Targeting polo-like kinase 1 to treat kidney diseases.

Globally, ∼850 million individuals suffer from some form of kidney disease. This staggering figure underscores the importance of continued research and innovation in the field of nephrology to develop effective treatments and improve overall global kidney health. In current research, the polo-like kinase (Plk) family has emerged as a group of highly conserved enzyme kinases vital for proper cell cycle regulation. Plks are defined by their N-terminal kinase domain and C-terminal polo-box domain, which regulate their catalytic activity, subcellular localization, and substrate recognition. Among the Plk family members, Plk1 has garnered significant attention due to its pivotal role in regulating multiple mitotic processes, particularly in the kidneys. It is a crucial serine-threonine (Ser-Thr) kinase involved in cell division and genomic stability. In this review, we delve into the types and functions of Plks, focusing on Plk1's significance in processes such as cell proliferation, spindle assembly, and DNA damage repair. The review also underscores Plk1's vital contributions to maintaining kidney homeostasis, elucidating its involvement in nuclear envelope breakdown, anaphase-promoting complex/cyclosome activation, and the regulation of mRNA translation machinery. Furthermore, the review discusses how Plk1 contributes to the development and progression of kidney diseases, emphasizing its overexpression in conditions such as acute kidney injury, chronic kidney disease, and so forth. It also highlights the importance of exploring Plk1 modulators as targeted therapies for kidney diseases in future. This review will help in understanding the role of Plk1 in kidney disease development, paving the way for the discovery and development of novel therapeutic approaches to manage kidney diseases effectively.

Natriuretic peptide system in hypertension: Current understandings of its regulation, targeted therapies and future challenges.

The natriuretic peptide system (NPS) is the key driving force of the heart's endocrine function. Recent developments in NPS-targeted therapies have been found promising and effective against cardiovascular diseases, including hypertension. Notably, after discovering crosstalk between NPS and the renin-angiotensin-aldosterone system (RAAS), various combinations such as neprilysin/angiotensin II receptor type 1 AT1 receptor inhibitors and neprilysin/renin inhibitors have been preclinically and clinically tested against various cardiac complications. However, the therapeutic effects of such combinations on the pathophysiology of hypertension are poorly understood. Furthermore, the complicated phenomena underlying NPS regulation and function, particularly in hypertension, are still unexplored. Mounting evidence suggests that numerous regulatory mechanisms modulate the expression of NPS, which can be used as potential targets against hypertension and other cardiovascular diseases. Therefore, this review will specifically focus on epigenetic and other regulators of NPS, identifying prospective regulators that might serve as new therapeutic targets for hypertension. More importantly, it will shed light on recent developments in NPS-targeted therapies, such as M-atrial peptides, and their latest combinations with RAAS modulators, such as S086 and sacubitril-aliskiren. These insights will aid in the development of effective therapies to break the vicious cycle of high blood pressure during hypertension, ultimately addressing the expanding global heart failure pandemic.

A structure-based pharmacophore modelling approach to identify and design new neprilysin (NEP) inhibitors: An in silico-based investigation.

Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid ß protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.

Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity.

Acute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI-diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI-diabetes comorbidity management. This study aimed to investigate the therapeutic potential of esculetin and phloretin combination against AKI-diabetes comorbidity by network pharmacology followed by validation by molecular docking and dynamics. The curative targets for diabetes, AKI, esculetin, and phloretin were obtained from DisGeNET, GeneCards, SwissTargetPrediction database. Further, the protein-protein interaction of the potential targets of esculetin and phloretin against AKI-diabetes comorbidity was investigated using the STRING database. Gene ontology and pathway enrichment analysis were performed with the help of the DAVID and KEGG databases, followed by network construction and analysis via Cytoscape. Molecular docking and dynamic simulations were performed to validate the targets of esculetin and phloretin against AKI-diabetes comorbidity. We obtained 6341 targets for AKI-diabetes comorbidity. Further, a total of 54 and 44 targets of esculetin and phloretin against AKI-diabetes comorbidity were retrieved. The top 10 targets for esculetin selected based on the degree value were AKR1B1, DAO, ESR1, PLK1, CA3, CA2, CCNE1, PRKN, HDAC2, and MAOA. Similarly, phloretin's 10 key targets were ACHE, CDK1, MAPK14, APP, CDK5R1, CCNE1, MAOA, MAOB, HDAC6, and PRKN. These targets were enriched in 58 pathways involved in the pathophysiology of AKI-diabetes comorbidity. Further, esculetin and phloretin showed an excellent binding affinity for these critical targets. The findings of this study suggest that esculetin and phloretin combination as a multicomponent multitarget therapy has the potential to prevent AKI-diabetes comorbidity.

