects in patients with diabetes, focusing on several pathways involved and the interplay between them. It also explores their upcoming role in ameliorating the evolution of chronic kidney disease in patients with diabetes.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.
{"title":"Regulating miRNAs Expression by Resveratrol: Novel Insights based on Molecular Mechanism and Strategies for Cancer Therapy.","authors":"Atoosa Keshavarzmotamed, Vahide Mousavi, Niloufar Masihipour, Atefe Rahmati, Rohollah Mousavi Dehmordi, Behrooz Ghezelbash, Mina Alimohammadi, Alireza Mafi","doi":"10.2174/0118761429249717230920113227","DOIUrl":"https://doi.org/10.2174/0118761429249717230920113227","url":null,"abstract":"<p><p>Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-19DOI: 10.2174/0118761429251911231011092145
Juan Hao, Jian Wu, Quanjun Yang, Kan Lu, Yi Xu, Yiyue Chen, Jibo Liu, Xiaohong Shao, Chunling Zhu, Yaqin Ding, Xin Xie
Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.
Objective: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.
Methods: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.
Results: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.
Conclusion: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.
{"title":"Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model.","authors":"Juan Hao, Jian Wu, Quanjun Yang, Kan Lu, Yi Xu, Yiyue Chen, Jibo Liu, Xiaohong Shao, Chunling Zhu, Yaqin Ding, Xin Xie","doi":"10.2174/0118761429251911231011092145","DOIUrl":"https://doi.org/10.2174/0118761429251911231011092145","url":null,"abstract":"<p><strong>Background: </strong>Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.</p><p><strong>Objective: </strong>The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.</p><p><strong>Methods: </strong>Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.</p><p><strong>Results: </strong>In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.</p><p><strong>Conclusion: </strong>GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50164218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The incidence of nonalcoholic fatty liver disease (NAFLD) has been rising worldwide in parallel with diabetes and metabolic syndrome. NAFLD refers to a spectrum of liver abnormalities with a variable course, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma. Pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a prominent part in the regulation of endogenous metabolic genes in NAFLD. Recent studies have suggested that PXR has therapeutic potential for NAFLD, yet the relationship between PXR and NAFLD remains controversial. In this review, PXR is proposed to play a dual role in the development and progression of NAFLD. Its activation will aggravate steatosis of the liver, reduce inflammatory response, and prevent liver fibrosis. In addition, the interactions between PXR, substance metabolism, inflammation, fibrosis, and gut microbiota in non-alcoholic fatty liver were elucidated. Due to limited therapeutic options, a better understanding of the contribution of PXR to the pathogenesis of NAFLD should facilitate the design of innovative drugs targeting NAFLD.
{"title":"Dual Role of Pregnane X Receptor in Nonalcoholic Fatty Liver Disease.","authors":"Yuan Xu, Ziming An, Shufei Wang, Yiming Ni, Mingmei Zhou, Qin Feng, Xiaojun Gou, Meiling Xu, Ying Qi","doi":"10.2174/0118761429259143230927110556","DOIUrl":"https://doi.org/10.2174/0118761429259143230927110556","url":null,"abstract":"<p><p>The incidence of nonalcoholic fatty liver disease (NAFLD) has been rising worldwide in parallel with diabetes and metabolic syndrome. NAFLD refers to a spectrum of liver abnormalities with a variable course, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma. Pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a prominent part in the regulation of endogenous metabolic genes in NAFLD. Recent studies have suggested that PXR has therapeutic potential for NAFLD, yet the relationship between PXR and NAFLD remains controversial. In this review, PXR is proposed to play a dual role in the development and progression of NAFLD. Its activation will aggravate steatosis of the liver, reduce inflammatory response, and prevent liver fibrosis. In addition, the interactions between PXR, substance metabolism, inflammation, fibrosis, and gut microbiota in non-alcoholic fatty liver were elucidated. Due to limited therapeutic options, a better understanding of the contribution of PXR to the pathogenesis of NAFLD should facilitate the design of innovative drugs targeting NAFLD.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71490309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-15DOI: 10.2174/1874467217666230915125613
Kiran Singh Sharma, Sumit Kumar
Background: Psoriasis is an acute to chronic multifunctional inflammatory skin disorder mediated through T-cell activation, dendritic cell intervention, local vascular variations, atypical keratinocyte proliferation, and neutrophil activation, leading to a skin disorder with no permanent cure.
