Assessing the impact of MSH3 and MSH6 polymorphisms on lung cancer risk in North Indian patients undergoing platinum chemotherapy through molecular dynamics simulation.

The present study investigated the relationship between MSH3 and MSH6 genes in lung cancer patients. Genotyping of lung cancer patients and healthy controls was performed. Odds ratio values were calculated and survival analysis performed. Patients with mutant genotype (TT) for MSH6 polymorphism have 1.5-fold risk for the development of lung cancer (p = 0.03). For non-smokers, the mutant-type genotype had a threefold increased risk of lung cancer (p = 0.01). Patients administered with docetaxel and carbo/cisplatin and carrying GT genotype for MSH6 polymorphism, patients reported a decrease in median survival time (4.9 vs 9.13 months). MSH3 and MSH6 polymorphisms are involved in modulating the risk towards lung cancer. MSH6 polymorphism is associated with high mortality rate for patients undergoing cisplatin and docetaxel chemotherapy.

Regulatory landscape and challenges in CAR-T cell therapy development in the US, EU, Japan, and India.

Chimeric Antigen Receptor-T cell (CAR-T) therapy has evolved as a revolutionary cancer treatment modality, offering remarkable clinical responses by harnessing the power of a patient's immune system to target and eliminate cancer cells. However, the development and commercialization of CAR-T cell therapies are accompanied by complex regulatory requirements and challenges. This therapy falls under the regulatory category of advanced therapy medicinal products. The regulatory framework and approval tools of regenerative medicine, especially CAR-T cell therapies, vary globally. The present work comprehensively analyses the regulatory landscape and challenges in CAR-T cell therapy development in four key regions: the United States, the European Union, Japan, and India. This work explores the unique requirements and considerations for preclinical studies, clinical trial design, manufacturing standards, safety evaluation, and post-marketing surveillance in each jurisdiction. Due to their complex nature, developers and manufacturers face several challenges. In India, despite advancements in treatment protocols and government-sponsorships, there are still several difficulties regarding access to treatment for the increasing number of cancer patients. However, India's first indigenously developed CAR-T cell therapy, NexCAR19, for B-cell lymphoma or leukemia, approved and available at a low cost compared to other available CAR-T therapies, raises great hope in the battle against cancer. Several strategies are proposed to address the identified hurdles from global and Indian perspectives. It discusses the benefits of aligning regulatory requirements across regions, eventually facilitating international development and enabling access to this transformative therapy.

Enhancing cancer immunotherapy: Exploring strategies to target the PD-1/PD-L1 axis and analyzing the associated patent, regulatory, and clinical trial landscape.

Cancer treatment modalities and their progression is guided by the specifics of cancer, including its type and site of localization. Surgery, radiation, and chemotherapy are the most often used conventional treatments. Conversely, emerging treatment techniques include immunotherapy, hormone therapy, anti-angiogenic therapy, dendritic cell-based immunotherapy, and stem cell therapy. Immune checkpoint inhibitors' anticancer properties have drawn considerable attention in recent studies in the cancer research domain. Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) checkpoint pathway are key regulators of the interactions between activated T-cells and cancer cells, protecting the latter from immune destruction. When the ligand PD-L1 attaches to the receptor PD-1, T-cells are prevented from destroying cells that contain PD-L1, including cancer cells. The PD-1/PD-L1 checkpoint inhibitors block them, boosting the immune response and strengthening the body's defenses against tumors. Recent years have seen incredible progress and tremendous advancement in developing anticancer therapies using PD-1/PD-L1 targeting antibodies. While immune-related adverse effects and low response rates significantly limit these therapies, there is a need for research on methods that raise their efficacy and lower their toxicity. This review discusses various recent innovative nanomedicine strategies such as PLGA nanoparticles, carbon nanotubes and drug loaded liposomes to treat cancer targeting PD-1/PD-L1 axis. The biological implications of PD-1/PD-L1 in cancer treatment and the fundamentals of nanotechnology, focusing on the novel strategies used in nanomedicine, are widely discussed along with the corresponding guidelines, clinical trial status, and the patent landscape of such formulations.