Immunosuppressants against acute kidney injury: what to prefer or to avoid?

BACKGROUND: Acute kidney injury (AKI) is a critical global health issue associated with high mortality rates, particularly in patients undergoing renal transplants and major surgeries. These individuals often receive immunosuppressants to dampen immune responses, but the impact of these drugs on AKI remains unclear. OBJECTIVE: This review aims to provide a detailed understanding of the effects of different classes of immunosuppressants against AKI, elucidating their role in either exacerbating or mitigating the occurrence or progression of AKI. METHODS: Several preclinical and clinical reports were analyzed to evaluate the impact of various immunosuppressants on AKI. Relevant preclinical and clinical studies were reviewed through different databases such as Scopus, PubMed, Google Scholar, and ScienceDirect, and official websites like https://clinicaltrials.gov to understand the mechanisms underlying the effects of immunosuppressants on kidney function. RESULTS AND DISCUSSION: Specific immunosuppressants have been linked to the progression of AKI, while others demonstrate renoprotective effects. However, there is no consensus on the preferred or avoided immunosuppressants for AKI patients. This review outlines the classes of immunosuppressants commonly used and their impact on AKI, providing guidance for physicians in selecting appropriate drugs to prevent or ameliorate AKI. CONCLUSION: Understanding the effects of immunosuppressants on AKI is crucial for optimizing patient care. This review highlights the need for further research to determine the most suitable immunosuppressants for AKI patients, considering both their efficacy and potential side effects.

Exploring Potential of Nano-formulations in the Treatment of Alzheimer's Disease through Nasal Route.

OBJECTIVE: Alzheimer's disease, a progressive neurodegenerative disorder, severely impacts cognitive function and daily living. The current treatment provides only symptomatic relief, and thus, disease-modifying therapies targeting underlying causes are needed. Although several potential therapies are in various stages of clinical trials, bringing a new Alzheimer's drug to market remains challenging. Hence, researchers are also exploring monoclonal antibodies, tau protein inhibitors, and anti-inflammatory drugs as treatment options. Conventionally designed dosage forms come with limitations like poor absorption, first-pass metabolism, and low bioavailability. They also cause systemic adverse effects because these designed systems do not provide target- specific drug delivery. Thus, in this review, the authors highlighted the current advancements in the development of intranasal nanoformulations for the treatment of Alzheimer's disease. This strategy of delivering anti-Alzheimer drugs through the nasal route may help to target the drug exactly to the brain, achieve rapid onset of action, avoid first-pass metabolism, and reduce the side effects and dose required for administration. CONCLUSION: Delivering drugs to the brain through the nasal route for treating Alzheimer's disease is crucial due to the limited efficacy of existing treatments and the profound impact of the disease on patients and their families. Thus, by exploring innovative approaches such as nose-to-brain drug delivery, it is possible to improve the quality of life for individuals living with Alzheimer's and alleviate its societal burden.

Nanostructured Lipid Carriers of Donepezil Hydrochloride for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's Disease (AD) is a long-term brain disorder that worsens over time. A cholinesterase inhibitor called Donepezil HCl (DNZ) is used to treat and control AD. Due to its failure to reach the appropriate concentration in the brain cells, its efficacy upon oral administration is limited, and thus investigation of alternative administration route is necessary. OBJECTIVE: The objective of this study was to develop donepezil HCl-loaded Nanostructured Lipid Carriers (NLCs) that can bypass the blood-brain barrier and thus be directly delivered to the brain through the nasal route. This method improves availability at the site of action, reduces the negative effects of oral medication, and ensures an expedited commencement of action. METHOD: High-pressure homogenization and ultrasonication were used to formulate NLCs. Glyceryl Monostearate (GMS) as a solid lipid, Tween 80 as a surfactant, and Poloxamer 407 as a co-- surfactant were used. In this study, argan oil was employed as a liquid lipid as well as a penetration enhancer. RESULTS: The chosen NLCs displayed a particle size of 137.34 ± 0.79 nm, a PDI of 0.365 ± 0.03, and a zeta potential of -10.4 mV. The selected formulation showed an entrapment efficiency of 84.05 ± 1.30% and a drug content of 77.02 ± 0.23%. The concentration of the drug in the brain after intravenous and intranasal administration of DNZ NLCs at 1 h was found to be 0.490 ± 0.007 and 4.287 ± 0.115, respectively. Thus, the concentration of DNZ achieved in the brain after intranasal administration of DNZ NLCs was approximately 9 times more than the concentration when administered by intravenous route. CONCLUSION: The DNZ-loaded NLCs, when administered via nasal route, showed markedly improved drug availability in the brain, suggesting an efficient drug delivery strategy to treat Alzheimer's disease.