Objective: This review aims to find a potent, secure, and dependable medication, with a more scientific examination of herbal resources and recent targeted immunobiological therapies.
Method: Reports evaluating the effectiveness of biologics & herbal remedies for the topical therapy of psoriasis against control therapies were taken into consideration (placebo or active therapy). The work examined cellular circuits involved in inflammation with its immunogenetic mechanism behind various options available for treating psoriasis in addition to the role of agents inducing psoriasis.
Results: The extent of psoriasis can range from small, localized spots to total body coverage, and it can happen at any stage of life. Several theories exist for clarification however, the exact cause of psoriasis is not entirely understood. Researchers have discovered genetic loci linkages, environmental changes, drug induction, lifestyle conditions, some infections, etc. resulting in this disorder. There are numerous known conventional medical treatments for psoriasis, ranging from topical and systemic medicines to phototherapy or combinations of both with recent immunobiological treatment. However, the majority of these treatments are ineffective and have a variety of side effects that limit their long-term usage, such as cutaneous atrophy, tissue toxicity, mutagenicity, and immunosuppression.
Conclusion: Herbal extracts or isolated compounds can be considered as a substitute for conventional psoriasis treatment. Unfortunately, many investigations often provide a small amount of facts about the safety and effectiveness of topically applied herbal remedies for the treatment of psoriasis. Thus, further factual evidences and validations are needed to promote herbal options, which must be supported by rigorous animal studies or clinical trials using standardised materials and compositions.
{"title":"Current strategies for the management of psoriasis with potential pharmacological pathways using herbals and immuno-biologicals.","authors":"Kiran Singh Sharma, Sumit Kumar","doi":"10.2174/1874467217666230915125613","DOIUrl":"https://doi.org/10.2174/1874467217666230915125613","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is an acute to chronic multifunctional inflammatory skin disorder mediated through T-cell activation, dendritic cell intervention, local vascular variations, atypical keratinocyte proliferation, and neutrophil activation, leading to a skin disorder with no permanent cure.</p><p><strong>Objective: </strong>This review aims to find a potent, secure, and dependable medication, with a more scientific examination of herbal resources and recent targeted immunobiological therapies.</p><p><strong>Method: </strong>Reports evaluating the effectiveness of biologics & herbal remedies for the topical therapy of psoriasis against control therapies were taken into consideration (placebo or active therapy). The work examined cellular circuits involved in inflammation with its immunogenetic mechanism behind various options available for treating psoriasis in addition to the role of agents inducing psoriasis.</p><p><strong>Results: </strong>The extent of psoriasis can range from small, localized spots to total body coverage, and it can happen at any stage of life. Several theories exist for clarification however, the exact cause of psoriasis is not entirely understood. Researchers have discovered genetic loci linkages, environmental changes, drug induction, lifestyle conditions, some infections, etc. resulting in this disorder. There are numerous known conventional medical treatments for psoriasis, ranging from topical and systemic medicines to phototherapy or combinations of both with recent immunobiological treatment. However, the majority of these treatments are ineffective and have a variety of side effects that limit their long-term usage, such as cutaneous atrophy, tissue toxicity, mutagenicity, and immunosuppression.</p><p><strong>Conclusion: </strong>Herbal extracts or isolated compounds can be considered as a substitute for conventional psoriasis treatment. Unfortunately, many investigations often provide a small amount of facts about the safety and effectiveness of topically applied herbal remedies for the treatment of psoriasis. Thus, further factual evidences and validations are needed to promote herbal options, which must be supported by rigorous animal studies or clinical trials using standardised materials and compositions.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-15DOI: 10.2174/1874467217666230915125622
Yejiao Ruan, Guangrong Lu, Yaojun Yu, Yue Luo, Hao Wu, Yating Shen, Zejun Gao, Yao Shen, Zhenzhai Cai, Liyi Li
Introduction: Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed.
Method: In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression.
Results: Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression.
Conclusion: Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.
{"title":"PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway.","authors":"Yejiao Ruan, Guangrong Lu, Yaojun Yu, Yue Luo, Hao Wu, Yating Shen, Zejun Gao, Yao Shen, Zhenzhai Cai, Liyi Li","doi":"10.2174/1874467217666230915125622","DOIUrl":"https://doi.org/10.2174/1874467217666230915125622","url":null,"abstract":"<p><strong>Introduction: </strong>Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed.</p><p><strong>Method: </strong>In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression.</p><p><strong>Results: </strong>Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression.</p><p><strong>Conclusion: </strong>Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}