Current Research in Pharmacology and Drug Discovery最新文献

{"title":"Endoplasmic reticulum stress in pancreatic β-cell dysfunction: The potential therapeutic role of dietary flavonoids","authors":"Kingsley C. Mbara ,&nbsp;Marthe C.D. Fotsing ,&nbsp;Derek T. Ndinteh ,&nbsp;Claudine N. Mbeb ,&nbsp;Chinekwu S. Nwagwu ,&nbsp;Rene Khan ,&nbsp;Kopang C. Mokhetho ,&nbsp;Himansu Baijnath ,&nbsp;Manimbulu Nlooto ,&nbsp;Shoeshoe Mokhele ,&nbsp;Carmen M. Leonard ,&nbsp;Vuyelwa J. Tembu ,&nbsp;Clemence Tarirai","doi":"10.1016/j.crphar.2024.100184","DOIUrl":"10.1016/j.crphar.2024.100184","url":null,"abstract":"<div><p>Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum (ER) stress is a fact of life that contributes to β-cell loss or dysfunction. Despite recent advances in research, the existing treatment approaches such as lifestyle modification and use of conventional therapeutics could not prevent the loss or dysfunction of pancreatic β-cells to abrogate the disease progression. Therefore, targeting ER stress and the consequent unfolded protein response (UPR) in pancreatic β-cells may be a potential therapeutic strategy for diabetes treatment. Dietary phytochemicals have therapeutic applications in human health owing to their broad spectrum of biochemical and pharmacological activities. Flavonoids, which are commonly obtained from fruits and vegetables worldwide, have shown promising prospects in alleviating ER stress. Dietary flavonoids including quercetin, kaempferol, myricetin, isorhamnetin, fisetin, icariin, apigenin, apigetrin, vitexin, baicalein, baicalin, nobiletin hesperidin, naringenin, epigallocatechin 3-O-gallate hesperidin (EGCG), tectorigenin, liquiritigenin, and acacetin have shown inhibitory effects on ER stress in pancreatic β-cells. Dietary flavonoids modulate ER stress signaling components, chaperone proteins, transcription factors, oxidative stress, autophagy, apoptosis, and inflammatory responses to exert their pharmacological effects on pancreatic β-cells ER stress. This review focuses on the role of dietary flavonoids as potential therapeutic adjuvants in preserving pancreatic β-cells from ER stress. Highlights of the underlying mechanisms of action are also presented as well as possible strategies for clinical translation in the management of DM.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100184"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000117/pdfft?md5=e9be6bef98dc4f953504348decab6dff&pid=1-s2.0-S2590257124000117-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141135981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scaling approaches for the prediction of human clearance of LNA-i-mir-221: A retrospective validation","authors":"Massimiliano Fonsi ,&nbsp;Jacques Fulbert ,&nbsp;Pierre-Andre Billat ,&nbsp;Mariamena Arbitrio ,&nbsp;Pierosandro Tagliaferri ,&nbsp;Pierfrancesco Tassone ,&nbsp;Maria Teresa Di Martino","doi":"10.1016/j.crphar.2024.100197","DOIUrl":"10.1016/j.crphar.2024.100197","url":null,"abstract":"<div><p>LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100197"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000245/pdfft?md5=14be37eb3e3e1daad2b299ed49e09672&pid=1-s2.0-S2590257124000245-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141952149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of survival rate and persistence predictors of baricitinib in real-world data from a large cohort of rheumatoid arthritis patients","authors":"Simone Parisi ,&nbsp;Becciolini Andrea ,&nbsp;Ditto Maria Chiara ,&nbsp;Lo Gullo Alberto ,&nbsp;Larosa Maddalena ,&nbsp;Scolieri Palma ,&nbsp;Addimanda Olga ,&nbsp;Reta Massimo ,&nbsp;Paroli Marino (Prof) ,&nbsp;Caccavale Rosalba ,&nbsp;Visalli Elisa ,&nbsp;Foti Rosario ,&nbsp;Amato Giorgio ,&nbsp;De Lucia Francesco ,&nbsp;Dal Bosco Ylenia ,&nbsp;Foti Roberta ,&nbsp;Farina Antonella ,&nbsp;Girelli Francesco ,&nbsp;Bernardi Simone ,&nbsp;Camellino Dario ,&nbsp;Fusaro Enrico","doi":"10.1016/j.crphar.2024.100178","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100178","url":null,"abstract":"<div><h3>Objectives</h3><p>The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate.</p></div><div><h3>Methods</h3><p>This is a retrospective, multicentric, Italian, longitudinal study. All patients were enrolled according to the following criteria: a) age ≥ 18 years old; b) diagnosed with RA according 2010 ACR/EULAR classification criteria; c) treated with baricitinib. In order to describe baricitinib clinical efficacy, the survival rate was evaluated by The Kaplan–Meier curve. Then, predictive factors of drug retention rate were assessed by performing the Cox analysis, identifying which risk factors influenced treatment persistence.</p></div><div><h3>Results</h3><p>Overall, we included 478 patients treated with baricitinib. Among them, 380 (79.5%) were females. Baricitinib's survival rate was 94.6% at 6 months, 87.9% at 12 months, 81.7% at 24 months and 53.4% at 48 months. The Cox analysis regression showed that a higher bDMARDs/tsDMARD line of therapy seems to be a negative prognostic factor for the drug retention rate (HR 1.26 CI 95% 1.07–1.49, p = 0.006.