Nanoapatite-Loaded κ-Carrageenan/Poly(vinyl alcohol)-Based Injectable Cryogel for Hemostasis and Wound Healing.

Immediate control of excessive bleeding and prevention of infections are of utmost importance in the management of wounds. Cryogels have emerged as promising materials for the rapid release of medication and achieving hemostasis. However, their quick release properties pose the challenge of exposing patients to high concentrations of drugs. In this study, hybrid nanocomposites were developed to address this issue by combining poly(vinyl alcohol) and κ-carrageenan with whitlockite nanoapatite (WNA) particles and ciprofloxacin, aiming to achieve rapid hemostasis and sustained antibacterial effects. A physically cross-linked cryogel was obtained by subjecting a blend of poly(vinyl alcohol) and κ-carrageenan to successive freezing-thawing cycles, followed by the addition of WNA. Furthermore, ciprofloxacin was introduced into the cryogel matrix for subsequent evaluation of its wound healing properties. The resulting gel system exhibited a 3D microporous structure and demonstrated excellent swelling, low cytotoxicity, and outstanding mechanical properties. These characteristics were evaluated through analytical and rheological experiments. The nanocomposite cryogel with 4% whitlockite showed extended drug release of 71.21 ± 3.5% over 21 days and antibacterial activity with a considerable growth inhibition zone (4.19 ± 3.55 cm). Experiments on a rat model demonstrated a rapid hemostasis property of cryogels within an average of 83 ± 4 s and accelerated the process of wound healing with 96.34% contraction compared to the standard, which exhibited only ∼78% after 14 days. The histopathological analysis revealed that the process of epidermal re-epithelialization took around 14 days following the skin incision. The cryogel loaded with WNAs and ciprofloxacin holds great potential for strategic utilization in wound management applications as an effective material for hemostasis and anti-infection purposes.

Molecular Insights into the Crosstalk Between Immune Inflammation Nexus and SARS-CoV-2 Virus.

COVID-19, a type of viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 has challenged the world as global pandemic. It has marked the identification of third generation of extremely pathogenic zoonotic coronaviruses of twenty-first century posing threat to humans and mainly targeting the lower respiratory tract. In this review, we focused on not only the structure and virology of SARS-COV-2 but have discussed in detail the molecular immunopathogenesis of this novel virus highlighting its interaction with immune system and the role of compromised or dysregulated immune response towards disease severity. We attempted to correlate the crosstalk between unregulated inflammatory outcomes with disrupted host immunity which may play a potential role towards fatal acute respiratory distress syndrome that claims to be life-threatening in COVID-19. Exploration and investigation of molecular host-virus interactions will provide a better understanding on the mechanism of fatal COVID-19 infection and also enlighten the escape routes from the same.

Molecular epigenetic dynamics in breast carcinogenesis.

Breast cancer has become one of the most common dreadful diseases that target women across the globe. The most obvious reasons we associate with it are either genetic mutations or dysregulation of pathways. However, there is yet another domain that has a significant role in influencing the genetic mutations and pathways. Epigenetic mechanisms influence these pathways either independently or in association with genetic mutations, thereby expediting the process of breast carcinogenesis. Breast cancer is governed by various transduction pathways such as PI3K/AKT/mTOR, NOTCH, ß Catenin, NF-kB, Hedgehog, etc. There are many proteins as well that serve to be tumor suppressors but somehow lose their ability to function. This may be because of either genetic mutation or a process that represses their function. Apart from these, there are a lot of individual factors like puberty, breastfeeding, abortion, parity, circadian rhythm, alcohol consumption, pollutants, and obesity that drive these mutations and hence alter the pathways. Epigenetic mechanisms like DNA methylation, histone modifications, and lncRNAs directly or indirectly bring alterations in the proteins that are involved in the pathways. They do this by either promoting the transcription of genes or by repressing it at the ground genetic level that advances breast carcinogenesis. Epigenetics precedes genetic mutation in driving carcinogenesis and so, it needs to be explored further to diversify the possibilities of target specific treatments. In this review, the general role of DNA methylation, histone modification, and lncRNAs in breast cancer and their role in influencing the oncogenic signaling pathways along with the various factors governing them have been discussed for a better understanding of the role of epigenetics in breast carcinogenesis.

