A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity.

Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocardium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca2+/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy-dependent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contributing to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.

RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21.

BACKGROUND: Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. METHODS: Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity. RESULTS: Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart. CONCLUSION: Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity.

Cardiac RGS7 and RGS11 drive TGFß1-dependent liver damage following chemotherapy exposure.

Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor ß1 (TGFß1) and TGFß superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFß1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFß1 from the heart and the profibrotic and pro-oxidant actions of TGFß1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation.

Cardiotoxicity remains a major limitation in the clinical utility of anthracycline chemotherapeutics. Regulator of G-protein Signaling 7 (RGS7) and inflammatory markers are up-regulated in the hearts of patients with a history of chemotherapy particularly those with reduced left-ventricular function. RGS7 knockdown in either the murine myocardium or isolated murine ventricular cardiac myocytes (VCM) or cultured human VCM provided marked protection against doxorubicin-dependent oxidative stress, NF-κB activation, inflammatory cytokine production, and cell death. In exploring possible mechanisms causally linking RGS7 to pro-inflammatory signaling cascades, we found that RGS7 forms a complex with acetylase Tip60 and deacetylase sirtuin 1 (SIRT1) and controls the acetylation status of the p65 subunit of NF-κB. In VCM, the detrimental impact of RGS7 could be mitigated by inhibiting Tip60 or activating SIRT1, indicating that the ability of RGS7 to modulate cellular acetylation capacity is critical for its pro-inflammatory actions. Further, RGS7-driven, Tip60/SIRT1-dependent cytokines released from ventricular cardiac myocytes and transplanted onto cardiac fibroblasts increased oxidative stress, markers of transdifferentiation, and activity of extracellular matrix remodelers emphasizing the importance of the RGS7-Tip60-SIRT1 complex in paracrine signaling in the myocardium. Importantly, while RGS7 overexpression in heart resulted in sterile inflammation, fibrotic remodeling, and compromised left-ventricular function, activation of SIRT1 counteracted the detrimental impact of RGS7 in heart confirming that RGS7 increases acetylation of SIRT1 substrates and thereby drives cardiac dysfunction. Together, our data identify RGS7 as an amplifier of inflammatory signaling in heart and possible therapeutic target in chemotherapeutic drug-induced cardiotoxicity.

Digital transformation challenges in sustainable financial service systems using novel interval-valued Pythagorean fuzzy double normalization-based multiple aggregation approach.

Recently, financial service systems have had essential impacts on public policies, the economic performance of firms, and all forms of industry and commerce. These systems play an important role in determining whether a society (which includes a wide range of members, from governmental institutions to individual consumers) has been successfully considered an environmentally sustainable path. The literature shows that the people who work in the financial sector are mostly unaware of the pressure and rationale behind sustainable development and its bearing on their work; however, those who work in the relevant research and policy areas generally ignore the vitality of the role of the financial sector in such a development. The study of interval-valued Pythagorean fuzzy sets (IVPFSs) indicates an urge for a decision approach to implementing the available information for rational decisions properly. Inspired by the advantage of IVPFSs, an extended decision methodology called the IVPF rank-sum weighting method (RSWM)-double normalization-based multi-aggregation (DNMA) is discussed. In this line, the IVPF-RSWM is applied to find the subjective weights of digital transformation challenges of sustainable financial service systems (SFSS), and the DNMA framework is developed to obtain the preferences of SFSSs in the banking sector. A case study to assess the main digital transformation challenges in SFSSs of the banking sector is undertaken. Further, comparison and sensitivity investigations are taken to illustrate the advantage of the presented approach.

Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt c, BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. 1H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through N-nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC.

Assessments of in vitro and in vivo antineoplastic potentials of ß-sitosterol-loaded PEGylated niosomes against hepatocellular carcinoma.

