Synergistically engineered nanotransethosomes for co-delivery of methotrexate and baicalin for enhanced transdermal delivery against rheumatoid arthritis: formulation, characterisation and in vivo pharmacodynamic evaluation.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease that significantly impacts the quality of life of those affected. Owing to the complex pathophysiology of RA, it is not possible for any singular treatment to entirely impede the progression of the disease. Hence, the current study aimed to adopt a holistic and synergistic approach towards the management of RA by means of a co-delivery strategy involving methotrexate (MTH), a conventional slow-acting anti-rheumatic drug, and baicalin (BCN), a bioactive phytochemical using a transethosomal (TRS) gel formulation.Purpose: The present study aims to evaluate the potential benefits of administering MTH and BCN in nanoparticulate form, which may lead to improved stability and solubility, as well as enhanced penetration into the arthritic tissues of interest.Methods and results: The MTH-BCN-TRS that were synthesised exhibited small particle size of 151.3 nm and polydispersity index of 0.125, as well as a favourable zeta potential of -32.22 mV. Additional assessments were conducted, including a pharmacokinetic analysis, TEM, skin permeation analysis and confocal microscopy. According to the Confocal laser scanning microscopy (CLSM) study, the formulated MTH-BCN-TRS gel exhibited superior MTH and BCN permeation through the skin layers when compared to the MTH-BCN suspension gel. The MTT experiment on Raw 264.7 and SW982 cell lines revealed a considerable reduction (p < .05) in the IC50 value of the MTH-BCN-TRS formulation (9.2 mM and 43.2 mM, respectively) in comparison to the drug suspension. According to the findings of the in vivo study, it was found that the MTH-BCN-TRS gel exhibits significantly promising anti-arthritic properties when compared to the conventional diclofenac gel. This was demonstrated through histopathological studies and radiographic analysis. Furthermore, skin irritation investigation on Wistar albino rats confirmed that the formulated MTH-BCN-TRS is a safe option for topical treatment on the skin. The present study has confirmed that the formulated TRS vesicles are a valuable carrier for the transdermal delivery of MTH and BCN, which may be used for the management of rheumatoid arthritis.

Identification of expression profiles and prognostic value of RFCs in colorectal cancer.

Colorectal cancer (CRC) ranks among the most prevalent cancers globally, with its incidence closely tied to DNA damage. The Replication Factor C (RFC) complexes comprises five protein subunits: RFC1, RFC2, RFC3, RFC4, and RFC5. These RFC complexes play crucial roles in DNA replication, repair pathways, activities post DNA damage, and ATP-dependent processes during DNA synthesis. However, the impact of RFC complexes proteins on CRC prognosis remains unclear. To explore this, we employed a computational analysis approach, utilizing platforms such as the DepMap portal, GEPIA, DAVID Bioinformatics for KEGG pathway analysis, Human Protein Atlas (HPA), STRING, and TIMER. Our results indicate that the mRNA levels of RFC1 and RFC5 were the least expressed among CRC cell lines compared to other RFC complex subunits. Notably, low RFC1 and RFC5 expression was correlated with poor prognosis in terms of CRC patients' overall survival (OS). Immunohistochemical results from the Human Protein Atlas demonstrated medium staining for RFC1, RFC2, and RFC5 in CRC tissues. Furthermore, the low expression of RFC1 and RFC5 showed a significant correlation with high expression levels of miR-26a-5p and miR-636, impacting cell proliferation through mismatch repair, DNA replication, and the nucleotide excision repair pathway. Although the precise functions of RFC1 in cancer are still unknown, our findings suggest that the small-molecule single target, CHEMBL430483, and multiple target molecules could be potential treatments for CRC. In conclusion, the elevated expression of miR-26a-5p and miR-636 targeting RFC1 and RFC5 expression holds promise as a potential biomarker for early-stage CRC detection. These insights provide novel directions and strategies for CRC therapies.

Levocabastine ameliorates cyclophosphamide-induced cardiotoxicity in Swiss albino mice: Targeting TLR4/NF-κB/NLRP3 signaling pathway.