</p></div><div><h3>Conclusion</h3><p>Real-life study confirms baricitinib effectiveness up to 4 years, but previous treatment with bDMARDs was a negative prognostic factor for its survival rate.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100178"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000051/pdfft?md5=de00ff9c3ff118ac9487540fc26e78bb&pid=1-s2.0-S2590257124000051-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139935265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The polyphenolic compound punicalagin protects skin fibroblasts from UVA radiation oxidative damage","authors":"Giada Bianchetti ,&nbsp;Patrizia Bottoni ,&nbsp;Giuseppe Tringali ,&nbsp;Giuseppe Maulucci ,&nbsp;Elisabetta Tabolacci ,&nbsp;Maria Elisabetta Clementi","doi":"10.1016/j.crphar.2024.100186","DOIUrl":"10.1016/j.crphar.2024.100186","url":null,"abstract":"<div><p>Polyphenols are a class of natural compounds that act as antioxidants, neutralising harmful free radicals that would damage cells and increase the risk of diseases such as cancer, diabetes and heart disease. They also reduce inflammation, which is thought to be at the root of many chronic diseases.</p><p>We are investigating the photoprotective effects of punicalagin, a type of polyphenolic compound mainly found in pomegranates, against UVA-induced damage in human skin fibroblasts. Punicalagin increases cell viability and reduces the high levels of ROS generated by photooxidative stress through its ability to modulate the Nrf2 transcriptional pathway. Interestingly, activation of the Nrf2 pathway results in an increase in reduced glutathione, NADH, and subsequently protects mitochondrial respiratory capacity. Integrating molecular and imaging approaches, our results demonstrate a potential cytoprotective effect of punicalagin against UVA-induced skin damage through an anti-apoptotic mechanism.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100186"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000130/pdfft?md5=d12cefebb62aea6cad9d5e2fd6a20512&pid=1-s2.0-S2590257124000130-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141134124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sildenafil prevents chronic psychosocial stress-induced working memory impairment: Role of brain-derived neurotrophic factor","authors":"Tareq I. Jibril ,&nbsp;Karem H. Alzoubi ,&nbsp;Nizar M. Mhaidat ,&nbsp;Omar F. Khabour ,&nbsp;Mohammad A.Y. Alqudah ,&nbsp;Abeer M. Rababa’h ,&nbsp;Nasr Alrabadi ,&nbsp;Doaa Al-udatt","doi":"10.1016/j.crphar.2024.100182","DOIUrl":"10.1016/j.crphar.2024.100182","url":null,"abstract":"<div><h3>Background</h3><p>Psychosocial stress, a common feature in modern societies, impairs cognitive functions. It is suggested that stress hormones and elevated excitatory amino acids during stress are responsible for stress-induced cognitive deficits. Reduced brain-derived neurotrophic factor (BDNF) levels, increased oxidative stress, and alteration of synaptic plasticity biomarkers are also possible contributors to the negative impact of stress on learning and memory. Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor and the first oral therapy for the treatment of erectile dysfunction. It has been shown that sildenafil improves learning and memory and possesses antioxidant properties. We hypothesized that administering sildenafil to stressed rats prevents the cognitive deficit induced by chronic psychosocial stress.</p></div><div><h3>Methods</h3><p>Psychosocial stress was generated using the intruder model. Sildenafil 3 mg/kg/day was administered intraperitoneally to animals. Behavioral studies were conducted to test spatial learning and memory using the radial arm water maze. Then, the hippocampal BDNF level and several antioxidant markers were assessed.</p></div><div><h3>Results</h3><p>This study revealed that chronic psychosocial stress impaired short-term but not long-term memory. The administration of sildenafil prevented this short-term memory impairment. Chronic psychosocial stress markedly reduced the level of hippocampal BDNF (P˂0.05), and this reduction in BDNF was normalized by sildenafil treatment. In addition, neither chronic psychosocial stress nor sildenafil significantly altered the activity of measured oxidative parameters (P &gt; 0.05).</p></div><div><h3>Conclusion</h3><p>Chronic psychosocial stress induces short-term memory impairment. The administration of sildenafil citrate prevented this impairment, possibly by normalizing the level of BDNF.