Renal Research Articles

Therapeutical Approach to Arterial Hypertension - Current State of the Art.

Arterial hypertension (AH) is recognized as the most common illness within the group of cardiovascular diseases and the most massive chronic non-infectious disease in the world. The number of hypertensive patients worldwide has reached 1.28 billion, contributing to an increase in cardiovascular diseases and premature death globally. The high prevalence of hypertension emphasizes the importance of effectively treating this condition. Elevated blood pressure often leads to lethal complications (heart failure, stroke, renal disorders, etc.) if left untreated. Considering an increase in AH prevalence in the future, a successful therapeutical approach to this disease and its complications is essential. The goal of AH treatment is to maintain normotensive blood pressure through various approaches, including lifestyle changes, a well-balanced diet, increased physical activity, psychoeducation, and, when necessary, pharmacotherapy. The evolving pharmacotherapeutic landscape reflects the progress made in our understanding of hypertension and emphasizes the need for continuous innovation to meet the challenges posed by this prevalent global health concern. The journey toward more effective and tailored treatments for hypertension is ongoing, and the introduction of new medications plays a pivotal role in shaping the future of antihypertensive pharmacotherapy.

Comprehensive phytochemical profiling and biological activities of Hodgsonia heteroclita subsp. indochinensis seed extracts

Hodgsonia heteroclita subsp. indochinensis, a member of the Cucurbitaceae family, is utilized in traditional medicinal remedies based on indigenous wisdom. This study aimed to comprehensively identify and analyze the bioactive phytoconstituents within H. heteroclita subsp. indochinensis seeds. Seeds were sequentially extracted with n-hexane, ethyl acetate, and methanol. Liquid chromatography-mass spectrometry analysis detected ferulic acid, salicylic acid, cucurbitacin E, stigmasterol glucoside, and ß-sitosterol glucoside in all extracts. The total phenolic content in the HH(S)-EtOAc and HH(S)-MeOH was 14.22 ± 1.58 and 12.98 ± 1.03 mg gallic acid equivalent/g, respectively. Consequently, the HH(S)-EtOAc demonstrated antioxidant activity with an IC50 of 1.10 ± 0.28 mg/mL, while the HH(S)-MeOH displayed strong antioxidant potential with an IC50 of 0.04 ± 0.00 mg/mL according to an ABTS assay. Antibacterial evaluations of both the HH(S)-hexane and HH(S)-EtOAc revealed significant activity against Staphylococcus aureus (zone of inhibition (ZOI): 13.67 ± 2.31 and 11.67 ± 1.53 mm, respectively) but limited activity against Escherichia coli (ZOI: 7.33 ± 0.58 and 7.67 ± 0.58 mm, respectively). Additionally, the extracts exhibited low minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values, ranging from 62.50 to 250 mg/mL. The antiproliferative activity of seed extracts was assessed against two breast cancer cell lines (MCF-7 and MDA-MB-231), normal breast cells (MCF10A), and human embryonic kidney (HEK) 293T cells, through MTT and clonogenic assays. The results revealed IC50 values exceeding 400 μg/mL, indicating that the extracts are safe. Furthermore, all seed extracts (50 μg/mL) exhibited potent anti-inflammatory activity, evident by their substantial inhibition of nitric oxide production (p < 0.001) and inducible nitric oxide synthase (iNOS) gene expression (p < 0.05) in LPS-induced RAW264.7. These findings demonstrate the potential for H. heteroclita subsp. indochinensis seed extracts in the development of functional foods, nutraceuticals, and dietary supplements due to their diverse bioactive compounds and substantial biological activities, particularly their anti-inflammatory effects.

Role of omega-3 fatty acids in reducing proteinuria: A systematic review and meta-analysis.