Cyclophosphamide (CP), although a potent anti-cancer drug, causes cardiotoxicity as a side effect that limits its use. Hence, a specific medicine that can lower cardiotoxicity and be utilised as an adjuvant in cancer treatment is very much needed. In this light, we intended to assess the protective potential of levocabastine (LEV) on CP-induced cardiotoxicity in Swiss albino mice. Mice were administered LEV (50 and 100 µg/kg, i.p.) daily for 14 days and CP at 200 mg/kg, intraperitoneally once on the 7th day. On the 15th day, mice were weighed, blood withdrawn then sacrificed and hearts were removed to estimate various biochemical and histopathological parameters. CP 200 mg/kg significantly increased cardiac troponin T, LDH, CK-MB, interleukin-1ß, IL-6, TNF-α, TBARS, nitrite, and decreased CAT, GSH, and SOD levels, thus, manifested cardiac damage, inflammation, oxidative stress, and nitrative stress, cumulatively causing cardiotoxicity. CP also elevated the expression of various markers including cleaved caspase-3, NF-κB, TLR4, NLRP3, and fibrotic lesions in cardiac tissues, whereas decreased hematological parameters (RBCs, platelets, and Hb) to confirm cardiotoxicity. LEV and fenofibrate (FF) treatment reversed these changes towards normal and showed a significant protective effect against CP. The results showed the protective role of LEV in restoring CP-induced cardiotoxicity in terms of inflammation, apoptosis, oxidative stress, cardiac injury and histopathological damage. Thus, levocabastine can be used as an adjuvant to cyclophosphamide in cancer treatment but a thorough study with various animal cancer models is further needed to establish the fact.

Nanoemulsion potentiates the anti-cancer activity of Myricetin by effective inhibition of PI3K/AKT/mTOR pathway in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is a heterogeneous tumor with a poor prognosis and high metastatic potential, resulting in poor clinical outcomes, necessitating investigation to devise effective therapeutic strategies. Multiple studies have substantiated the anti-cancer properties of the naturally occurring flavonoid "Myricetin" in various malignancies. However, the therapeutic application of Myricetin is impeded by its poor water solubility and low oral bioavailability. To overcome this limitation, we aimed to develop nanoemulsion of Myricetin (Myr-NE) and evaluate its advantage over Myricetin alone in TNBC cells. The nanoemulsion was formulated using Capryol 90 (oil), Tween 20 (surfactant), and Transcutol HP (co-surfactant). The optimized nano-formulation underwent an evaluation to determine its size, zeta potential, morphology, stability, drug encapsulation efficiency, and in vitro release properties. The anti-cancer activity of Myr-NE was further studied to examine its distinct impact on intracellular drug uptake, cell-viability, anti-tumor signaling, oxidative stress, clonogenicity, and cell death, compared with Myricetin alone in MDA-MB-231 (TNBC) cells. The in vitro drug release and intracellular drug uptake of Myricetin was significantly increased in Myr-NE formulation as compared to Myricetin alone. Moreover, Myr-NE exhibited significant inhibition of cell proliferation, clonogenicity, and increased apoptosis with ~ 2.5-fold lower IC50 as compared to Myricetin. Mechanistic investigation revealed that nanoemulsion augmented the anti-cancer efficacy of Myricetin, most likely by inhibiting the PI3K/AKT/mTOR pathway, eventually leading to enhanced cell death in TNBC cells. The study provides substantial experimental evidence to support the notion that the Myr-NE formulation has the potential to be an effective therapeutic drug for TNBC treatment.

Curcumin Nanoemulsion: Unveiling Cardioprotective Effects via ACE Inhibition and Antioxidant Properties in Hypertensive Rats.