LC-MS characterized methanolic extract of zanthoxylum armatum possess anti-breast cancer activity through Nrf2-Keap1 pathway: An in-silico, in-vitro and in-vivo evaluation.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum armatum DC (Rutaceae) containing flavonoids, alkaloids, coumarins, lignans, amides and terpenoid is well-known for its curative properties against various ailments including cancer. In the current research, phytochemicals present in the methanolic extract of Zanthoxylum armatum bark (MeZb) were characterized by LC-MS/MS analysis and chemotherapeutic potential of this extract was determined on DMBA-induced female Sprague Dawley rats. MATERIALS AND METHODS: A simple and fast high-performance liquid chromatography-mass spectroscopy (LC-MS/MS) of MeZb was established followed by in-vitro antioxidant assays. This was followed by in-silico docking analysis as well as cytotoxicity assessment. Successively in-vivo study of MeZb was performed in DMBA-induced Sprague Dawley rats possessing breast cancer along with detailed molecular biology studies involving immunofluorescence, RT-qPCR and Western blot analysis. RESULTS: LC-MS/MS investigation revealed the presence of compounds belonging to flavonoid, alkaloid and glycoside groups. MeZb revealed potential antioxidant activity in in-vitro antioxidant assays and strong binding energy of identified compounds was seen from the in-silico study with both HO1 and Keap1 receptor. Furthermore, the antioxidant action of MeZb was proven from the in-vivo analysis of antioxidant marker enzymes (lipid peroxidation, enzymic and non-enzymic antioxidants). This study also revealed upregulation of protective Nrf-2 following downregulation of Keap1 after MeZb treatment with respect to untreated cancerous rats. CONCLUSION: These results exhibited anti-breast-cancer potential of MeZb through Nrf2-Keap1 pathway which may be due to the flavonoids, alkaloids and glycosides present in it.

Quercetin loaded folate targeted plasmonic silver nanoparticles for light activated chemo-photothermal therapy of DMBA induced breast cancer in Sprague Dawley rats.

Currently, the paucity of free drugs in conventional chemotherapy for breast-cancer curbs the desired therapeutic efficiency, often aggravating systemic toxicity. Quercetin (QRC) is a potential chemotherapeutic bio-flavonoid that is associated with poor hydrophilicity. In contrast to spherical silver nanoparticles (AgNPs), anisotropic AgNPs exhibit prominent plasmonic tunability in the near infrared (NIR) region allowing deep tissue penetration and endowing them with the ability to act as photothermal transducers as well. In this study, we optimized a simple and novel method for synthesizing folate-receptor-targeted-plasmonic silver-nanoparticles (QRC-FA-AgNPs) to serve as an efficient nanoscopic carrier system for breast cancer-cell targeted delivery of QRC and to induce photothermal therapy. A one-pot chemical synthesis method was followed for synthesizing the QRC-FA-AgNPs by finely tailoring the hydrogen bond between the reductant and stabilizer. Detailed characterization through UV-visible, near infrared (UV-vis-NIR) spectroscopy, Fourier transform infrared (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and energy-dispersive X-ray spectroscopy (EDX), along with particle-size, zeta-potential analysis, drug-loading and release capacity and stability studies were also performed. In vitro targeted cellular uptake, viability studies, chemo-photothermal efficacy, induction of apoptosis and the reactive oxygen species (ROS) generating potential were studied in the MDA-MB-231 cell-line and in vivo evaluation of the chemo-photothermal efficacy of QRC-FA-AgNPs was performed using a 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast-carcinogenesis model in Sprague Dawley rats. Unlike conventional AgNPs, these novel pentagonal QRC-FA-AgNPs (<50 nm) manifested a robust plasmon tunability in the NIR (>800 nm) region. Detailed in vitro and in vivo studies revealed their active role in improving breast-cancer conditions by allowing controlled and targeted discharge of QRC at the tumor site, along with evoking hyperthermia under NIR laser irradiation that induced selective ablation of cancer cells. Following successful cellular internalization, the photothermal efficacy of QRC-FA-AgNPs supplemented their chemotherapeutic potency, allowing apoptosis and restraining the tumor growth. This current study highlighted the augmented efficacy of plasmonic QRC-FA-AgNPs in comparison to free quercetin, thus the development of a potential nanocarrier based on the pleiotropic function of plasmonic AgNPs may provide an efficient combined chemo-photothermal based strategy for the assassination of breast-cancer cells.

Quinazolinone derivative BNUA-3 ameliorated [NDEA+2-AAF]-induced liver carcinogenesis in SD rats by modulating AhR-CYP1B1-Nrf2-Keap1 pathway.

Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species-mediated stress alter different molecular signalling pathways and gene expressions. Quinazoline derivatives are recognized for their diversified biological activities including anticancer properties. The current study was designed for evaluation of chemotherapeutic efficacy of a synthetic quinazolinone derivative BNUA-3 against hepatocellular cancer in Sprague-Dawley (SD) rats. A detailed in vivo analysis was performed by administrating BNUA-3 (15, 30 mg/kg b.w. for 28 days, i.p.) in N-Nitrosodiethylamine + 2-Acetylaminofluorene induced partially hepatectomized liver cancer in SD rats. This was followed by morphological evaluations, biochemical estimations and analysis of different mRNA and protein expressions. The results demonstrated the potency of BNUA-3 in efficient restoration of the altered morphology of liver, its protective effect against lipid peroxidation, enzymic and non-enzymic antioxidants levels in liver tissue which was disrupted after cancer induction. The study also demonstrated downregulation of AhR, CYP1B1 and Keap1 expressions with subsequent augmentation of protective Nrf2, HO-1, NQO1 and GSTA1 expressions thus, revealing the chemotherapeutic potency of BNUA-3 in inhibiting liver carcinogenesis through AhR/CYP1B1/Nrf2/Keap1 pathway.

Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer.