Significance of LncRNAs in AKI-to-CKD transition: A therapeutic and diagnostic viewpoint.

Acute kidney injury to chronic kidney disease (AKI-to-CKD) transition is a complex intermingling of characteristics of both AKI and CKD. Pathophysiologically, the transition lasts seven days after the AKI episode and thereafter silently progresses towards CKD. Growing reports confirm that the AKI-to-CKD transition is heavily regulated by epigenetic modifiers. Long non-coding RNAs (lncRNAs) share a diverse role in gene regulation at transcriptional and translational levels and have been reported to be involved in the regulation and progression of AKI-to-CKD transition. Several lncRNAs have been considered potential biomarkers for diagnosing kidney disease, including AKI and CKD. Targeting lncRNAs gives a promising therapeutic strategy against kidney diseases. The primitive role of lncRNA in the progression of the AKI-to-CKD transition is yet to be fully understood. As known, the lncRNAs could be used as a biomarker and a therapeutic target to halt the CKD development and progression after AKI. This review aims to deepen our understanding of the current knowledge regarding the involvement of lncRNAs in the AKI-to-CKD transition. This review primarily discusses the role of lncRNAs and the change in their mechanisms during different stages of kidney disease, such as in AKI, AKI-to-CKD transition, and CKD. Further, we have discussed the potential diagnostic and pharmacological outcomes of targeting lncRNAs to prevent or slow the progression of AKI-to-CKD transition.

Altered Igf2 imprint leads to accelerated adipogenesis and early onset of metabolic syndrome in male mice following gestational arsenic exposure.

Developmental exposure to environmental pollutants has been shown to promote adverse health outcomes in offspring. Exposure to heavy metals such as arsenic which also has endocrine-disrupting activity is being increasingly linked with cancers, diabetes, and lately with Metabolic Syndrome (MetS). In this work, we have assessed the effects of preconceptional plus gestational arsenic exposure on the developmental programming of MetS in offspring. In our study, only gestational arsenic exposure led to reduced birth weight, followed by catch-up growth, adiposity, elevated serum triglycerides levels, and hyperglycemia in male offspring. Significant adipocyte dysfunction was observed in offspring with increased hypertrophy, insulin resistance, and chronic inflammation in epididymal white adipose tissue. Adipose tissue regulates the metabolic health of individuals and its dysfunction resulted in elevated serum levels of metabolism-regulating adipokines (Leptin, Resistin) and pro-inflammatory cytokines (PAI-1, TNFα). The progenitor adipose-derived stem cells (AdSCs) from exposed progeny had increased proliferation and adipogenic potential with excess lipid accumulation. We also found increased activation of Akt, ERK1/2 & p38 MAPK molecules in arsenic-exposed AdSCs along with increased levels of phospho-Insulin-like growth factor-1 receptor (p-IGF1R) and its upstream activator Insulin-like growth factor-2 (IGF2). Overexpression of Igf2 was found to be due to arsenic-mediated DNA hypermethylation at the imprinting control region (ICR) located -2kb to -4.4 kb upstream of the H19 gene which caused a reduction in the conserved zinc finger protein (CTCF) occupancy. This further led to persistent activation of the MAPK signaling cascade and enhanced adipogenesis leading to the early onset of MetS in the offspring.

Renoprotective effect of esculetin against ischemic acute kidney injury-diabetic comorbidity.