Proteinuria, a hallmark of renal and systemic disorders, is associated with adverse outcomes, especially in chronic kidney disease and cardiovascular disease. Omega-3 fatty acids have garnered attention for their cardiovascular benefits and potential therapeutic effects on proteinuria. This systematic review and meta-analysis aimed to evaluate the impact of omega-3 fatty acid supplementation on proteinuria levels across various kidney-related conditions. Studies published from 1989 to 2023 were systematically identified, including randomized controlled trials, cohort, case-control, and cross-sectional studies. Nine studies involving a total of 347 participants were included in the analysis. The meta-analysis revealed a neutral overall effect size of omega-3 fatty acid supplementation on proteinuria levels, assessed under both common and random effect models. Despite the lack of statistically significant evidence supporting the efficacy of omega-3 fatty acids in reducing proteinuria, the variability in interventions and patient populations suggests potential individual responses. The find-ings highlight the heterogeneity in responses to omega-3 fatty acid supplementation and emphasize the need for cautious interpretation. While no definitive conclusion can be drawn, the results underscore the importance of targeted research focusing on specific subgroups or conditions that may benefit from omega-3 supplementation. These findings contribute to the evolving understanding of personalized kidney health strategies and pave the way for further exploration and optimization of omega-3 fatty acids' therapeutic applications.

Simultaneous therapeutic and diagnostic applications of magnetic PLGA nanoparticles loaded with doxorubicin in rabbit.

In this study, DOX (Doxorubicin) and Fe3O4 magnetic nanocrystals (SPIONs (Superparamagnetic iron oxide nanocrystals)) were encapsulated in the PLGA-PEG: poly(lactide-co-glycolide)-b-poly(ethylene glycol) nanoparticles for theranostic purposes. The final prepared formulation which is called NPs (Nanoparticles) exhibited a particle size with a mean diameter of ~ 209nm and a sufficient saturation magnetization value of 1.65 emu/g. The NPs showed faster DOX release at pH 5.5 compared to pH 7.4. Also, the cytotoxicity effect of NPs increased compared to Free-DOX alone in C6 glioma cancer cells. For in vivo investigations, the 2.2 Kg rabbits were injected with NPs formulations via a central articular anterior vein in their ears. Furthermore, the images of rabbit organs were depicted via MR (Magnetic resonance) and fluorescent imaging techniques. A negative contrast (dark signal) was observed in T2 (Relaxation Time) weighted MR images of IV (Intravenously)-injected rabbits with NPs compared to the control ones. The organ's florescent images of NPs-injected rabbits showed a high density of red color related to the accumulation of DOX in liver and kidney organs. These data showed that the NPs have no cytotoxicity effect on the heart. Also, the results of histopathological tests of different organs showed that the groups receiving NPs and Free-DOX were almost similar and no significant difference was seen, except for the cardiac tissue in which the pathological effects of NPs were significantly less than the Free-DOX. Additionally, pharmacokinetic studies were also conducted at the sera and whole bloods of IV-injected rabbits with NPs and Free-DOX. The pharmacokinetic parameters showed that NPs could enhance the DOX retention in the serum compared to the Free-DOX. Altogether, we aimed to produce a powerful delivery nanosystem for its potential in dual therapeutic and diagnostic applications which are called theranostic agents.

Renal sinus adipose tissue: exploratory study of metabolic features and transcriptome compared with omental and subcutaneous adipose tissue.

The objective was to study metabolic characteristics and transcriptome of renal sinus adipose tissue (RSAT) located around renal arteries and veins. Adipose tissue biopsies from RSAT, omental (OAT), and subcutaneous (SAT) depots were obtained from healthy kidney donors (20 female, 20 male). Adipocyte glucose uptake rate and cell size were measured, and gene expression analyses using transcriptomics were performed. RSAT adipocytes were significantly smaller, with a higher basal glucose uptake rate, than adipocytes from SAT and OAT. Transcriptomic analyses revealed 29 differentially expressed genes between RSAT and OAT (RSAT: 23 lower, 6 higher) and 1214 differentially expressed genes between RSAT and SAT (RSAT: 859 lower, 355 higher). RSAT demonstrated molecular resemblance to OAT, both exhibiting lower metabolic gene expression and higher expression of immune-related pathways, including IL-17, TNFα, and NF-κB signaling than SAT. Weighted gene coexpression network analysis associated RSAT with immune response and nucleic acid transport processes. Despite its location near the renal hilum, RSAT closely resembled OAT and there was a lack of expression in the classical brown adipose tissue genes. Gene enrichment analyses suggest an inflammatory environment in RSAT compared with SAT and, to some extent, OAT. The findings suggest specific RSAT functions that could impact renal function and, possibly, the development of renal and cardiometabolic disorders.