Background and Objectives: Curcumin, derived from Curcuma longa, is a well-known traditional medicinal compound recognized for its therapeutic attributes. Nevertheless, its efficacy is hampered by limited bioavailability, prompting researchers to explore the application of nanoemulsion as a potential alternative. Materials and Methods: This study delves into the antihypertensive effects of curcumin nanoemulsion (SNEC) by targeting the renin-angiotensin-aldosterone system (RAAS) and oxidative stress in deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats. To gauge the cardio-protective impact of SNEC in DOCA salt-induced hypertension, molecular docking was undertaken, uncovering curcumin's high affinity and adept binding capabilities to the active site of angiotensin-converting enzyme (ACE). Additionally, the investigation employed uninephrectomized rats to assess hemodynamic parameters via an AD instrument. Serum ACE, angiotensin II, blood urea nitrogen (BUN), and creatinine levels were quantified using ELISA kits, while antioxidant parameters were evaluated through chemical assays. Result: The outcomes of the molecular docking analysis revealed robust binding of curcumin to the ACE active site. Furthermore, oral administration of SNEC significantly mitigated systolic, diastolic, and mean arterial blood pressure in contrast to the DOCA-induced hypertensive group. SNEC administration also led to a reduction in left ventricular end-diastolic pressure (LVEDP) and an elevation in the maximum rate of left ventricular pressure rise (LV (dP/dt) max). Moreover, SNEC administration distinctly lowered serum levels of ACE and angiotensin II compared to the hypertensive DOCA group. Renal markers, including serum creatinine and BUN, displayed a shift toward normalized levels with SNEC treatment. Additionally, SNEC showcased potent antioxidant characteristics by elevating reduced glutathione, catalase, and superoxide dismutase levels, while decreasing the concentration of thiobarbituric acid reactive substances. Conclusions: Collectively, these findings underscore that curcumin nanoemulsion exerts noteworthy cardio-protective effects through ACE activity inhibition and remarkable antioxidant properties.

Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-ß signaling molecules.

Cyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP (in vitro), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection (in vivo). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study's outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1ß (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-ß-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-ß1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson's' trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.

Association between insulin and Nrf2 signalling pathway in Alzheimer's disease: A molecular landscape.

Insulin, a well-known hormone, has been implicated as a regulator of blood glucose levels for almost a century now. Over the past few decades, the non-glycemic actions of insulin i.e. neuronal growth and proliferation have been extensively studied. In 2005, Dr. Suzanne de La Monte and her team reported that insulin might be involved in the pathogenesis of Alzheimer's Disease (AD) and thus coined a term "Type-3 diabetes" This hypothesis was supported by several subsequent studies. The nuclear factor erythroid 2- related factor 2 (Nrf2) triggers a cascade of events under the regulation of distinct mechanisms including protein stability, phosphorylation and nuclear cytoplasmic shuttling, finally leading to the protection against oxidative damage. The Nrf2 pathway has been investigated extensively in relevance to neurodegenerative disorders, particularly AD. Many studies have indicated a strong correlation between insulin and Nrf2 signalling pathways both in the periphery and the brainbut merely few of them have focused on elucidating their inter-connective role in AD. The present review emphasizes key molecular pathways that correlate the role of insulin with Nrf2 during AD. The review has also identified key unexplored areas that could be investigated in future to further establish the insulin and Nrf2 influence in AD.

Icariin ameliorates oxidative stress-induced inflammation, apoptosis, and heart failure in isoproterenol-challenged Wistar rats.

