Molecular Docking of Bacterial Protein Modulators and Pharmacotherapeutics of Carica papaya Leaves as a Promising Therapy for Sepsis: Synchronising In Silico and In Vitro Studies.

Sepsis is a serious health concern globally, which necessitates understanding the root cause of infection for the prevention of proliferation inside the host's body. Phytochemicals present in plants exhibit antibacterial and anti-proliferative properties stipulated for sepsis treatment. The aim of the study was to determine the potential role of Carica papaya leaf extract for sepsis treatment in silico and in vitro. We selected two phytochemical compounds, carpaine and quercetin, and docked them with bacterial proteins, heat shock protein (PDB ID: 4PO2), surfactant protein D (PDB ID: 1PW9), and lactobacillus bacterial protein (PDB ID: 4MKS) against imipenem and cyclophosphamide. Quercetin showed the strongest interaction with 1PW9 and 4MKS proteins. The leaves were extracted using ethanol, methanol, and water through Soxhlet extraction. Total flavonoid content, DPPH assay, HPTLC, and FTIR were performed. In vitro cytotoxicity of ethanol extract was screened via MTT assay on the J774 cell line. Ethanol extract (EE) possessed the maximum number of phytocomponents, the highest amount of flavonoid content, and the maximum antioxidant activity compared to other extracts. FTIR analysis confirmed the presence of N-H, O-H, C-H, C=O, C=C, and C-Cl functional groups in ethanol extract. Cell viability was highest (100%) at 25 µg/mL of EE. The present study demonstrated that the papaya leaves possessed antibacterial and cytotoxic activity against sepsis infection.

ZnO Nanoparticles of Rubia cordifolia Extract Formulation Developed and Optimized with QbD Application, Considering Ex Vivo Skin Permeation, Antimicrobial and Antioxidant Properties.

The objective of the current research is to develop ZnO-Manjistha extract (ZnO-MJE) nanoparticles (NPs) and to investigate their transdermal delivery as well as antimicrobial and antioxidant activity. The optimized formulation was further evaluated based on different parameters. The ZnO-MJE-NPs were prepared by mixing 10 mM ZnSO4·7H2O and 0.8% w/v NaOH in distilled water. To the above, a solution of 10 mL MJE (10 mg) in 50 mL of zinc sulfate was added. Box-Behnken design (Design-Expert software 12.0.1.0) was used for the optimization of ZnO-MJE-NP formulations. The ZnO-MJE-NPs were evaluated for their physicochemical characterization, in vitro release activity, ex vivo permeation across rat skin, antimicrobial activity using sterilized agar media, and antioxidant activity by the DPPH free radical method. The optimized ZnO-MJE-NP formulation (F13) showed a particle size of 257.1 ± 0.76 nm, PDI value of 0.289 ± 0.003, and entrapment efficiency of 79 ± 0.33%. Drug release kinetic models showed that the formulation followed the Korsmeyer-Peppas model with a drug release of 34.50 ± 2.56 at pH 7.4 in 24 h. In ex vivo studies ZnO-MJE-NPs-opt permeation was 63.26%. The antibacterial activity was found to be enhanced in ZnO-MJE-NPs-opt and antioxidant activity was found to be highest (93.14 ± 4.05%) at 100 µg/mL concentrations. The ZnO-MJE-NPs-opt formulation showed prolonged release of the MJE and intensified permeation. Moreover, the formulation was found to show significantly (p < 0.05) better antimicrobial and antioxidant activity as compared to conventional suspension formulations.

Folic acid modified precision nanocarriers: charting new frontiers in breast cancer management beyond conventional therapies.

Breast cancer presents a significant global health challenge, ranking highest incidence rate among all types of cancers. Functionalised nanocarriers offer a promising solution for precise drug delivery by actively targeting cancer cells through specific receptors, notably folate receptors. By overcoming the limitations of passive targeting in conventional therapies, this approach holds the potential for enhanced treatment efficacy through combination therapy. Encouraging outcomes from studies like in vitro and in vivo, underscore the promise of this innovative approach. This review explores the therapeutic potential of FA (Folic acid) functionalised nanocarriers tailored for breast cancer management, discussing various chemical modification techniques for functionalization. It examines FA-conjugated nanocarriers containing chemotherapeutics to enhance treatment efficacy and addresses the pharmacokinetic aspect of these functionalised nanocarriers. Additionally, the review integrates active targeting via folic acid with theranostics, photothermal therapy, and photodynamic therapy, offering a comprehensive management strategy. Emphasising rigorous experimental validation for practical utility, the review underscores the need to bridge laboratory research to clinical application. While these functionalised nanocarriers show promise, their credibility and applicability in real-world settings necessitate thorough validation for effective clinical use.

A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part II: nanocarrier design and development in focus.