Facile‐Prepared Size‐Controllable Nanogels for Enhancing Bidirectional Translocation, Control Efficiency, and Security of Nanopesticide

AbstractNanopesticides have been acknowledged by International Union of Pure and Applied Chemistry as a critical tool for revolutionizing future agricultural practices. However, the existing nanopesticides are often plagued by high costs, strict preparation conditions, uncontrollable size, and poor stability. Herein, taking the non‐systemic insecticide lambda‐cyhalothrin (LC) as a model pesticide, a series of LC‐loaded poly(octyl acrylate) nanogel formulations (LONFs) simultaneously featuring easy‐preparation, size‐controllable, and targeted delivery using microemulsion polymerization are developed. By adjusting the ratio of surfactants, the size of LONFs can be accurately designed to be 20, 50, 100, and 200 nm, exhibiting good stability under unconventional storage conditions (0 °C, 54 °C, ultraviolet radiation). Furthermore, reducing the particle diameter enhances the bidirectional translocation of LONFs in Vicia faba L., potentially reaching an optimal diameter (≈20 nm) for unique and rapid transport. LONFs increase the acute toxicity of LC to Aphis craccivora compared to conventional microemulsions (with a maximum reduction of 82.40% in LC50 at 24 h). Additionally, LONFs alter the lethal process of LC in human embryonic kidney 293T cells, with minimal cytotoxicity at a concentration of general application (40 mg L−1). This strategy simultaneously considers convenience, size controllability, and efficiency, providing a feasible method for the industrial development of nanopesticides.

Production of a magnetic nanocomposite for biological and hyperthermia applications based on chitosan-silk fibroin hydrogel incorporated with carbon nitride

Hydrogels based on natural polymers have lightened the path of novel drug delivery systems, wound healing, and tissue engineering fields because they are renewable, non-toxic, biocompatible, and biodegradable. Furthermore, applying modified hydrogels can upgrade their biological activity. Herein, Chitosan (CS) was used to create a hydrogel using terephthaloyl thiourea as a cross-linker. Silk fibroin (SF) and carbon nitride (CN) were added to the hydrogel to enhance its strength and biocompatibility. Finally, CS hydrogel/SF/CN was in situ magnetized using Fe3O4 magnetic nanoparticles (MNPs) and manufactured as a nanobiocomposite for improved hyperthermia. The structural properties of the nanobiocomposite were assessed using several analytical techniques, including VSM, FTIR, TGA, EDX, XRD, and FESEM. The saturation magnetization of this magnetic nanocomposite was 23.94 emu/g. The hemolytic experiment on the nanobiocomposite resulted in ca. 98 % cell survival, with a hemolysis rate of 1.69 %. Anticancer property is confirmed by a 20.0 % reduction in cell viability of BT549 cells at 1.75 mg/mL concentration compared to 0.015 mg/mL. The nanocomposite is non-toxic to the human embryonic kidney cell line (HEK293T), indicating its potential for biomedical applications. Finally, the magnetic nanocomposite's hyperthermia behavior was examined using a specific absorption rate (SAR), achieving the highest value of 47.44 W/g at 200.0 kHz. When subjected to an alternating magnetic field, the nanobiocomposite may perform well in hyperthermia therapy. These results indicate that the magnetic nanobiocomposite has the potential to perform well in hyperthermia therapy when subjected to an alternating magnetic field.