Mitophagy maintains cellular homeostasis by eliminating damaged mitochondria. Accumulated damaged mitochondria can lead to oxidative stress and cell death. Induction of the PINK1/Parkin-mediated mitophagy is reported to be renoprotective in acute kidney injury (AKI). Esculetin, a naturally available coumarin, has shown protective action against diabetic complications. However, its effect on AKI-diabetes comorbidity has not been explored yet. Therefore, we aimed to investigate the renoprotective effect of esculetin against AKI under diabetic conditions via regulating PINK1/Parkin-mediated mitophagy. For this, type 1 diabetic male Wistar rats were treated with two doses of esculetin (50 and 100 mg/kg/day orally) for five days followed by AKI induction by bilateral ischemic-reperfusion injury (IRI). NRK-52E cells grown in high glucose were exposed to sodium azide (10 mM) for induction of hypoxia/reperfusion injury (HRI) in-vitro. Esculetin (50 µM) treatment for 24 h was given to the cells before HRI. The in-vitro samples were utilized for cell viability and ΔΨm assay, immunoblotting, and immunofluorescence. Rats' plasma, urine, and kidney samples were collected for biochemical analysis, histopathology, and western blotting. Our results showed a significant decrease in kidney injury-specific markers and increased expression of mitophagy markers (PINK1 and Parkin) with esculetin treatment. Moreover, esculetin prevented the HRI and hyperglycemia-induced decrease in ΔΨm and autophagosome marker. Also, esculetin therapy reduced oxidative stress via increased Nrf2 and Keap1 expression. Esculetin attenuated AKI under diabetic condition by preventing mitochondrial dysfunction via inducing PINK1/Parkin-mediated mitophagy, suggesting its potential as an effective therapy for preventing AKI-diabetes comorbidity.

Impaired mitophagy and increased oxidative stress are major contributors to AKI development.Esculetin treatment reduces oxidative stress in AKI-diabetes comorbidity.Esculetin activated Nrf2/PINK1/Parkin axis and improved mitophagy.Esculetin can be a potential therapy for AKI-diabetes comorbidity prevention and management.

Phloretin: a comprehensive review of its potential against diabetes and associated complications.

OBJECTIVES: Phloretin is ubiquitous in apples (Malus domestica) and other fruits and has potential antidiabetic properties. Considering the preclinical potential of phloretin, its transition to clinical observations has unintentionally been neglected, particularly within the diabetic population. Furthermore, a comprehensive understanding of its pharmacokinetics remains elusive. This review seeks to offer valuable insights into phloretin's physical properties, pharmacokinetics, and pharmacodynamics, aiming to unveil opportunities for additional research on its therapeutic potential in the context of diabetes. KEY FINDINGS: All pharmacokinetic reports of phloretin confirm that the utilization of phloretin gets enhanced during diabetic conditions. Phloretin targets pathomechanisms such as glucose transporter 4 (GLUT4) and peroxisome proliferator's activity-activated receptor-γ (PPAR-γ) to decrease insulin resistance in diabetic conditions. Moreover, phloretin targets inflammatory, oxidative, and apoptotic signaling to minimize the progression of diabetes-associated macro- and microvascular complications. SUMMARY: The pleiotropic antidiabetic action of phloretin is mainly dependent on its pharmacokinetics. Nevertheless, further investigation into the altered pharmacokinetics of phloretin during diabetic conditions is essential. Additionally, the results derived from clinical studies utilized apples, apple extract, and supplements containing phloretin. Greater emphasis should be placed on future clinical studies to assess the potential of phloretin as a standalone compound.

Molecular insights into P2X signalling cascades in acute kidney injury.

Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes. More importantly, certain P2X receptor subtypes upon activation exacerbate the situation by promoting the release of extracellular ATP. While therapeutic investigations have primarily focused on P2X4 and P2X7 subtypes in the context of AKI, while understanding about other subtypes still remains limited. Whilst some P2X antagonists show promising results against different types of kidney diseases, their role in managing AKI remains unexplored. Henceforth, understanding the intricate interplay between P2X receptors and AKI is crucial for developing targeted interventions. This review elucidates the functional alterations of all P2X receptors during normal kidney function and AKI, offering insights into their involvement in AKI. Notably, we have highlighted the current knowledge of P2X receptor antagonists and the possibilities to use them against AKI in the future. Furthermore, the review delves into the pathways influenced by activated P2X receptors during AKI, presenting potential targets for future therapeutic interventions against this critical condition.

Targeting DNA methylation in diabetic kidney disease: A new perspective.