Immobilization of catalase on functionalized magnetic nanoparticles: a statistical approach.

Magnetic nanoparticles (MNPs) Fe3O4, by virtue of easily modifiable surface, high surface-to-mass ratio and super-paramagnetic properties, are one of suitable candidates for the enzyme immobilization. Optimization of five important variables viz. concentration of 3-aminopropyl-tri-ethoxy-silane (APTES), glutaraldehyde (GA) and enzyme, time and temperature of loading was carried out using central composite type of experimental design without blocks giving 50 experiments including eight replicates at the central point. Characterization, stability and reusability studies were also carried out with optimized preparation. Results established the correlation between observed and response surface method (RSM) equation envisaged value (R 2 0.99, 0.97 and 0.98 for enzyme's activity, its loading over MNPs and corresponding specific activity, respectively. The predicted values suggested by RSM equation were 64.00 mM of APTES, 10.97 µL of GA, 14.50 mg mL-1 of enzyme for 67 min at 22.6 °C, resulted in activity 32.1 U mg-1 MNPs, while specific activity was 97.7 U mg-1. Transmission electron microscopy (TEM) showed the sizes of MNPs (10.5 ± 1.7 nm), APTES-MNPs (10.23 ± 1.74 nm), GA-APTES-MNPs (11.84 ± 1.49 nm) and Catalase-GA-APTES-MNPs (13.32 ± 2.74 nm) were statistically similar. The enzyme MNPs preparation retained 81.65% activity after 144 h at 4 °C (free enzyme retained 7.87%) and 64.34% activity after 20 reuse cycles. Statistical optimized MNPs-based catalase preparation with high activity and magnetic strength was stable and can be used for further studies related to its application as analytical recyclable enzyme or magnetically oriented delivery in the body. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03173-8.

Antidepressant and anxiolytic effects of Garcinia indica fruit rind via monoaminergic pathway.

Depression and anxiety are the most crippling neuropsychiatric disorders of this modern era. These mostly occur as anxiety followed by depression or in mixed state. Therefore, there is an urgent need of a safe and effective treatment, which proves its worth in this ailment. What else than a conventional food would be a better choice for a convenient therapy. Therefore, Garcinia indica, commonly known as Kokam, fruit rind has been used in the present study to investigate its antidepressant and anti-anxiety potential using forced swim test, tail suspension test, and reserpine-induced hypothermia; and elevated plus maze, hole-board test, and light dark model, respectively. Garcinia indica fruit rind given to mice with food for consecutive 14 days at 0.5, 1, and 2% w/w significantly (p < 0.05) reduced despair behavior in forced swim test, immobility duration in tail suspension test, and also switched the hypothermia (reserpine induced) to normal temperature significantly (p < 0.05). Garcinia indica significantly (p < 0.05) raised the time elapsed and count of entries in open arms of elevated plus maze, enhanced incidence of head dipping in holes of hole board along with duration of expending time in lit compartment of light dark model, exhibiting its anti-anxiety effect. Garcinia indica significantly reduced monoamine oxidase and malondialdehyde levels providing support to neuroprotective potential of fruit rind. The mechanistic study showed the participation of G. indica at α1-adrenoceptor and D2-dopamine receptor, by attenuating prazosin and sulpiride-induced increase in immobility duration. Garcinia indica fruit rind showed a significant antidepressant and anxiolytic effect while no effect on locomotor activity, i.e., no psycho-stimulation.

Chitosan-assisted immobilization of serratiopeptidase on magnetic nanoparticles, characterization and its target delivery.