Comparison of the In Vivo Efficacy of Cuban (Raydel®) and Chinese (BOC Science) Policosanol in Alleviating Dyslipidemia and Inflammation via Safeguarding Major Organs and Reproductive Health in Hyperlipidemic Zebrafish: A Twelve-Week Consumption Study.

Policosanol is a blend of long-chain aliphatic alcohols (LCAAs) and is well-known for several health-beneficial activities; however, the functionality of policosanol varied substantially based on the composition of LCAAs. In this study, two distinct policosanols, Raydel® (extracted from Cuban sugarcane wax) and BOC Sciences (extracted from Chinese sugarcane wax), were dietarily supplemented (0.1% w/w) for 12 weeks in hyperlipidemic zebrafish to examine their influence on the blood lipid profile and functionality of the liver, kidney, and reproductive organs. The results demonstrated a noteworthy impact of both policosanols on preventing high-cholesterol diet (HCD, 4% w/w)-induced dyslipidemia by decreasing total cholesterol (TC) and triglyceride (TG) levels in the plasma. However, compared to BOC Sciences, the Raydel® policosanol exhibited a significantly (p < 0.05) higher efficacy in reducing HCD-induced TC and TG levels. A substantial effect was observed exclusively with the Raydel® policosanol in mitigating HCD-impaired low-density-lipoprotein cholesterol (LDL-C) and high-density-lipoprotein cholesterol (HDL-C) levels. Hepatic histology and immunohistochemistry (IHC) analysis revealed the higher efficacy of Raydel® policosanol over BOC Sciences policosanol to prevent HCD-provoked fatty liver changes, cellular senescence, oxidative stress, and interleukin (IL)-6 production. Consistently, a significantly higher effect of Raydel® over BOC Sciences policosanol was observed on the protection of kidney, testis, and ovary morphology hampered by HCD consumption. In addition, Raydel® policosanol exhibited a notably stronger effect (~2-fold, p < 0.05) on the egg-laying ability of the zebrafish compared to policosanol from BOC Sciences. Furthermore, Raydel® policosanol plays a crucial role in improving embryo viability and mitigating developmental defects caused by the intake of an HCD. Conclusively, Raydel® policosanol displayed a substantially higher efficacy over BOC Sciences policosanol to revert HCD-induced dyslipidemia, the functionality of vital organs, and the reproductive health of zebrafish.

Safety of proteasome inhibitor drugs for the treatment of multiple myeloma post-marketing: a pharmacovigilance investigation based on the FDA adverse event reporting system

ABSTRACT Background The use of proteasome inhibitors (PIs), namely Bortezomib and Carfilzomib, revolutionized multiple myeloma (MM) treatment. Understanding their distinct adverse event (AE) profiles aids in tailored treatment plans. Research design and methods We analyzed FDA Adverse Event Reporting System (FAERS) data (Q1 2012-Q4 2023) for Bortezomib and Carfilzomib, utilizing reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN). Results FAERS yielded 19,720 Bortezomib and 12,252 Carfilzomib AE reports. Males aged 45–65 exhibited higher AE susceptibility. Common AE systems included Infections, Nervous System Disorders, Blood Disorders, General Disorders, Cardiac Disorders, and Renal Disorders. New Bortezomib signals were sepsis and colitis. Carfilzomib exhibited elevated cardiac and renal toxicity but reduced peripheral neuropathy and thrombocytopenia. Conclusions FAERS analysis revealed new AE signals (sepsis, colitis) for Bortezomib and highlighted Carfilzomib’s heightened cardiac and renal risks compared to Bortezomib. Balancing PIs’ benefits and risks is crucial for clinical decision-making.