ß-sitosterol (BS), a phytosterol, exhibits ameliorative effects on hepatocellular carcinoma (HCC) due to its antioxidant activities. However, its poor aqueous solubility and negotiated bioavailability and short elimination half-life is a huge limitation for its therapeutic applications. To overcome these two shortcomings, BS-loaded niosomes were made to via, film hydration method and process parameters were optimized using a three-factor Box-Behnken design. The optimized formulation (BSF) was further surface-modified with polyethylene glycol (PEG). The resulting niosomes (BSMF) have spherical shapes, particle sizes, 219.6 ± 1.98 nm with polydispersity index (PDI) and zeta potential of 0.078 ± 0.04 and -19.54 ± 0.19 mV, respectively. The drug loading, entrapment efficiency, and drug release at 24 h of the BSMF were found to be 16.72 ± 0.09%, 78.04 ± 0.92%, and 75.10 ± 3.06%, respectively. Moreover, BSMF showed significantly greater cytotoxic potentials on Hep G2 cells with an enhanced cellular uptake relative to pure BS and BSF. The BSMF also displayed potentially improved curative property of HCC in albino wistar rat. Thus, the BSMF could be one of the promising therapeutic modalities for HCC treatment in terms of targeting potential resulting in enhanced therapeutic efficacy.

Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling.

We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through 1H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.

Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80 mg/kg dose) treatment normalized the expression of caspase-mediated apoptotic factors, i.e. BAX and Bcl-2 proteins, as established through Western blot analysis. Later, 1H NMR-based serum metabolomics study revealed that levels of perturbed metabolites in DEN-induced rat serum returned to normal after ZAF administration. Altogether, the antineoplastic potential of ZAF was found to be comparable, and to some degree better, than the marketed chemotherapeutic 5-flurouracil, which may be beneficial for anti-HCC treatment from a future drug design perspective.

Novel 1,4-benzothazines obliterate COX-2 mediated JAK-2/STAT-3 signals with potential regulation of oxidative and metabolic stress during colorectal cancer.

1,4-benzothiazines have ameliorative effects through inhibition of COX-2 mediated STAT-3 pathways at G-protein couple receptor site. As per this scenario, we recently prepared and tested novel 1,4-benzothiazine derivatives against HT-29 human colon cancer cell line. Two compounds namely AR13 and AR15 showed higher inhibitions among all the synthesized compounds. In the present context, we conducted the in vivo antiproliferative action and identified the molecular mechanism associated to cytotoxic action of AR13 and AR15 in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) model. Various physiological, oxidative stress, histopathology, ELISA, qRT-PCR, western blot and NMR-based metabolomics were accomplished to evaluate the anticancer effect of titled compounds. Both compounds were subjected to histological and biochemical tests to observe the protective action of the compounds. ELISA showed potential role of these compounds to normalize increased levels of IL-2, IL-6 and COX-2 mediators. This action was more pronounced for COX-2 rather than IL-2 and IL-6. Gene expression analyses further revealed that both of them attenuated the over-expressed COX-2 gene. Furthermore, it was confirmed that these compounds exerted antitumor potential via preventing COX-2 induced JAK-2 and STAT-3 phosphorylation. This action was substansiated by immunohistochemistry using JAK2, p-JAK2, STAT3 and p-STAT3 targets in colon tissue. Finally, score plots of PLS-DA models exhibited significant metabolic discriminations between the treated and CRC groups, and both compounds showed ability to restore the imbalance of multiple metabolites during CRC. In conclusion, our study provided the evidence towards better antiproliferative effect of AR13 and AR15 in DMH-induced CRC through the blockade of COX-2/JAK-2/STAT-3 signal transduction pathway and could be demonstrated as useful anti-CRC candidate molecules for future anticancer therapy.

ω-3 Fatty Acid Synergized Novel Nanoemulsifying System for Rosuvastatin Delivery: In Vitro and In Vivo Evaluation.