BACKGROUND: Magnetic nanoparticles (MNPs) gained attentions as universal carrier for drug delivery and for enzyme immobilization. PURPOSE: Target delivery of serratiopeptidase for treatment using this enzyme and applications in drug delivery. METHOD: Serratiopeptidase was immobilized on chitosan amino-functionalized MNPs by covalent bonding through glutaraldehyde. Targeting of MNPs with immobilized enzyme (EMNPs) was carried out in vitro in modified diffusion cell and in vivo in rats. RESULTS AND DISCUSSION: MNPs and EMNPs were 15.43 ± 5.22 and 18.43 ± 3.23 nm (transmission electron microscopy), crystallite size 16.89 and 21.05 nm (X-ray diffraction) and saturation magnetization 62 and 35.2 emug(-1), respectively. Maximum protein and enzyme loading on EMNPs were 264 mg g(-1) and 325 U g(-1), respectively. In the molecular level, maximum 52 enzyme molecules could bind to each particle showing residual activity 68%, little effect on KM and Vmax, good storage stability. Magnetic targeting of EMNPs increased the delivery (permeation) of drug through membrane in vitro and the enhanced anti-inflammatory effect on carrageenan-induced paw oedema in rats in vivo at much lower doses of enzyme than the doses required for treatment with free enzyme. CONCLUSIONS: The enzymatic preparation of MNPs showed enhanced effects (permeation enhancement and anti-inflammatory activity) at lower concentration with magnetic targeting.

Preparation, characterization and targeted delivery of serratiopeptidase immobilized on amino-functionalized magnetic nanoparticles.

Targeted delivery of serratiopeptidase enzyme immobilized on magnetic nanoparticles (MNPs) of Fe3O4 has been reported for the treatment using this enzyme. The enzyme was immobilized by covalent bonding through glutaraldehyde after amino functionalization of MNPs and parameters was studied. The enzyme bound MNPs (EMNPs) were characterized for size, crystallographic identity, phase purity, zeta potential and magnetic properties along with elemental and thermal analysis. The binding of enzyme had little effect on sizes (~10-17 nm) and on magnetic properties, but the zeta potential increased from -25 mV to +14.5 mV with surface amino groups up to 350 µmoles g(-1) MNPs, to stabilize its suspensions. In the molecular level, maximum of 17 molecules of enzyme could bind to each particle of MNPs that showed residual activity 67%, decreased KM and Vmax, good storage stability. Magnetic targeting of EMNPs increased the delivery (permeation) of drug through the membrane in in vitro study and enhanced the anti-inflammatory effect on carrageenan induced paw oedema in rats in in vivo study at much lower doses of enzyme than the doses required for treatment with free enzyme.

Preliminary evaluation of in vitro cytotoxicity and in vivo antitumor activity of Premna herbacea Roxb. in Ehrlich ascites carcinoma model and Dalton's lymphoma ascites model.

In the present study, the root nodules of Premna herbacea Roxb. (PH) was investigated for its in vitro cytotoxicity and in vivo antitumor activity. Two extracts, aqueous and alcoholic; two fractions of alcoholic extract, ethyl acetate and butanol fractions were screened for their in vitro cytotoxicity by brine shrimp lethality (BSL) assay, trypan blue exclusion assay and MTT assay. Alcoholic extract and its ethyl acetate fraction were found to be the most effective in BSL assay, trypan blue exclusion assay. In vivo antitumor activity was screened in the Ehrlich ascites carcinoma (EAC) model and the Dalton lymphoma ascites (DLA) model. The extracts and the fractions were tested at two dosages (250 and 500 mg/kg) by intraperitoneally (i.p.) route on every alternate day upto 13th day. Cisplatin was used as positive control in both studies in single dose (day 1) 3.5 mg/kg by i.p. route. In EAC model, ascites tumor was induced by inoculating 2.5 million of EAC cells i.p. alcoholic extract at 500 mg/kg was the most effective in elevating MST, reduction in body weight in EAC induced tumor. Only the effective extract i.e., alcoholic extract were studied for hematological and antioxidant parameter. It showed a restoring effect on altered hematological parameters and a significant improvement in biochemical parameters at 250 mg/kg dose of alcoholic extract. These results explain the toxicity of 500 mg/kg might be high. In the Dalton lymphoma ascites (DLA) model, solid tumor was developed by i.m. injection of 1 million DLA cells. Both the extracts and the fractions possessed potent antitumor activity against solid tumor models by significantly reducing the solid tumor weight and volume.