Synthesis of nitrogen-rich porous carbon via a molecular confinement strategy for activating peroxymonosulfate in bisphenol A degradation: Role of singlet oxygen and electron transfer process

Nitrogen-doped porous carbon (NPC) catalysts show potential for activating peroxymonosulfate (PMS) to treat water pollution. However, nitrogen (N) experiences significant loss during pyrolysis, posing challenges for synthesizing N-rich carbon catalysts. This study innovatively proposed a molecular confinement strategy using the C−S−C bond formed between graphitic carbon nitride and mercaptan. Under this confinement, we successfully synthesized NPC-15 with a high N content (21.4 at%), surpassing most catalysts reported in the literature. NPC-15/PMS system showed excellent performance in degrading bisphenol A (BPA), achieving complete degradation within 3 min (kobs = 1.771 min−1), surpassing the effectiveness of most previously reported catalysts. The NPC-15/PMS system exhibited excellent performance and stability under various conditions, reducing BPA toxicity to ecological and human embryonic kidney cells. Moreover, it maintained stability during long-term continuous operation in a fixed-bed reactor, showing promise for practical applications. Through experiments and theoretical calculations, the mechanism of NPC-15 activating PMS was comprehensively investigated. The NPC/PMS system operated via a dual non-radical pathway involving singlet oxygen and electron transfer process induced by pyridinic N and graphitic N dual active sites. Pyridinic N promoted the generation of 1O2, while graphitic N supported the electron transfer process. This study introduced a new strategy for the preparation of N-rich carbon catalysts and proposed a novel method for the removal of emerging pollutants in water.

Ruthenium-p-Cymene Complexes Incorporating Substituted Pyridine–Quinoline Ligands with –Br (Br-Qpy) and –Phenoxy (OH-Ph-Qpy) Groups for Cytotoxicity and Catalytic Transfer Hydrogenation Studies: Synthesis and Characterization

Organometallic ruthenium complexes with p-cymene = 1-methyl-4-(1-methylethyl)-benzene and N^N = bidentate polypyridyl ligands constitute interesting candidates with biological and catalytic properties. Towards this aim, we have synthesized four ruthenium(II)–arene complexes of the type [Ru(η6-p-cymene)(N^N)Cl][X] (N^N = Br-Qpy = 6-bromo-4-phenyl-2-pyridin-2-yl-quinoline, X = Cl− (1a); PF6− (1b); N^N = OH-Ph-Qpy = 4-(4-phenyl-2-(pyridin-2-yl)quinolin-6-yl)phenol, X = Cl− (2a); PF6− (2b)). This is the first report of ruthenium(II) p-cymene complexes incorporating substituted pyridine–quinoline ligands, with –Br and –C6H4OH groups in the 6-position of quinoline. We also refer to the cytotoxicity of the ligands and their possible effect of modulating the activity of the ruthenium(II) complexes. These were characterized by a combination of spectroscopic methods (ATR-IR, UV–Vis, multinuclear NMR), elemental analysis, and conductivity measurements. The solid-state structure of 2b, determined by single-crystal X-ray diffraction, reveals a three-legged piano-stool geometry. The in vitro cytotoxic activities of the new complexes were evaluated in HEK293T (human embryonic kidney cells) and in HeLa cells (cervical cancer cells), via the MTT assay. Poor in vitro anticancer activities were observed for the HeLa cancer cell line, with 2a being the most potent (IC50 = 75 μΜ). The cytotoxicity of Br-Qpy in HEK293T is comparable to that of cisplatin. Both complexes 1a and 1b successfully catalyze the transfer hydrogenation of benzophenone to benzhydrol by 2-propanol at 82 °C. The catalytic performance of 1a in the ratio of S:Cat:B = 400:1:40 (S = substrate, Cat = catalyst, B = base = KOiPr) leads to a conversion of 94%, within 3 h of reaction. Presumably, catalytic transformation takes place via ruthenium(II) hydride species being the active catalyst.