The present study was undertaken to improve rosuvastatin (RSV) bioavailability and pharmacological response through formation of SNES using Perilla frutescens oil as lipid carrier. The composition of oil was estimated by fatty acid methyl ester (FAME) analysis using gas chromatography. Solubility of RSV in Perilla frutescens oil and Cremophor EL was 25.0 ± 3.0 and 60.0 ± 5.0 mg/mL, respectively. Later, nanophasic maps and a central composite design were employed to determine the maximum nanoemulsion region and further optimize SNES in this study. Finally, the optimized formulation was evaluated in vitro and in vivo. FAME analysis revealed that PUFA content was 70.3% of total fatty acid. Optimized SNES formulation demonstrated particle size of 17.90 nm, dissolution 98.80%, cloud point 45°C, emulsification time 2 min, and viscosity 241.41 ± 5.52 cP. The hypolipidemic property of SNES was further explored using Triton X-100-induced hyperlipidemic rat model, and there were reductions of serum cholesterol, triglyceride, and LDL and VLDL levels in the SNES-treated group as compared to the toxic control. Pharmacokinetic study of SNES revealed significantly higher C max (60.13 ± 25.43 ng/mL) and AUC0-∞ (6195 ± 42.38 ng h/mL) vis-à-vis marketed tablet (284.80 ± 13.44 ng/mL, 3131.72 ± 51.93 ng h/mL, respectively). RSV was successfully incorporated into ω-3 fatty acid-based SNES with improved pharmacokinetic parameters (~ 2-fold improved bioavailability) and better hypolipidemic properties, owing to the synergistic effects of hepatic lipid regulation itself. The results clearly explicated that ω-3 fatty acid-based SNES effectively enhanced bioavailability and pharmacological responses of RSV, suggesting that these formulations may be useful as alternative for hyperlipidemia treatment in future drug design perspective.

Appraisal of folate functionalized bosutinib cubosomes against hepatic cancer cells: In-vitro, In-silico, and in-vivo pharmacokinetic study.

Targeted therapies enhance the efficacy of tumour screening and management while lowering side effects. Multiple tumours, including liver cancer, exhibit elevated levels of folate receptor expression. This research attempted to develop surface-functionalised bosutinib cubosomes against hepatocellular carcinoma. The novelty of this work is the anti-hepatic action of bosutinib (BST) and folic acid-modified bosutinib cubosomes (BSTMF) established through proto-oncogene tyrosine-protein kinase (SrC)/ focal adhesion kinase(FAK), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and cell cytotoxicity. Later, the in-vivo pharmacokinetics of BSTMF were determined for the first time. The strong affinity of folic acid (FA) for folate receptors allows BSTMF to enter cells via FA receptor-mediated endocytosis. The particle size of the prepared BSTMF was 188.5 ± 2.25 nm, and its zeta potential was -20.19 ± 2.01 mV, an encapsulation efficiency of 90.31 ± 3.15 %, and a drug release rate of 76.70 ± 2.10 % for 48 h. The surface architecture of BSTMF was identified using transmission electron microscopy (TEM) and Atomic force microscopy (AFM). Cell-line studies demonstrated that BSTMF substantially lowered the viability of Hep G2 cells compared to BST and bosutinib-loaded cubosomes (BSTF). BSTMF demonstrated an elevated BST concentration in tumour tissue than in other organs and also displayed superior pharmacokinetics, implying that they hold potential against hepatic cancers. This is the first study to show that BSTMF may be effective against liver cancer by targeting folate receptors and triggering SrC/FAK-dependent apoptotic pathways. Multiple parameters demonstrated that BSTMF enhanced anticancer targeting, therapeutic efficacy, and safety in NDEA-induced hepatocellular carcinoma.

A Comprehensive Review on Exosome: Recent Progress and Outlook.

Exosomes are intrinsic membrane-based vesicles that play a key role in both normal and pathological processes. Since their discovery, exosomes have been investigated as viable drug delivery systems and clinical indicators because of their magnitude and effectiveness in delivering biological components to targeted cells. Exosome characteristics are biocompatible, prefer tumor recruitment, have tunable targeting efficiency, and are stable, making them outstanding and eye-catching medication delivery systems for cancer and other disorders. There is great interest in using cell-released tiny vesicles that activate the immune system in the age of the fast development of cancer immunotherapy. Exosomes, which are cell-derived nanovesicles, have a lot of potential for application in cancer immunotherapy due to their immunogenicity and molecular transfer function. More significantly, exosomes can transfer their cargo to specified cells and so affect the phenotypic and immune-regulation capabilities of those cells. In this article, we summarize exosomes' biogenesis, isolation techniques, drug delivery, applications, and recent clinical updates. The use of exosomes as drug-delivery systems for small compounds, macromolecules, and nucleotides has recently advanced. We have tried to give holistic and exhaustive pieces of information showcasing current progress and clinical updates of exosomes.