Diabetic kidney disease (DKD) is a leading diabetic complication causing significant mortality among people around the globe. People with poor glycemic control accompanied by hyperinsulinemia, dyslipidemia, hypertension, and obesity develop diabetic complications. These diabetic patients develop epigenetic changes and suffer from diabetic kidney complications even after subsequent glucose control, the phenomenon that is recognized as metabolic memory. DNA methylation is an essential epigenetic modification that contributes to the development and progression of several diabetic complications, including DKD. The aberrant DNA methylation pattern at CpGs sites within several genes, such as mTOR, RPTOR, IRS2, GRK5, SLC27A3, LCAT, and SLC1A5, associated with the accompanying risk factors exacerbate the DKD progression. Although drugs such as azacytidine and decitabine have been approved to target DNA methylation for diseases such as hematological malignancies, none have been approved for the treatment of DKD. More importantly, no DNA hypomethylation-targeting drugs have been approved for any disease conditions. Understanding the alteration in DNA methylation and its association with the disease risk factors is essential to target DKD effectively. This review has discussed the abnormal DNA methylation pattern and the kidney tissue-specific expression of critical genes involved in DKD onset and progression. Moreover, we also discuss the new possible therapeutic approach that can be exploited for treating DNA methylation aberrancy in a site-specific manner against DKD.

Voclosporin: Unique Chemistry, Pharmacology and Toxicity Profile, and Possible Options for Implementation into the Management of Lupus Nephritis.

Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney's filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug-drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.

Anti-adipogenic action of a novel oxazole derivative through activation of AMPK pathway.

Obesity is a chronic disorder with multifactorial etiology, including genetic, medical, dietary and other environmental factors. Both natural and synthetic heterocyclic compounds, especially oxazoles, represent an interesting group of compounds and have gained much attention due to their remarkable biological activities. Therefore, a library of 3,3-DMAH (3,3-dimethylallylhalfordinol) inspired N-alkylated oxazole bromide salts with varied substitutions were prepared and screened using the 3T3-L1 model of adipogenesis and HFD-induced obesity model in Syrian golden hamsters. Several compounds in the synthesized series displayed remarkable anti-adipogenic potential on the differentiation of 3T3-L1 preadipocytes. Compound 19e, displayed the most potent activity of all and selected for further studies. Compound 19e inhibited mitotic clonal expansion of 3T3-L1 cells and enhanced the mitochondrial oxygen consumption rate of the cells during early phase of differentiation via AMPK activation. 19e also improved the dyslipidaemia in high calorie diet fed Syrian Golden Hamsters. Therefore, compound 19e can serve as a potential lead against adipogenesis and dyslipidaemia models and could be further investigated to affirm its significance as a drug candidate.

Metabolic reprogramming: Unveiling the therapeutic potential of targeted therapies against kidney disease.

As a high-metabolic-rate organ, the kidney exhibits metabolic reprogramming (MR) in various disease states. Given the >800 million cases of kidney disease worldwide in 2022, understanding the specific bioenergetic pathways involved and developing targeted interventions are vital needs. The reprogramming of metabolic pathways (glucose metabolism, amino acid metabolism, etc.) has been observed in kidney disease. Therapies targeting these specific pathways have proven to be an efficient approach for retarding kidney disease progression. In this review, we focus on potential pharmacological interventions targeting MR that have advanced through Phase III/IV clinical trials for the management of kidney disease and promising preclinical studies laying the groundwork for future clinical investigations.

Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation.

AIM: Targeting Toll-like receptor 4 (TLR4) and Angiotensin II type 1 receptor (AT1R) could provide renoprotection during acute kidney injury (AKI) mainly by regulating inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Phloretin (TLR4 inhibitor) as an add-on therapy to losartan (AT1R inhibitor) could provide more therapeutic benefits against AKI under diabetic condition. We aimed to study the effect of phloretin as an add-on therapy to losartan against AKI under diabetic condition. MAIN METHODS: To mimic diabetic AKI condition, bilateral ischemia-reperfusion injury (BIRI) was done in diabetic male Wistar rats, and sodium azide treatment was given to high glucose NRK52E cells to mimic hypoxia-reperfusion injury. In diabetic rats, phloretin (50 mg/kg/per os (p.o.)) and losartan (10 mg/kg/p.o.) treatment was given for 4 days and 1 h prior to surgery while in NRK52E cells, both drugs (phloretin 50 µM and losartan 10 µM) were given 24 h prior to the hypoxia condition. The in vivo and in vitro samples were further used for different experiments. KEY FINDINGS: Treatment with phloretin and losartan decreased diabetic and AKI biomarkers such as plasma creatinine, blood urea nitrogen (BUN), and kidney injury molecular 1 (KIM1). Moreover, a combination of phloretin and losartan significantly preserved ΔΨm and kidney morphology potentially by inhibiting TLR4-associated inflammation and AT1R-associated mitochondrial dysfunction, thereby oxidative stress. SIGNIFICANCE: Combination therapy of phloretin and losartan was more effective than monotherapies. Both drugs target TLR4/MyD88/NF-κB pathway and reduce inflammation and mitochondrial dysfunction in AKI under diabetic condition.