An eco-friendly convenient approach for the synthesis of guar gum integrated copper nanoparticles: Investigation of its catalytic activity in the C[sbnd]N Ullmann coupling reactions and study of its anti-human kidney cancer effects

We carried out this research was in order to evaluate the potency of guar gum (GG) hydrogel to conduct CuO NPs synthesis by adopting an eco-friendly approach as well as to study its role as catalyst and in relieving cancerous cell lines. In this context, we accomplished the CuO NPs/GG synthesis by employing a simple one-step approach and identified its characters through UV–Visible (UV–Vis) spectroscopy, X-ray diffraction (XRD), transmission electronic microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-rays spectroscopy (EDS), elemental mapping and ICP-OES analysis. XRD and TEM results of CuO NPs/GG showed the face centered cubic (fcc) structures and predominantly spherical shaped with a size of 20–30 nm. After the characterization, the prepared CuO NPs/GG nanocatalyst was used as catalyst in the N-arylation of amines (indole and imidazoles) through C(aryl)-N chemical bond arrangement from the related aryl halides (I, Br, Cl) by Ullmann-type coupling reactions. It is worth mentioning that the novel catalyst has the potential of being recycled seven times without much change in activity. Furthermore, the anti-kidney cancer properties of CuO NPs/GG nanocomposite were assessed by MTT assay about the cytotoxicity and anti-human on normal (HUVEC) and human kidney cell lines i.e. ACHN, CaKi-2 and HEC293. The corresponding IC50 values were 18.5, 17.2, and 15.6 µg/mL, respectively. The viability of malignant human kidney cell line reduced dose-dependently in the presence of the nano bio-composite. After clinical study, CuO NPs/GG nano bio-composite can be utilized as an efficient drug in the treatment of human kidney cancer in human.

Circadian clock disruption and growth of kidney cysts in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 and PKD2 genes, and often progresses to kidney failure. ADPKD progression is not uniform among patients, suggesting that factors secondary to the PKD1/2 gene mutation could regulate the rate of disease progression. Here we tested the effect of circadian clock disruption on ADPKD progression. Circadian rhythms are regulated by cell-autonomous circadian clocks composed of clock proteins. BMAL1 is a core constituent of the circadian clock. To disrupt the circadian clock, we deleted Bmal1 gene in the renal collecting ducts of the Pkd1 RC/RC (RC/RC) mouse model of ADPKD (RC/RC; Bmal1 f/f ; Pkhd1 cre , called DKO mice), and in Pkd1 knockout mouse inner medullary collecting duct cells ( Pkd1Bmal1 KO mIMCD3 cells). Only male mice were used. Human nephrectomy ADPKD kidneys and Pkd1 KO mIMCD3 cells showed reduced Bmal1 gene expression compared to normal controls. When compared to RC/RC kidneys, DKO kidneys showed significantly altered clock gene expression, increased cyst growth, cell proliferation, apoptosis and fibrosis. DKO kidneys also showed increased lipogenesis and cholesterol synthesis-related gene expression, and increased tissue triglyceride levels compared to RC/RC kidneys. Similarly, in vitro, Pkd1Bmal1 KO cells showed altered clock genes, increased lipogenesis and cholesterol synthesis-related genes, and reduced fatty-acid oxidation-related gene expression compared to Pkd1KO cells. The Pkd1Bmal1 KO cells showed increased cell proliferation compared to Pkd1KO cells, which was rescued by pharmacological inhibition of lipogenesis. Renal collecting duct specific Bmal1 gene deletion disrupts the circadian clock and triggers accelerated ADPKD progression by altering lipid metabolism-related gene expression. Lack of BMAL1, a circadian clock protein in renal collecting ducts disrupted the clock and increased cyst growth and fibrosis in an ADPKD mouse model.BMAL1 gene deletion increased cell proliferation by increasing lipogenesis in kidney cells.Thus, circadian clock disruption could be a risk factor for accelerated disease progression in patients with ADPKD.