Targeting caspase pathway by novel N-Me aziridine derivatives for hepatocellular carcinoma drug discovery.

Azaheterocycles are three-membered rings, known as aziridines, that occur naturally and have pharmaceutical applications.These compounds are present as several secondary metabolites produced by plants and microorganisms.Recent studies have demonstrated the effectiveness of aziridine derivatives (N-H/N-Me) as anticancer agents.We synthesized 18 compounds containing an N-Me enone aziridine group, the chemistry of which has been previously published. However, these compounds have drug-likeness properties; therefore, we aimed to demonstrate their drug-like properties using in silico and in vitro investigations.The molecular structures of the compounds were optimized using density functional theory (DFT). The ADMET parameters of the derivatives were calculated using SwissADME and PreADMET. Additionally, these derivatives were evaluated for their ability to bind to caspase-3 and caspase-9 and then subjected to molecular docking. The lead chemical AY128 maintained stable complexes with target proteins during molecular dynamics simulations, as evidenced by the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) parameters. In vitro cytotoxicity and ELISA tests showed that the novel aziridine derivatives, especially AY128, had strong anticancer activity against HepG2 hepatocellular carcinoma cells.Our study suggests that AY128 may be a potential drug candidate for hepatocellular carcinoma through the caspase-3 and caspase-9-dependent apoptotic pathways.Communicated by Ramaswamy H. Sarma.

A Comprehensive Review on PCSK9 as Mechanistic Target Approach in Cancer Therapy.

PCSK9 is a strongly expressed protein in the liver and brain that binds to the LDLR and regulates cholesterol in the liver effectively. Other receptors with which it interacts include VLDLR, LRP1, ApoER2, and OLR1. PCSK9 gain-of-function results in lysosomal degradation of these receptors, which may result in hyperlipidemia. PCSK9 deficiency results in a lower amount of cholesterol, which reduces cholesterol's accessibility to cancer cells. PCSK9 regulates several proteins and signaling pathways in cancer, including JNK, NF-κВ, and the mitochondrial-mediated apoptotic pathway. In the liver, breast, lungs, and colon tissue, PCSK9 initiates and facilitates cancer development, while in prostate cancer cells, it induces apoptosis. PCSK9 has a significant impact on brain cancer, promoting cancer cell survival by manipulating the mitochondrial apoptotic pathway and exhibiting apoptotic activity in neurons by influencing the NF-κВ, JNK, and caspase-dependent pathways. The PCSK9 impact in cancer at different organs is explored in this study, as well as the targeted signaling mechanisms involved in cancer growth. As a result, these signaling mechanisms may be aimed for the development and exploration of anti-cancer drugs in the immediate future.

Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines.

Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1ß, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

New Scope of Targeted Therapies in Lung Carcinoma.

Lung Cancer (LC) is the leading cause of cancer deaths worldwide. Recent research has also shown LC as a genomic disease, causing somatic mutations in the patients. Tests related to mutational analysis and genome profiles have lately expanded significantly in the genetics/genomics field of LC. This review summarizes the current knowledge about different signalling pathways of LC based on the clinical impact of molecular targets. It describes the main molecular pathways and changes involved in the development, progression, and cellular breakdown of LC and molecular changes. This review focuses on approved and targeted experimental therapies such as immunotherapy and clinical trials that examine the different targeted approaches to treating LC. We aim to clarify the differences in the extent of various genetic mutations in DNA for LC patients. Targeted molecular therapies for LC can be continued with advanced racial differences in genetic changes, which have a significant impact on the choice of drug treatment and our understanding of the profile of drug susceptibility/ resistance. The most relevant genes described in this review are EGFR, KRAS, MET, BRAF, PIK3CA, STK11, ERBB3, PTEN, and RB1. Combined research efforts in this field are required to understand the genetic difference in LC outcomes in the future.