INTRODUCTION: The current treatment modalities available for Parkinson's disease (PD) prove inadequate due to the inherent constraints in effectively transporting bioactive compounds across the blood-brain barrier. The utilization of synergistic combinations of multiple drugs in conjunction with advanced nanotechnology, emerges as a promising avenue for the treatment of PD, offering potential breakthroughs in treatment efficacy, targeted therapy, and personalized medicine. AREAS COVERED: This review provides a comprehensive analysis of the efficacy of multifactorial interventions for PD, simultaneously addressing the primary challenges of conventional therapies and highlighting how advanced technologies can help overcome these limitations. Part II focuses on the effectiveness of nanotechnology for improving pharmacokinetics of conventional therapies, through the synergistic use of dual or multiple therapeutic agents into a single nanoformulation. Significant emphasis is laid on the advancements toward innovative integrations, such as CRISPR/Cas9 with neuroprotective agents and stem cells, all effectively synergized with nanocarriers. EXPERT OPINION: By using drug combinations, we can leverage their combined effects to enhance treatment efficacy and mitigate side effects through lower dosages. This article is meant to give nanocarrier-mediated co-delivery of drugs and the strategic incorporation of CRISPR/Cas9, either as an independent intervention or synergized with a neuroprotective agent.

A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part I: exploring theoretical insights and pharmacological advances.

INTRODUCTION: Parkinson's disease (PD) is a neurological condition defined by a substantial reduction in dopamine-containing cells in the substantia nigra. Levodopa (L-Dopa) is considered the gold standard in treatment. Recent research has clearly shown that resistance to existing therapies can develop. Moreover, the involvement of multiple pathways in the nigrostriatal dopaminergic neuronal loss suggests that modifying the treatment strategy could effectively reduce this degeneration. AREAS COVERED: This review summarizes the key concerns with treating PD patients and the combinations, aimed at effectively managing PD. Part I focuses on the clinical diagnosis at every stage of the disease as well as the pharmacological treatment strategies that are applied throughout its course. It methodically elucidates the potency of multifactorial interventions in attenuating the disease trajectory, substantiating the rationale for co-administration of dual or multiple therapeutic agents. Significant emphasis is laid on evidence-based pharmacological combinations for PD management. EXPERT OPINION: By utilizing multiple drugs in a combination fashion, this approach can leverage the additive or synergistic effects of these agents, amplify the spectrum of treatment, and curtail the risk of side effects by reducing the dose of each drug, demonstrating significantly greater efficacy.

Nanoparticle Mediated Gene Therapy: A Trailblazer Armament to Fight CNS Disorders.

Central nervous system (CNS) disorders account for boundless socioeconomic burdens with devastating effects among the population, especially the elderly. The major symptoms of these disorders are neurodegeneration, neuroinflammation, and cognitive dysfunction caused by inherited genetic mutations or by genetic and epigenetic changes due to injury, environmental factors, and disease-related events. Currently available clinical treatments for CNS diseases, i.e., Alzheimer's disease, Parkinson's disease, stroke, and brain tumor, have significant side effects and are largely unable to halt the clinical progression. So gene therapy displays a new paradigm in the treatment of these disorders with some modalities, varying from the suppression of endogenous genes to the expression of exogenous genes. Both viral and non-viral vectors are commonly used for gene therapy. Viral vectors are quite effective but associated with severe side effects, like immunogenicity and carcinogenicity, and poor target cell specificity. Thus, non-viral vectors, mainly nanotherapeutics like nanoparticles (NPs), turn out to be a realistic approach in gene therapy, achieving higher efficacy. NPs demonstrate a new avenue in pharmacotherapy for the delivery of drugs or genes to their selective cells or tissue, thus providing concentrated and constant drug delivery to targeted tissues, minimizing systemic toxicity and side effects. The current review will emphasize the role of NPs in mediating gene therapy for CNS disorders treatment. Moreover, the challenges and perspectives of NPs in gene therapy will be summarized.

Nanotechnology revolutionises breast cancer treatment: harnessing lipid-based nanocarriers to combat cancer cells.

One of the most common cancers that occur in females is breast cancer. Despite the significant leaps and bounds that have been made in treatment of breast cancer, the disease remains one of the leading causes of death among women and a major public health challenge. The therapeutic efficacy of chemotherapeutics is hindered by chemoresistance and toxicity. Nano-based lipid drug delivery systems offer controlled drug release, nanometric size and site-specific targeting. Breast cancer treatment includes surgery, chemotherapy and radiotherapy. Despite this, no single method of treatment for the condition is currently effective due to cancer stem cell metastasis and chemo-resistance. Therefore, the employment of nanocarrier systems is necessary in order to target breast cancer stem cells. This article addresses breast cancer treatment options, including modern treatment procedures such as chemotherapy, etc. and some innovative therapeutic options highlighting the role of lipidic nanocarriers loaded with chemotherapeutic drugs such as nanoemulsion, solid-lipid nanoparticles, nanostructured lipid carriers and liposomes, and their investigations have demonstrated that they can limit cancer cell growth, reduce the risk of recurrence, as well as minimise post-chemotherapy metastasis. This article also explores FDA-approved lipid-based nanocarriers, commercially available formulations, and ligand-based formulations that are being considered for further research.