Breast cancer is one of the biggest global dilemmas and its current therapy is to target the hormone receptors by the use of partial agonists/antagonists. Potent drugs for breast cancer treatment are Tamoxifen, Trastuzumab, Paclitaxel, etc. which show adverse effects and resistance in patients. The aim of the study has been on certain phytochemicals which has potent actions on ERα, PR, EGFR and mTOR inhibition. The current study is performed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The 3D structures of ERα, PR, EGFR and mTOR were obtained from the protein data bank and docked with 23 3D PubChem structures of furanocoumarin compounds using FlexX. Drug-likeness property was checked by applying the Lipinski's rule of five on the furanocoumarins to evaluate anti-breast cancer activity. Antagonist and inhibition assay of ERα, EGFR and mTOR respectively has been performed using appropriate in-vitro techniques. The results confirm that Xanthotoxol has the best docking score for breast cancer followed by Bergapten, Angelicin, Psoralen and Isoimperatorin. Further, the in-vitro results also validate the molecular docking analysis. This study suggests that the selected furanocoumarins can be further investigated and evaluated for breast cancer treatment and management strategies.

Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways.

Oxysterol receptors LXRs (α and ß) are recently reported to be one of the novel and potential therapeutic targets in reducing cell proliferation and tumor growth in different system model. Activation of LXRs is correlated with modification of PI3K/Akt pathway. LXRs are also found to play a critical role in maintaining lipid homeostatais by regulating ABCA1, IDOL, SREBP1, LDLR and also certain lipogenic genes such as FASN and SCD1. In the present study a potential furanocoumarin, Bergapten (BeG) has been evaluated for its anticancer property on Hepatocellular Carcinoma (HCC) on LXR axis. The molecular docking analysis was carried out for BeG on LXR (α & ß) using Maestro tool and compared with reference ligands. This was followed by in vitro (HepG2 cell lines) and in vivo (on NDEA induced HCC in Wistar albino rats) anticancer evaluation of BeG. The docking results revealed polar and hydrophobic interactions of BeG with LXR (α,ß). The in vitro studies revealed the potential of BeG in lowering the accumulation of lipid droplets in HepG2 cells which was correlated with increase in LXR (α,ß) protein expressions. Furthermore, the in vivo studies demonstrated the potential of BeG in ameliorating the cancer induced alterations in body weight, liver weight and significant restoration of the changes in mRNA and protein expressions of LXR(α,ß), ABCA1, IDOL, SREBP1 and LDLR. BeG also modulated the expressions of PI3K, Akt and certain lipogenic genes like FASN and SCD1 and reduced the lipid droplets level in liver cancer cells. These results provide evidence and validates the critical role of BeG in maintaining the lipid homeostasis and justifies its anticancer potential against NDEA-induced HCC.

Taxifolin binds with LXR (α & ß) to attenuate DMBA-induced mammary carcinogenesis through mTOR/Maf-1/PTEN pathway.

AIM: 7,12-dimethylbenz(a)anthracene(DMBA), a PAH derivative initializes cascades of signaling events that alters a variety of enzymes responsible for lipid and glucose homeostasis resulting in enhanced availability and consumption of energy producing molecules for the development of carcinogenesis. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) is a key enzyme regulating the pathway of synthesis of cholesterol whereas liver-X-receptor (LXR) regulates lipid, carbohydrate metabolism in various malignancies including mammary carcinogenesis (MC). In this study Taxifolin (TAX), a potential flavanoid has been subjected to evaluate its anti-cancer potential on (MC). METHODS: We designed to screen the molecular docking analysis of TAX on LXRα, LXRß, HMG-CoAR, mTOR and PTEN using MAESTRO tool comparing with their reference ligands. MC was developed by the administration of DMBA in the air pouch (under the mammary fat pad) of the female Sprague-Dawley rats (55 days old). After 90 days of cancer induction, the chemotherapeutic potential of TAX was evaluated by administering TAX at different doses (10, 20 and 40 mg/kg b.w./day). Then western blot and RT-qPCR analysis were performed for determination of the protein and mRNA expressions respectively. RESULTS: The docking analysis revealed significant interaction with LXR (α&ß), HMG-CoAR, mTOR and PTEN. The docking results were validated with the enzyme inhibition assay using HMG-CoAR (EC 1.1.1.34). TAX inhibited the HMG-CoAR activity with an IC50 value of 97.54 ±â€¯2.5 nM whereas the reference molecule pavastatin revealed an IC50 value of 84.35 ±â€¯1.2 nM. Moreover, TAX modulated the energy regulation on DMBA-induced MC in SD-rats by significantly restoring the cancer-induced alterations in body weight, tumor growth and lipid, lipoproteins, lipid metabolizing enzymes and glycolytic enzymes. TAX interacted with LXRs, HMG-CoAR, metabolic enzymes and restored the altered metabolism that accelerates uncontrolled cell proliferation in MC. Moreover, TAX also altered the mRNA and protein expressions of HMG-CoAR, LXR (α,ß), Maf1, PTEN, phosphoinositide 3-kinase (PI3K), Akt, mTOR, fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in a dose dependent manner. CONCLUSION: These results validate the anti-cancer potential of TAX in DMBA-induced MC through LXR-mTOR/Maf1/PTEN axis.