Appraisal of anti-gout potential of colchicine-loaded chitosan nanoparticle gel in uric acid-induced gout animal model.

Present study is aimed at transdermal delivery of colchicine-loaded chitosan nanoparticles. The nanoformulations were prepared utilising spontaneous emulsification method and optimised through 23 factorial designs. The optimised formulation (CHNP-OPT) displayed an average particle size of 294 ± 3.75 nm, entrapment efficiency 92.89 ± 1.1% and drug content 83.45 ± 2.5%, respectively. In vitro release study demonstrated 89.34 ± 2.90% release over a period of 24 h. Further, CHNP-OPT incorporated into HPMC-E4M (hydroxypropyl methylcellulose) to form transdermal gel. CHNPgel displayed 74.65 ± 1.90% permeation and stability over a period of 90 days. The anti-gout potential of CHNPgel formulation was evaluated in vivo against monosodium urate (MSU) crystal-induced gout in animal model. There was significant reduction in uric acid level, during MSU administration, when compared with the conventional gel of colchicine. The enhanced therapeutic potential was witnessed through X-ray. The study revealed that colchicine-loaded CHNPgel proved their supremacy over plain colchicine and can be an efficient delivery system for gout treatment.

Assessment of hyaluronic acid-modified imatinib mesylate cubosomes through CD44 targeted drug delivery in NDEA-induced hepatic carcinoma.

This study aimed at the development of hyaluronic acid-functionalised imatinib mesylate cubosomes (HA-IM-CBs) that might be useful in CD44 targeting against hepatic cancer. The HA-IM-CBs had a 130.7 ±â€¯2.92 nm particle size, -31.40 ±â€¯2.76 mV zeta potential, and 76.14 ±â€¯2.69% release. The architecture of HA-IM-CBs was confirmed using HR-TEM and AFM. When compared to plain IM and IM-CBs, in vitro experiments revealed that HA-IM-CBs outperformed by significantly reducing cell viability. DAPI staining and ROS corroborated the apoptotic effects. Biodistribution and Pharmacokinetics studies showedthat HA-IM-CBs exhibit a higher drug concentration in tumour tissue and better pharmacokinetic activity. This is the first study to show that HA-IM-CBs had CD44 targeting activity against HCC. CD44 regulates apoptosis via Bcl-2 family proteins and caspases, which interact with HA. Higher levels of e-NOS, BAD, BAX, and Cyt C and lower expressions of Bcl-xl, i-NOS, and Bcl-2 demonstrated the anti-HCC potential of HA-IM-CBs in qrt-PCR investigations. The remarkable therapeutic potential of HA-IM-CBs began with substantial stimulation of CD44 regulated caspase-mediated mitochondrial apoptotic pathway, accountable for their anti-HCC activity. The perturbed metabolites are restored to acceptable levels as indicated by metabolomic studies (1H NMR). Interestingly, the antineoplastic effect of HA-IM-CBs was proven to be potentially valuable against HCC.

Mechanistic exploration of the activities of poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid against hepatocellular carcinoma at cellular and molecular levels.

The effectiveness of betulinic acid (B) and PLGA loaded nanoparticles of B (Bnp) against hepatocellular carcinoma (HCC) was established and reported earlier. In continuation of our previous report, the present study described the molecular mechanisms of their antineoplastic responses. In this context, the antineoplastic properties of both B and Bnp were evaluated on DEN-induced HCC rat model. The quantitative real-time polymerase chain reaction and western blot analyses revealed that HCC was developed through lower expressions of e-NOS, BAX, BAD, Cyt C and higher expressions of i-NOS, Bcl-xl, Bcl-2. B and Bnp normalised the expressions of these apoptogenic markers. Particularly, both activated i-NOS and e-NOS mediated Bcl-2 family proteins→CytC→Caspase 3 and 9 signalling cascades. The 1H-NMR-based metabolomics study also demonstrated that the perturbed metabolites in DEN-induced rat serum restored to the normal level following both treatments. Moreover, the antineoplastic potential of Bnp was found to be comparable with the marketed product, 5-flurouracil.