An Integrative Review of Micro-Credentials and Digital Badges for Pharmacy Educators.

Micro-credentials (MCs) and digital badges (DBs) have gained popularity in recent years as a means to supplement traditional degrees and certifications. MCs and DBs can play a significant role in supporting student-centered learning by offering personalized and flexible learning pathways, emphasizing real-world relevance and practical skills, and fostering a culture of continuous learning and growth. However, barriers currently exist within health professions education, including pharmacy education, that could limit the full adoption and implementation of MCs and DBs. Research on the use of MCs and DBs in Doctor of Pharmacy degree programs is sparse. In this integrative review, literature on the use of MCs and DBs in health professions education is reviewed, and perspectives on the benefits, issues, and potential future uses within Doctor of Pharmacy degree programs are presented.

Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a growing epidemic worldwide and a leading cause of end-stage kidney disease. Mineralocorticoid receptor (MR) blockade using Finerenone is a recently approved therapeutic approach to slow down the progression of DKD in patients with type 2 diabetes in addition to other therapies such as angiotensin-II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), sodium-glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) analogs. This review elaborates on the pathophysiologic pathways activated by aldosterone (the human mineralocorticoid) in DKD, the pharmacology of three different generations of mineralocorticoid receptor antagonists (MRAs), specifically, spironolactone, eplerenone, and finerenone, and the mechanisms by which these MRAs elicit their protective effects on the kidney under diabetic settings.

Nano drug delivery systems for antisense oligonucleotides (ASO) therapeutics.

Cancer, infectious diseases, and metabolic and hereditary genetic disorders are a global health burden affecting millions of people, with contemporary treatments offering limited relief. Antisense technology treats diseases by targeting their causal agents using its ability to alter or inhibit endogenous or malfunctioning genes. Nine antisense oligonucleotide (ASO) drugs that represent four different chemical classes have been approved for the treatment of rare diseases, including nusinersen, the first new oligonucleotide-based drug. Advances in medicinal chemistry, understanding the molecular pathways, and the availability of vast genetic data have resulted in enormous improvements in the therapeutic performance of ASO drugs; however, their susceptibility to degradation in the circulation, rapid renal clearance, and immunostimulatory adverse effects greatly limit their clinical applications. An increasing number of ASO-based therapeutics is being tested in clinical trials. Improvements to the delivery of ASO drugs could potentially change the therapeutic landscape for many conditions in the near future. This review describes the technological advances and developments in drug delivery systems pertaining to ASO therapeutics.

Myrtenal attenuates oxidative stress and inflammation in a rat model of streptozotocin-induced diabetes.

The present study was aimed to investigate the effect of myrtenal on diabetes-associated oxidative stress, lipid peroxidation (LPO), and inflammation using a rat model of streptozotocin (STZ)-induced diabetes. Following the induction of diabetes in male Wistar rats using STZ (40 mg/kg body weight), myrtenal (80 mg/kg body weight) was administered orally to diabetic rats for four weeks and then sacrificed to harvest tissues. We measured the levels of antioxidants, LPO, and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and the p65 subunit of nuclear factor-kappa B (NF-kB p65). Diabetic rats revealed increased levels of LPO, proinflammatory cytokines, and NF-kB p65, and decreased levels of antioxidants in the liver and pancreas. Supplementation with myrtenal significantly attenuated the diabetes-induced changes in the liver and pancreas of diabetic rats. Our findings suggest that myrtenal may serve as an antioxidant and anti-inflammatory agent against diabetes-associated oxidative stress and inflammation.HighlightsOral administration of myrtenal improved the antioxidant status in the liver and pancreas of diabetic rats.Myrtenal treatment diminished inflammation in the liver and pancreas of diabetic rats.Myrtenal supplementation averts oxidative stress and inflammation in diabetic rats.Myrtenal could serve as a potent antioxidant and anti-inflammatory agent in the management of diabetes.

Renoprotective mechanisms of sodium-glucose co-transporter 2 (SGLT2) inhibitors against the progression of diabetic kidney disease.

Sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) have emerged as a promising class of antidiabetic drugs with cardioprotective and renoprotective effects in patients with type 2 diabetes (T2D). The sodium-glucose co-transporters 1 and 2 (SGLT 1 and SGLT2) located in the renal proximal tubules are responsible for glucose reabsorption from the glomerular filtrate back into the systemic circulation. Inhibition of SGLT2, which accounts for about 90% of the glucose reabsorption, leads to a significant reduction in blood glucose levels and a concomitant increase in the urinary excretion of glucose (glycosuria). Multiple mechanisms contribute to the nephroprotective effects of SGLT2-Is in T2D patients. These include: (1) Restoration of the tubuloglomerular feedback by increasing sodium delivery at macula densa, leading to afferent arteriolar constriction and reduced glomerular hyperfiltration, (2) Decreased activation of the intra-renal renin-angiotensin-aldosterone system, which also contributes to reducing glomerular hyperfiltration, (3) Increased production of ketone bodies, which serves as an alternate fuel for adenosine triphosphate production in mitochondria, which helps in attenuating inflammation, and (4) Protection against hypoxia, oxidative stress, and fibrosis. This review elaborates on the key mechanisms that underlie the nephroprotective effects and the adverse effects of SGLT2-Is in T2D patients with progressive diabetic kidney disease.

Smart Nanocarriers for the Delivery of Nucleic Acid-Based Therapeutics: A Comprehensive Review.

Nucleic acid-based therapies are promising therapeutics for the treatment of several systemic disorders, and they offer an exciting opportunity to address emerging biological challenges. The scope of nucleic acid-based therapeutics in the treatment of multiple disease states including cancers has been widened by recent progress in Ribonucleic acids (RNA) biology. However, cascades of systemic and intracellular barriers, including rapid degradation, renal clearance, and poor cellular uptake, hinder the clinical effectiveness of nucleic acid-based therapies. These barriers can be circumvented by utilizing advanced smart nanocarriers that efficiently deliver and release the encapsulated nucleic acids into the target tissues. This review describes the current status of clinical trials on nucleic acid-based therapeutics and highlights representative examples that provide an overview on the current and emerging trends in nucleic acid-based therapies. A better understanding of the design of advanced nanocarriers is essential to promote the translation of therapeutic nucleic acids into a clinical reality.

Corrigendum to "Renoprotective Effects of Aldose Reductase Inhibitor Epalrestat against High Glucose-Induced Cellular Injury".

[This corrects the article DOI: 10.1155/2017/5903105.].

Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury.

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-ß), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-ß signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.

Molecular Mechanisms Underpinning Microparticle-Mediated Cellular Injury in Cardiovascular Complications Associated with Diabetes.

Microparticles (MPs) are small vesicles shed from the cytoplasmic membrane of healthy, activated, or apoptotic cells. MPs are very heterogeneous in size (100-1,000 nm), and they harbor proteins and surface antigens specific to cells they originate from. Virtually, all cells can shed MPs, and therefore, they can be found in all body fluids, but also entrapped in tissues. Of interest and because of their easy detection using a variety of techniques, circulating MPs were recognized as biomarkers for cell activation. MPs were also found to mediate critical actions in intercellular communication and transmitting biological messages by acting as paracrine vehicles. High plasma numbers of MPs were reported in many cardiovascular and metabolic disturbances that are closely associated with insulin resistance and low-grade inflammation and have been linked to adverse actions on cardiovascular function. This review highlights the involvement of MPs in cardiovascular complications associated with diabetes and discusses the molecular mechanisms that underpin the pathophysiological role of MPs in the onset and progression of cellular injury in diabetes.

Metformin Induces Different Responses in Clear Cell Renal Cell Carcinoma Caki Cell Lines.

Clear cell renal cell carcinoma (ccRCC) is the most common and lethal form of urological cancer diagnosed globally. Mutations of the von Hippel-Lindau (VHL) tumor-suppressor gene and the resultant overexpression of hypoxia-inducible factor (HIF)-1α protein are considered hallmarks of ccRCC. Persistently activated HIF-1α is associated with increased cell proliferation, angiogenesis, and epithelial⁻mesenchymal transition (EMT), consequently leading to ccRCC progression and metastasis to other organs. However, the VHL status alone cannot predict the differential sensitivity of ccRCC to cancer treatments, which suggests that other molecular differences may contribute to the differential response of ccRCC cells to drug therapies. In this study, we investigated the response to metformin (an antidiabetic drug) of two human ccRCC cell lines Caki-1 and Caki-2, which express wild-type VHL. Our findings demonstrate a differential response between the two ccRCC cell lines studied, with Caki-2 cells being more sensitive to metformin compared to Caki-1 cells, which could be linked to the differential expression of HIF-1 despite both cell lines carrying a wild-type VHL. Our study unveils the therapeutic potential of metformin to inhibit the progression of ccRCC in vitro. Additional preclinical and clinical studies are required to ascertain the therapeutic efficacy of metformin against ccRCC.