Objectives: Cardiovascular diseases are widespread across the globe, and heart failure (HF) accounts for the majority of heart-associated deaths. Target-based drug therapy is much needed for the management of heart failure. We have designed this study to evaluate icariin for its cardioprotective activity in the isoproterenol (ISO) induced postinfarction model. We have randomly distributed Wistar rats into seven groups, i.e., vehicle control; isoproterenol-treated; icariin per se; sildenafil per se; ISO + icariin 5; ISO + icariin 10; and ISO + sildenafil groups. ISO (85 mg/kg, subcutaneous) was administered at 24 hr for two consecutive days to produce cardiac injury, followed by icariin administration at 5 mg/kg and 10 mg/kg orally for 56 days. Materials and Methods: Rats were subjected to hemodynamic measurements biweekly. After 24 hr of the completion of dosing, animals were sacrificed, and markers for oxidative stress, fibrosis, inflammation, and cell death were measured. Transmission electron microscopy (TEM), histopathology, and MT staining of cardiac tissue were also done to assess the pathological and fibrotic architectural damage. Results: A significant decline in hemodynamics and an anti-oxidant collapse were found in ISO-intoxicated rats. Alterations in the levels of cyclic guanosine monophosphate (cGMP), interleukin-10 (IL-10), Tumor necrosis factor (TNF-α), and brain natriuretic peptide (BNP) were also observed in serum. Up-regulation of caspase-3, nuclear factor (NF-ĸB), and decline in expression of nuclear factor (NrF-2) contribute to cardiac damage. The treatment with icariin and sildenafil considerably reversed the toxic changes toward normal. Conclusion: Increased cGMP and Nrf2 expression and suppressed NF-ĸB-caspase-3 signaling play a pivotal role in icariin-mediated cardioprotection.

Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aß (1-42), IRS-1 (s307), GSK-3ß, TNF-α, IL-1ß, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

Expression of Angiopoetin-Like Protein-4 and Kidney Injury Molecule-1 as Preliminary Diagnostic Markers for Diabetes-Related Kidney Disease: A Single Center-Based Cross-Sectional Study.

The purpose of the study was to examine the urinary levels of kidney injury molecule-1 (KIM-1) and angiopoietin-like protein-4 (ANGPTL-4) in individuals with diabetic kidney disease (DKD) and their association with established DKD diagnostic markers such as albuminuria and estimated glomerular filtration rate (eGFR). Levels of ANGPTL-4 and KIM-1 were estimated in urine samples. A total of 135 participants were recruited into three groups: 45 diabetes type 2 patients in the control group and 90 DKD patients in two disease groups. Concentrations of ANGPTL-4 and KIM-1 were conclusively related to the urinary albumin-creatinine ratio (UACR). Also, the levels of both ANGPTL-4 and KIM-1 were negatively associated with the eGFR. Multivariable Poisson regression analysis showed that urinary ANGPTL-4 (PR: 3.40; 95% CI: 2.32 to 4.98; p < 0.001) and KIM-1 (PR: 1.25; 95% CI: 1.14 to 1.38; p < 0.001) were prevalent in DKD patients. Receiver operating characteristic (ROC) analysis of urinary ANGPTL-4 and KIM-1 in the combined form resulted in an area under curve (AUC) of 0.967 (95%CI: 0.932-1.000; p < 0.0001) in the microalbuminuria group and 1 (95%CI: 1.000-1.000; p < 0.0001) in the macroalbuminuria group. The association of urinary levels of ANGPTL-4 and KIM-1 with UACR and eGFR and significant prevalence in the diabetic kidney disease population illustrates the diagnostic potential of these biomarkers.

Application of a Quality by Design-based approach in development and validation of an RP-HPLC method for simultaneous estimation of methotrexate and mangiferin in dual drug-loaded liposomes.

The present study delineates the development of a novel rugged and sensitive stability-indicating risk-based HPLC method for the concurrent estimation of methotrexate and mangiferin in dual drug-loaded nanopharmaceuticals based on an analytical QbD approach. Preliminary screening trials along with systemic risk analysis were performed, endeavouring to explicate the critical method attributes, namely pH, percentage orthophosphoric acid content and percentage methanol content, that influence critical quality attributes. Box-Behnken design was utilized for the optimization of the tailing factor as response for methotrexate and mangiferin in short run time. The chromatographic conditions were optimized by performing 17 experimental runs acquired from Design-Expert software. The chromatographic conditions after the analysis of an optimized zone within the confines of the design space were chosen as mobile phase water-methanol adjusted to pH 3.0 with 0.05% orthophosphoric acid (65:35, v/v) and flow rate 1.0 ml/min using a C18 analytical column at an isosbestic wavelength of 265 nm. Furthermore, the validation of the optimized method was done in accordance with International Conference on Harmonization guidelines and were reckoned to be in the prescribed limits. The developed RP-HPLC method has a high degree of practical utility for synchronous detection of methotrexate and mangiferin in pharmaceutical nano-dosage forms such as protein-based-nanoparticles, nanocrystals, polymeric nanoparticles and metallic nanoparticles in in vivo and in vitro studies.