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100182"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000099/pdfft?md5=09936b28ff220b5c7507ae39caa4c86c&pid=1-s2.0-S2590257124000099-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140782465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the chemotherapeutic potential of two platinum(IV) complexes in skin cancer: in vitro and in vivo Insights","authors":"Amjad Slika ,&nbsp;Christina Haydar ,&nbsp;Joelle Bou Chacra ,&nbsp;Seba Al Alam ,&nbsp;Stephanie Mehanna ,&nbsp;Anthony Lteif ,&nbsp;Maria George Elias ,&nbsp;Krishant M. Deo ,&nbsp;Robin I. Taleb ,&nbsp;Janice R. Aldrich-Wright ,&nbsp;Costantine F. Daher","doi":"10.1016/j.crphar.2024.100205","DOIUrl":"10.1016/j.crphar.2024.100205","url":null,"abstract":"<div><div>The present study investigates the chemotherapeutic potential of two platinum (IV) complexes, P-PENT and P-HEX, against skin cancer <em>in vitro and in vivo</em>. Both complexes exhibited potent cytotoxicity against HaCaT-II-4 cells with IC₅₀ values of 0.8 ± 0.08 μM and 1.3 ± 0.16 μM respectively, while demonstrating 8-10-fold selectivity compared to mesenchymal stem cells (MSCs). Western blot analysis revealed significant modulation of key apoptotic and survival pathways, including upregulation of Bax/Bcl2 ratio, cleaved caspase 3, and cytochrome <em>c</em>, suggesting induction of intrinsic apoptosis. The complexes also inhibited PI3K and MAPK pathways, as evidenced by decreased p-AKT/AKT and p-ERK/ERK ratios. Flow cytometry confirmed significant apoptotic cell death. Both complexes also increased reactive oxygen species production. In a DMBA/TPA-induced skin carcinogenesis mouse model, both complexes significantly suppressed tumor growth at doses considerably lower than the maximum tolerated dose, with no detectable toxicity. A dose escalation study in BALB/c mice showed that P-PENT and P-HEX were approximately 5-fold and 4-fold more tolerated than cisplatin, respectively. In conclusion, the present study provides evidence that P-PENT and P-HEX may have the characteristics of an effective and potentially safe anti-tumor drug that could be used in skin cancer treatment.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100205"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142571501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term effects of neonatal pain and sucrose treatment","authors":"Khawla Nuseir ,&nbsp;Karem H. Alzoubi ,&nbsp;Ahmad Altarifi ,&nbsp;Manal Kassab ,&nbsp;Omar F. Khabour ,&nbsp;Nour F. Al-Ghraiybah ,&nbsp;Roa'a Obiedat","doi":"10.1016/j.crphar.2024.100176","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100176","url":null,"abstract":"<div><h3>Purpose</h3><p>In neonatal intensive care units, applying sucrose solution for analgesia is now a routine treatment for mild procedural pain. Studies of animal and human infants provide clear evidence of benefits in the short term, but few studies have investigated the long term benefits. Thus, we determined whether sucrose could ameliorate painful stimulation during infancy in Sprague–Dawley rats and also explored the long-term effects of repeated sucrose administration during infancy. Female and male rats were included to investigate sex-related differences.</p></div><div><h3>Methods</h3><p>Rat pups were stimulated either with painful or tactile stimuli for the first 14 days of their lives. Pups were pretreated either with sucrose or not treated before stimulation. Behavioral tests were conducted during adolescence and adulthood. Hotplate, rotarod, open field, elevated plus maze, and radial arm water maze tests were employed to assess the behavioral consequences of early life manipulations and treatments.</p></div><div><h3>Results</h3><p>Painful stimulation during infancy increased the sensitivity to pain later in life, and sucrose did not remedy this effect. Motility, coordination, anxiety, and cognition tests in adulthood obtained mixed results. Pain during infancy appeared to increase anxiety during adulthood. Learning and memory in adulthood were affected by pain during infancy, and sucrose had a negative effect even in the absence of pain. No sex-related differences were observed in any of the behavioral tests by employing this model of neonatal pain.</p></div><div><h3>Conclusion</h3><p>Painful stimulation during infancy resulted in deficiencies in some behavioral tests later in life. Sucrose pretreatment did not mitigate these shortcomings and it actually resulted in negative outcomes.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100176"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000038/pdfft?md5=e636825cbac4fe60817ad63f4c571321&pid=1-s2.0-S2590257124000038-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139653653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abelacimab: A leap forward in anticoagulation with FXI and FXIa Inhibition","authors":"Hisham A. Badreldin ,&nbsp;Nada Alsuhebany ,&nbsp;Mohammed Alzahrani ,&nbsp;Abdulmajeed M. Alshehri ,&nbsp;Maha Aldoughaim ,&nbsp;Saleh Alqifari ,&nbsp;Omar Yassin ,&nbsp;Lama Alfehaid ,&nbsp;Tariq Alqahtani","doi":"10.1016/j.crphar.2024.100179","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100179","url":null,"abstract":"<div><p>Direct Oral Anticoagulants (DOACs) have revolutionized the