Crosstalk Between Oxidative Stress and Endoplasmic Reticulum (ER) Stress in Endothelial Dysfunction and Aberrant Angiogenesis Associated With Diabetes: A Focus on the Protective Roles of Heme Oxygenase (HO)-1.

Type-2 diabetes prevalence is continuing to rise worldwide due to physical inactivity and obesity epidemic. Diabetes and fluctuations of blood sugar are related to multiple micro- and macrovascular complications, that are attributed to oxidative stress, endoplasmic reticulum (ER) activation and inflammatory processes, which lead to endothelial dysfunction characterized, among other features, by reduced availability of nitric oxide (NO) and aberrant angiogenic capacity. Several enzymatic anti-oxidant and anti-inflammatory agents have been found to play protective roles against oxidative stress and its downstream signaling pathways. Of particular interest, heme oxygenase (HO) isoforms, specifically HO-1, have attracted much attention as major cytoprotective players in conditions associated with inflammation and oxidative stress. HO operates as a key rate-limiting enzyme in the process of degradation of the iron-containing molecule, heme, yielding the following byproducts: carbon monoxide (CO), iron, and biliverdin. Because HO-1 induction was linked to pro-oxidant states, it has been regarded as a marker of oxidative stress; however, accumulating evidence has established multiple cytoprotective roles of the enzyme in metabolic and cardiovascular disorders. The cytoprotective effects of HO-1 depend on several cellular mechanisms including the generation of bilirubin, an anti-oxidant molecule, from the degradation of heme; the induction of ferritin, a strong chelator of free iron; and the release of CO, that displays multiple anti-inflammatory and anti-apoptotic actions. The current review article describes the major molecular mechanisms contributing to endothelial dysfunction and altered angiogenesis in diabetes with a special focus on the interplay between oxidative stress and ER stress response. The review summarizes the key cytoprotective roles of HO-1 against hyperglycemia-induced endothelial dysfunction and aberrant angiogenesis and discusses the major underlying cellular mechanisms associated with its protective effects.

The use of Socrative and Yammer online tools to promote interactive learning in pharmacy education.

BACKGROUND AND PURPOSE: Engagement of students in the didactic classroom setting restricts students' time spent towards active learning, which in turn, adversely affects the retention of concepts taught through traditional teaching methods. Thus, interactive learning is used as an alternative to engage students in the classroom and to enrich their learning experience. Integrating interactive learning activities has been shown to facilitate student learning and improve the learning outcomes. The objectives of this study are to assess the perceptions of students on the benefits and appropriateness of using online tools (e.g., Socrative and Yammer) to promote interaction of students with the instructor and other students in the classroom setting. EDUCATIONAL ACTIVITY AND SETTING: Students enrolled in the second and third professional years of the bachelor of pharmacy program at Qatar University were introduced to various interactive learning tools in two Pharmaceutical Sciences courses. Students were then surveyed to assess their perceptions about the benefits and appropriateness of the respective interactive learning tools introduced in the courses. FINDINGS: Our survey results indicate that the students are in favor of using online educational tools and believe that the use of interactive learning tools enhances their learning experience. SUMMARY: Pharmacy students at Qatar University perceive that the incorporation of online technology in Pharmaceutical Sciences courses enhances interactive learning in the classroom setting.

Role of Methylglyoxal in Diabetic Cardiovascular and Kidney Diseases: Insights from Basic Science for Application into Clinical Practice.

BACKGROUND: The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound - is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation. CONCLUSION: Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.

AMP-activated Protein Kinase as a Drug Target in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is a condition increasingly affecting millions of individuals worldwide and is ranked as the ninth leading cause of death in the United States. AMPactivated protein kinase (AMPK) is an energy sensor that plays a pivotal role in cellular homoeostasis. Deficiency in AMPK activity and autophagic signaling, and sustained activation of mammalian target of rapamycin (mTOR) signaling and endoplasmic reticulum (ER) stress have been shown to promote epithelial-to-mesenchymal transition (EMT) and renal cell apoptosis and contribute to CKD. Emerging evidences demonstrate that AMPK acts as a modulator of the aforementioned pathways that underpin the pathophysiology of CKD. Furthermore, pharmacological activators of AMPK such as metformin have been shown to exert renoprotective effects in experimental studies and improve clinical outcomes in patients with CKD. OBJECTIVE: The current review focuses on the nephroprotective effects of AMPK and its utility as a therapeutic target for the prevention and treatment of CKD.

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases.

Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

Renoprotective Effects of Aldose Reductase Inhibitor Epalrestat against High Glucose-Induced Cellular Injury.

Diabetic nephropathy (DN) is the leading cause of end stage renal disease worldwide. Increased glucose flux into the aldose reductase (AR) pathway during diabetes was reported to exert deleterious effects on the kidney. The objective of this study was to investigate the renoprotective effects of AR inhibition in high glucose milieu in vitro. Rat renal tubular (NRK-52E) cells were exposed to high glucose (30 mM) or normal glucose (5 mM) media for 24 to 48 hours with or without the AR inhibitor epalrestat (1 µM) and assessed for changes in Akt and ERK1/2 signaling, AR expression (using western blotting), and alterations in mitochondrial membrane potential (using JC-1 staining), cell viability (using MTT assay), and cell cycle. Exposure of NRK-52E cells to high glucose media caused acute activation of Akt and ERK pathways and depolarization of mitochondrial membrane at 24 hours. Prolonged high glucose exposure (for 48 hours) induced AR expression and G1 cell cycle arrest and decreased cell viability (84% compared to control) in NRK-52E cells. Coincubation of cells with epalrestat prevented the signaling changes and renal cell injury induced by high glucose. Thus, AR inhibition represents a potential therapeutic strategy to prevent DN.

Structure-activity relationship of piperine and its synthetic amide analogs for therapeutic potential to prevent experimentally induced ER stress in vitro.

Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using normal rat kidney (NRK-52E) cells. Five amide-substituted piperine analogs were synthesized and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability, and the expression of ER chaperone GRP78, the pro-apoptotic ER stress marker CHOP, and apoptotic caspases 3 and 12 (via western blotting). Our findings indicate that exposure to tunicamycin (0.5 µg/mL) for 2 h induces the expression of GRP78 and CHOP, and apoptotic markers (caspase-3 and caspase-12) and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP and cell death. Taken together, our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stress-related renal disorders. Graphical Abstract Piperine (PIP) reduces the expression of ER stress markers (GRP78 and CHOP) induced by pathologic stimuli and consequently decreases the activation of apoptotic caspase-12 and caspase-3; all of which contributes to its chemical chaperone and cytoprotective properties to protect renal cells against ER stress and ER stress-induced cell death, and would ultimately prevent the development of chronic kidney disease.

Metformin attenuates albumin-induced alterations in renal tubular cells in vitro.

Proteinuria (albuminuria) plays a crucial role in the etiology of chronic kidney disease (CKD) via alteration of multiple signaling pathways and cellular process in renal cells. The objectives of this study are to investigate the effects of activation of the energy-sensing molecule AMP-activated kinase (AMPK) in renal cells using metformin on endoplasmic reticulum (ER) stress, AKT, mTOR, epithelial-to-mesenchymal transition (EMT), autophagy, and apoptosis that are thought to mediate renal cell injury during proteinuria, and to dissect the AMPK- and non-AMPK mediated effects of metformin using an in vitro model of albumin-induced renal cell injury. Rat renal proximal tubular (NRK-52E) cells were exposed to 10 and 15 mg/ml of albumin for 72 h in the presence of 1 mM Metformin and/or 0.5 µM compound C, and assessed for alterations in the aforementioned pathways. Metformin treatment restored AMPK phosphorylation and augmented autophagy in renal cells exposed to albumin. In addition, metformin treatment attenuated the albumin-induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin-mediated inductions of EMT marker (α-SMA), pro-apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells. Blockade of metformin-induced AMPK activation with compound C blunted the ER defense response and autophagy but had no effect on the markers of EMT and apoptosis in our model. Our studies suggest that metformin protects renal cells against proteinuric cytotoxicity via suppression of AKT and mTOR activation, inhibition of EMT and apoptosis, and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms, respectively.

Aldose Reductase as a Drug Target for Treatment of Diabetic Nephropathy: Promises and Challenges.

Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus and the leading cause of end stage renal disease. One of the key pathways activated in DN is the polyol pathway, in which glucose is converted to sorbitol (a relatively nonmetabolizable sugar) by the enzyme aldose reductase (AR). Shunting of glucose into this pathway causes disruption to glucose metabolism and subsequently damages the tissues via increased oxidative stress, protein kinase c activation and production of advanced glycation end products (AGE) in the kidney. This review aims to provide a comprehensive overview of the AR enzyme structure, substrate specificity and topology in normal physiology; to elaborate on the deleterious effects of AR activation in DN; and to summarize the potential therapeutic benefits and major challenges associated with AR inhibition in patients with DN.