Exploring effects of Simvastatin on coagulation mediators to alleviate the advancement of high cholesterol diet triggered neurodegeneration.

The objectives of our study were to investigate the possible effect of Simvastatin in ameliorating high cholesterol diet (HCD)-induced neurodegeneration and to also investigate its possible action on coagulation mediators. In silico and in vitro studies were performed to evaluate the impact of Simvastatin on prime coagulation mediators. HCD was used to induce neuropathology in wistar rats and histopathological and immunohistochemical studies were performed to evaluate the efficacy of Simvastatin in preventing the advancement of neurodegeneration in obese rats. Biochemical analyses were used to estimate changes in lipid profile, oxidative stress, inflammatory and coagulation markers. Simvastatin showed good theoretical affinity to coagulation proteins, significantly reversed changes in inflammatory and coagulation biomarkers which were induced by HCD. Enhanced fibrinolytic activity of Simvastatin was revealed through in vitro analysis. Immunohistoanalysis showed raised level of Nrf2. Histopathological studies also supported neuroprotective potential of Simvastatin in HCD fed rats. Simvastatin demonstrated reduced hypercoagulation, enhanced fibrinolysis and reversed neurodegeneration in HCD exposed rats suggesting its potential role in preventing the progression of neurodegeneration in obesity.

Antimalarial and Plasmodium falciparum serpentine receptor 12 targeting effect of FDA approved purinergic receptor antagonist.

Intraerythrocytic stages of Plasmodium falciparum responsible for all clinical manifestations of malaria are regulated by array of signalling cascades that represent attractive targets for antimalarial therapy. G-protein coupled receptors (GPCRs) are druggable targets in the treatment of various pathological conditions, however, there is limited understanding about the role of GPCRs in malaria pathogenesis. In Plasmodium, serpentine receptors (PfSR1, PfSR10, PfSR12 and PfSR25) with GPCR-like membrane topology have been reported with the finite knowledge about their potential as antimalarial targets. We analyzed the localization of these receptors in malaria parasite by immunofluorescence assays. All four receptors were expressed in blood stages with PfSR12 expressing more in late intraerythrocytic stages. Further, we evaluated the druggability of PfSR12 using FDA-approved P2Y purinergic receptor antagonist, Prasugrel and its active metabolite R138727, which is proposed to be specific towards PfSR12. Interestingly, biophysical analysis indicated strong binding between PfSR12 and R138727 as compared to the prodrug Prasugrel. This binding interaction was further confirmed by thermal shift assay. Treatment of parasite with Prasugrel and R138727 resulted in growth inhibition of P. falciparum indicating an important role of purinergic signalling and PfSR12 in parasite survival. Next, progression studies indicated the inhibitory effect of Prasugrel begins in late erythrocyte stages corroborating with PfSR12 expression at these stages. Furthermore, Prasugrel also blocked in vivo growth of malaria parasite in a mouse experimental model. This study indicates the presence of P2Y type of purinergic signalling in growth and development of malaria parasite and suggests PfSR12, putative purinergic receptor druggability through Prasugrel.Communicated by Ramaswamy H. Sarma.

Effect of Nigella Sativa in Improving Blood Glucose Level in T2DM: Systematic Literature Review of Randomized Control Trials.