16-Hydroxy-ent-halima-5(10),13-dien-15,16-olide from Polyalthia longifolia targets adipogenesis by inhibiting mitotic clonal expansion and ameliorates dyslipidemia.

Obesity-related metabolic disorders are increasing at an alarming rate worldwide. The FDA has approved many molecules for weight loss therapy; most of them act on the gut level by inhibiting lipid uptake or on the central nervous system by controlling appetite. Limitations and drawbacks have propelled the search for new pharmacophores exhibiting favourable metabolic alteration at adipocytes, and natural products have always been there to prove their worth. In our efforts, we have identified 16-hydroxy-ent-halima-5(10),13-dien-15,16-olide (PLH), a halimane diterpene isolated from Polyalthia longifolia, demonstrating anti-adipogenic and anti-dyslipidemic activity. It inhibited adipogenesis in 3T3-L1 preadipocyte and C3H10T1/2 mesenchymal stem cell lines. Furthermore, it decreased set of adipogenic markers at transcript and protein levels. Cell cycle studies indicated that PLH halts the mitotic clonal expansion. Mechanistic studies shows that PLH activate Wnt/ß-catenin signaling pathway to inhibit the adipogenesis. The study suggested that PLH inhibited adipogenesis during the early phase of differentiation by targeting mitotic clonal expansion and arresting the cell cycle in the G1 phase of the cell cycle. It improved the dyslipidemic condition in HFD-fed hamsters by decreasing the body weight, fat mass, eWAT weight and improving the serum lipid profile. Overall, PLH has been found as a potential drug candidate and a pharmacophore for combating metabolic disorders including obesity and dyslipidemia.

Hippo signaling in acute kidney injury to chronic kidney disease transition: Current understandings and future targets.

Acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition is a slow but persistent progression toward end-stage kidney disease. Earlier reports have shown that Hippo components, such as Yes-associated protein (YAP) and its homolog Transcriptional coactivator with PDZ-binding motif (TAZ), regulate inflammation and fibrogenesis during the AKI-to-CKD transition. Notably, the roles and mechanisms of Hippo components vary during AKI, AKI-to-CKD transition, and CKD. Hence, it is important to understand these roles in detail. This review addresses the potential of Hippo regulators or components as future therapeutic targets for halting the AKI-to-CKD transition.

Nutraceuticals and network pharmacology approach for acute kidney injury: A review from the drug discovery aspect.

Acute kidney injury (AKI) has become a global health issue, with ∼12 million reports yearly, resulting in a persistent increase in morbidity and mortality rates. AKI pathophysiology is multifactorial involving oxidative stress, mitochondrial dysfunction, epigenetic modifications, inflammation, and eventually, cell death. Hence, therapies able to target multiple pathomechanisms can aid in AKI management. To change the drug discovery framework from "one drug, one target" to "multicomponent, multitarget," network pharmacology is evolving as a next-generation research approach. Researchers have used the network pharmacology approach to predict the role of nutraceuticals against different ailments including AKI. Nutraceuticals (herbal products, isolated nutrients, and dietary supplements) belong to the pioneering category of natural products and have shown protective action against AKI. Nutraceuticals have recently drawn attention because of their ability to provide physiological benefits with less toxic effects. This review emphasizes the nutraceuticals that exhibited renoprotection against AKI and can be used either as monotherapy or adjuvant with conventional therapies to boost their effectiveness and lessen the adverse effects. Additionally, the study sheds light on the application of network pharmacology as a cost-effective and time-saving approach for the therapeutic target prediction of nutraceuticals against AKI.