Palmitic acid complexed with control or advanced glycated albumin primes human kidney tubular cells to inflammation

Palmitic acid complexed with control or advanced glycated albumin primes human kidney tubular cells to inflammation

Extraction of anti-hyperglycaemic bioactive compounds from Phyllanthus niruri L. through solvent mixture design: In vitro and in vivo evaluation

BackgroundSpecies within Phyllanthus genus exhibit a diverse range of experimentally validated pharmacological activities. Notably, Phyllanthus niruri Linneo(Phyllanthaceae), commonly referred to as stonebreaker, is a native Central and South American species with a rich history of use in traditional ethnomedicine for treating gastrointestinal and renal disorders. PurposeThe aim of this study was to investigate the application of various solvent mixtures to optimize the extraction of anti-hyperglycemic secondary metabolites from P. niruri. MethodsTo optimize the extraction of anti-hyperglycemic compounds from P. niruri, a solvent mixture design strategy was employed. The optimized extracts were subjected to chemical characterization using spectrophotometric methods and HPLC-DAD analysis. Also, the influence of edaphoclimatic conditions on the composition of extracts was investigated. The anti-hyperglycaemic potential of the extracts was evaluated through both in vitro and in vivo assays. The in vitro studies included enzyme inhibition assays targeting α-glucosidase from two sources (yeast and pig). For in vivo studies, a rat model with oral starch overload was used to confirm the anti-hyperglycaemic activity of the extracts. ResultsAn optimal solvent mixture (70 % methanol and 30 % ethyl acetate) was found as effective for extracting compounds with anti-hyperglycemic potential from P. niruri. All the extracts obtained using this solvent inhibited both, yeast and pig α-glucosidase, with greater selectivity for inhibiting the yeast-derived enzyme. Extracts from aerial parts (AP) exhibited the strongest inhibitory activity. These extracts contained phenolic compounds, specifically flavonoids, but no condensed tannins were detected. Chromatographic analysis of profile revealed a major peak consistent with corilagin. In vivo studies using a dose of 500 mg kg-1 demonstrated that this extract significantly reduced blood sugar levels after starch overload in rats. ConclusionThis study demonstrates the importance of selecting appropriate solvent mixtures to extract bioactive compounds with anti-hyperglycemic properties from P. niruri. Our findings support the traditional use of this plant as a anti-hyperglycaemic agent in ethnomedicine.

A Highly Sensitive Lateral-Flow Strip Using Latex Microspheres to Detect NGAL in Urine Samples.

The incidence of kidney disease is increasing worldwide. Rapid and cost-effective approaches for early detection help prevent this disease. Neutrophil gelatinase-associated lipocalin protein (NGAL) is a novel biomarker for acute kidney injury (AKI) and chronic kidney disease (CKD). We aimed to develop a lateral flow strip (LFS) based on a lateral flow immunoassay method (LFIA), using latex microspheres (LMs) as a color labeling to detect NGAL in urine. The performance and potential of the developed LMs-LFS at a point-of-care (POC) testing were evaluated. The results showed that LMs-LFS successfully detected urinary NGAL within 15 min with high specificity without cross-reactivity to or interference from other endogenous substances in urine. The visual limit of detection (vLOD) was 18.75 ng/mL, and the limit of detection (LOD) was 1.65 ng/mL under the optimum condition. The LMs-LFS developed in this study showed a high correlation with the enzyme-linked immunosorbent assay (ELISA) method (R 2 = 0.973, n = 60 urine specimens) for detecting NGAL in urine. The LMs-LFS remained stable for at least six months at room temperature. The LMs-LFS can be a rapid, sensitive, and specific tool for the diagnosis and follow-up of renal disorders at the POC.

Live Cell Monitoring of Phosphodiesterase Inhibition by Sulfonylurea Drugs.

Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic β-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs.