BACKGROUND: Diabetes mellitus is a highly prevalent condition that affects people of all ages, races, and genders. Medicinal herbs have received a lot of attention from researchers, and they have suggested it to be a good adjuvant to oral diabetes medications because of their combined effects. OBJECTIVES: The purpose of this systematic review is to summarize the available evidences and literature of Randomized Control Trials (RCTs) on Nigella sativa (NS) in the management of Type 2 Diabetes Mellitus (T2DM). METHODS: A computerised database search was performed to obtain the relevant clinical trial studies. We searched the following PubMed and Google Scholar databases. Randomized controlled trials (RCTs) comparing NS versus any treatment for the management of T2DM in adults were eligible for inclusion. RESULTS: A total of 7 articles were retrieved for interpretation, complete assessment and data extraction in this systematic review. This systematic review seeks to give thorough information on the effects of NS on glucose and insulin profile status in patients with T2DM. INTERPRETATION & CONCLUSION: Different mechanisms are proposed which contribute to the anti-diabetic activity of NS. Various outcome parameters evaluated demonstrate a significant improvement in the management of T2DM and its complications upon intervention with NS.

Protective effect of rosmarinic acid on the transmembrane transporter Ctr1 expression in cisplatin-treated mice.

AIMS: Cisplatin (cis-diamminedichloroplatinum(II), CP) is a platinum-based anticancer drug widely used in the treatment of solid malignancies. However, its side effects, particularly nephrotoxicity, are limiting factors in its clinic use. Rosmarinic acid (RA), a natural antioxidant compound, is reported to attenuate oxidative stress and associated pathophysiological outcomes. Our study aimed to explore the protective effect of RA against CP-induced acute kidney injury (AKI). MATERIALS AND METHODS: We investigated the effect of RA at the dose of 100 mg/kg on AKI induced by CP (20 mg/kg) in mice. Various parameters of nephrotoxicity such as levels of serum electrolytes, albumin, and globulin were measured using standardized methods. Besides, a specific biomarker of damage to proximal tubular cells, kidney injury molecule-1 (Kim-1), was measured in the serum by ELISA. mRNA expression of Kim-1 and a transmembrane transporter, copper transporter 1 (Ctr1), was analyzed by quantitative reverse transcriptase-polymerase chain reaction. CTR1 expression was also analyzed by western blot technique. RESULTS: RA treatment restored the downregulated CTR1 , a renal transmembrane transporter in CP-treated mice. It was accompanied by a reduction in the level of serum albumin and globulin. Serum electrolytes such as Na+, K+, and Ca2+ in CP-treated mice were found to be restored with RA treatment. Moreover, RA also significantly downregulated the increased expression of nephrotoxicity biomarker KIM-1. CONCLUSIONS: Overall, RA proved to be an effective nephroprotective compound which afforded protection at cellular and subcellular levels with an appreciable modulatory effect on a transmembrane transporter.

Myricetin-induced apoptosis in triple-negative breast cancer cells through inhibition of the PI3K/Akt/mTOR pathway.

Breast cancer is still a severe origin of malignant demise in females, and its prevalence is rising worldwide. Triple-negative breast cancer (TNBC) is a diversified aggressive breast tumor distinguished by inadequate prognosis, early recurrence, high invasion, and extremely metastasized disease. Chemotherapy is being used to treat it; however, it has low efficacy. On the other hand, with the growing number of corroborations on subtypes of TNBC and molecular biology of tumors, significant advancement in TNBC targeted treatment has been made. Myricetin (MYR), a polyhydroxyflavonol compound widely found in nature, has been shown to possess anticancer effects in various cancers. Though, the mechanisms and impacts of MYR on metastasis of TNBC remain unclear. Early and late apoptotic cell death and cell proliferation inhibition were observed in MYR-treated TNBC cells. MYR modulated cell cycle, pro-angiogenic, and invasion effects via the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Protein kinase B (PKB/also known as AKT) signaling pathways. Moreover, it regulates the expression of MAPK, PI3K/AKT/mTOR, IκB/NF-κB, Hippo, STAT3, GSK-3ß, Nrf2/HO-1, TLR, eNOS / NO, ACE, and AChE. Here, we review the anticancer effects of MYR for TNBC and target the PI3K/AKT/mTOR pathway as a therapeutic target for the fruitful treatment of TNBC to summarize MYR's therapeutic potential.

Synthesis, biological evaluation, and in silico studies of indole-tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα.

We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.