treatment of thromboembolic disorders, offering targeted, effective, and safer alternatives to traditional anticoagulants like heparins and vitamin K antagonists (VKAs). Despite their benefits, DOACs have drawbacks, including an increased risk of gastrointestinal bleeding and unsuitability for patients with mechanical heart valves. Recent research has highlighted Factor XI (FXI) as a promising anticoagulation target due to its significant role in pathological thrombosis and minor involvement in normal hemostasis. Abelacimab, an antibody that inhibits FXI, has shown potential in transforming anticoagulation therapy by sparing hemostasis. This review provides a comprehensive analysis of abelacimab, examining its clinical pharmacology and its pharmacokinetic and pharmacodynamic properties. It scrutinizes abelacimab's safety profile and key monitoring parameters. The current evidence supporting its use and potential future research strengthening its position in anticoagulant therapy is also discussed. The objective is to enhance understanding and contribute to discussions around developing safer anticoagulants, particularly for patients at risk for thrombosis.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100179"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000063/pdfft?md5=57b84c5a9c099c657260d03887e08166&pid=1-s2.0-S2590257124000063-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140163560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms and therapeutic potential of natural flavonoids in diabetic nephropathy: Modulation of intracellular developmental signaling pathways","authors":"Mahaboob Khan Sulaiman","doi":"10.1016/j.crphar.2024.100194","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100194","url":null,"abstract":"<div><p>Recognized as a common microvascular complication of diabetes mellitus (DM), diabetic nephropathy (DN) is the principal cause of chronic end-stage renal disease (ESRD). Patients with diabetes have an approximately 25% risk of developing progressive renal disease. The underlying principles of DN control targets the dual outcomes of blood glucose regulation through sodium glucose cotransporter 2 (SGLT 2) blockade and hypertension management through renin-angiotensin-aldosterone inhibition. However, these treatments are ineffective in halting disease progression to kidney failure and cardiovascular comorbidities. Recently, the dysregulation of subcellular signaling pathways has been increasingly implicated in DN pathogenesis. Natural compounds are emerging as effective and side-effect-free therapeutic agents that target intracellular pathways. This narrative review synthesizes recent insights into the dysregulation of maintenance pathways in DN, drawing from animal and human studies. To compile this review, articles reporting DN signaling pathways and their treatment with natural flavonoids were collected from PubMed, Cochrane Library Web of Science, Google Scholar and EMBASE databases since 2000. As therapeutic interventions are frequently based on the results of clinical trials, a brief analysis of data from current phase II and III clinical trials on DN is discussed.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100194"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S259025712400021X/pdfft?md5=1f92eb2d0381845b0736d4728a947c8b&pid=1-s2.0-S259025712400021X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141582194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice","authors":"Katherine Keever ,&nbsp;Bardia Askari","doi":"10.1016/j.crphar.2024.100203","DOIUrl":"10.1016/j.crphar.2024.100203","url":null,"abstract":"<div><div>Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tissue is associated with obesity and atherosclerosis in LDLR^−/− mice fed a high fat-high carbohydrate. The present study was undertaken to determine whether inhibition of 5-lipoxygenase activating protein is efficacious in attenuating adipose tissue inflammation in LDLR^−/− mice fed a high fat-high carbohydrate. 10-week old male LDLR^−/− mice were fed a high fat-high carbohydrate diet for 22-weeks, with or without MK886 (40 mg/kg/day, <em>ad libitum</em>) a well-established 5-lipoxygenase activating protein inhibitor. All mice had an approximate 2-fold increase in total body weight, but a 6-week course of MK886 treatment had differential effects on adipose tissue size, without affecting macrophage accumulation. MK886 exacerbated the dyslipidemia, increased serum amyloid A content of high-density lipoproteins and caused a profound hepatomegaly. Dyslipidemia and increased serum amyloid A were concomitant with increases in atherosclerosis. In conclusion, MK886 paradoxically exacerbated hyperlipidemia and the pro-inflammatory phenotype in a mouse model of diet-induced atherosclerosis, possibly via a disruption of hepatic lipid metabolism and increased inflammation.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100203"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}