Organotin(IV) complexes derived from 2,6-diacetylpyridine bis(2-hydroxybenzoylhydrazone) as prospective anti-proliferative agents: Synthesis, characterization, structures and in vitro anticancer activity

Six organotin(IV) complexes, viz., [Me2Sn(L)] (1), [n-Bu2Sn(L)] (2), [n-Oct2Sn(L)] (3), [Bz2Sn(L)]·0.5C7H8 (4), [n-BuSn(L)Cl] (5), and [PhSn(L)Cl] (6), were synthesized using a 2,6-diacetylpyridine bis(2-hydroxybenzoylhydrazone), H2L. Compounds were characterized by Fourier transform infrared (FT-IR), High-resolution mass spectrometry (HRMS), and solutions Fourier transform nuclear magnetic resonance (FT-NMR) spectroscopies. The structures 1–6 were established by single-crystal X-ray diffraction (SC-XRD) analysis. Diffraction results evidenced that complexes 1–6 were seven-coordinated mononuclear species with the equatorial plane comprising the pentagonal N3O2 chelate ring of the doubly deprotonated L and two axial ligands, either R (R = Me, n-Bu, n-Oct, Bz) or R (n-Bu or Ph) and Cl ligands. Additionally, the photophysical properties were examined due to the enhanced conjugation and rigidity of the molecules while thermogravimetric analysis was carried out to evaluate the thermal stabilities of compounds. The anti-proliferative activity of the complexes 1–6 was tested against prostate cancer cells (DU-145) and normal human embryonic kidney cells (HEK-293). Among the compounds, dibutyltin compound 2 exhibited increased anti-proliferative activity, with an IC50 value of 6.16 ± 1.56 μM. The investigation of its mechanism of action involves using AO/EB (acridine orange/ethidium bromide) and ROS (reactive oxygen species) generation assays. This likely detects apoptotic morphological alterations in the nucleus of the cells, with ROS generation ultimately leading to apoptosis and cell death. The superior activity of 2 may be attributed to the C···H contacts and respective higher de outside and di inside distances from the Hirshfeld surface. Thus, these compounds could be a promising alternative to classical chemotherapy agents.

Immunohistochemical and Ultrastructural Characterization of Telocytes in Normal and Diabetic Human Kidneys.

Background: Telocytes are interstitial stromal cells identified in various human organs, including the kidney. Their presence and role in human diabetic kidney disease remain unknown. Methods: To identify and localize telocytes in glomerular and tubule-interstitial compartments, both normal and diabetic human renal tissues were examined using immunohistochemistry, immunofluorescence, and transmission electron microscopy. Results: Renal telocytes are elongated interstitial cells with long, thin telopodes, showing alternating thin and thick segments. They expressed CD34, Nestin, α-SMA, and Vimentin markers. Occasionally, c-Kit expression was observed in some rounded and spindle cells, while no positivity was detected for PDGFR-β and NG2. Telocytes were identified around Bowman's capsule, tubules, and peritubular capillaries in both normal and diabetic conditions. In diabetic renal samples, there was a significant increase in α-SMA expressing telocytes, leading to periglomerular fibrosis. These telocytes also exhibited a synthetic phenotype with proteoglycan deposition in the extracellular matrix and, in some cases, showed pre-adipocytic differentiation. Conclusions: Telocytes were identified in normal and diabetic human kidneys. These cells form an elastic mechanical scaffold in the interstitium and are present in all renal cortical compartments. In diabetic samples, their increased α-SMA expression and synthetic phenotype suggest their potential role in the pathogenesis of diabetic nephropathy.

A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity.

The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels-Alder reaction between trans-cyclooctenes (TCO) and the amine-functionalized tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d-Ubi-Tz, a tetrazine functionalised with the bacterial binding peptide d-Ubi29-41. While standard TCO did not improve toxicity against human proximal tubular kidney HK-2 cells, the installation of an aspartic acid-modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col-(TCO-Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d-Ubi-Tz in an in vivo infection model, whereas it remained inactive and non-harmful without the chemical trigger. This study constitutes the first example of a systemically acting two-component antibiotic with improved drug tolerability.