Rubia cordifolia L. Attenuates Diabetic Neuropathy by Inhibiting Apoptosis and Oxidative Stress in Rats.

BACKGROUND: Diabetic neuropathy is a debilitating manifestation of long-term diabetes mellitus. The present study explored the effects of the roots of Rubia cordifolia L. (R. cordifolia L.) in the Wistar rat model for diabetic neuropathy and possible neuroprotective, antidiabetic, and analgesic mechanisms underlying this effect. MATERIALS AND METHODS: Rats were divided into five experimental groups. An amount of 0.25% carboxy methyl cellulose (CMC) in saline and streptozotocin (STZ) (60 mg/kg) was given to group 1 and group 2, respectively. Group 3 was treated with STZ and glibenclamide simultaneously while groups 4 and 5 were simultaneously treated with STZ and hydroalcoholic extract of the root of R. cordifolia, respectively. Hot plate and cold allodynias were used to evaluate the pain threshold. The antioxidant effects of R. cordifolia were assessed by measuring Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). At the end of the study, sciatic nerve and brain tissues were collected for histopathological study. Bcl-2 proteins, cleaved caspase-3, and Bax were assessed through the Western blot method. RESULTS: R. cordifolia significantly attenuated paw withdrawal and tail flick latency in diabetic neuropathic rats. R. cordifolia significantly (p < 0.01) improved the levels of oxidative stress. It was found to decrease blood glucose levels and to increase animal weight in R. cordifolia-treated groups. Treatment with R. cordifolia suppressed the cleaved caspase-3 and reduced the Bax:Bcl2 ratio in sciatic nerve and brain tissue compared to the diabetic group. Histopathological analysis also revealed a marked improvement in architecture and loss of axons in brain and sciatic nerve tissues at a higher dose of R. cordifolia (400 mg/kg). CONCLUSION: R. cordifolia attenuated diabetic neuropathy through its antidiabetic and analgesic properties by ameliorating apoptosis and oxidative stress.

Ribociclib Nanostructured Lipid Carrier Aimed for Breast Cancer: Formulation Optimization, Attenuating In Vitro Specification, and In Vivo Scrutinization.

PURPOSE: The current investigation is on the explicit development and evaluation of nanostructured lipidic carriers (NLCs) through the oral route to overcome the inherent lacuna of chemotherapeutic drug, in which Ribociclib (RBO) was used for breast cancer to diminish the bioavailability issue. METHOD: The RBO-NLCs were prepared using the solvent evaporation method and optimized method by the Box-Behnken design (BBD). Various assessment parameters characterized the optimized formulation and their in vivo study. RESULTS: The prepared NLCs exhibited mean particle size of 114.23 ± 2.75 nm, mean polydispersity index of 0.649 ± 0.043, and high entrapment efficiency of 87.7 ± 1.79%. The structural analysis by TEM revealed the spherical size of NLCs and uniform drug distribution. An in vitro drug release study was established through the 0.1 N HCl pH 1.2, acetate buffer pH 4.5, and phosphate buffer pH 6.8 with % cumulative drug release of 86.71 ± 8.14, 85.82 ± 4.58, and 70.98 ± 5.69%, was found respectively, compared with the RBO suspension (RBO-SUS). In vitro intestinal gut permeation studies unveiled a 1.95-fold gain in gut permeation by RBO-NLCs compared with RBO-SUS. In vitro lipolysis suggests the drug availability at the absorption site. In vitro haemolysis study suggests the compatibility of NLCs to red blood cells compared to the suspension of the pure drug. The confocal study revealed the depth of penetration of the drug into the intestine by RBO-NLCs which was enhanced compared to RBO-SUS. A cell line study was done in MCF-7 and significantly reduced the IC50 value compared to the pure drug. The in vivo parameters suggested the enhanced bioavailability by 3.54 times of RBO-NLCs as compared to RBO-SUS. CONCLUSION: The in vitro, ex vivo, and in vivo results showed a prominent potential for bioavailability enhancement of RBO and effective breast cancer therapy.

An Insight to Brain Targeting Utilizing Polymeric Nanoparticles: Effective Treatment Modalities for Neurological Disorders and Brain Tumor.

The delivery of therapeutic molecules to the brain remains an unsolved problem to the researchers due to the existence of the blood-brain barrier (BBB), which halts the entry of unwanted substances to the brain. Central nervous system (CNS) disorders, mainly Parkinson's disease, Alzheimer's disease, schizophrenia, brain tumors, and stroke, are highly prevalent globally and are a growing concern for researchers due to restricting the delivery of pharmaceutical drugs to the brain. So effective treatment modalities are essential to combat the growing epidemic of CNS diseases. Recently, the growing attention in the field of nanotechnology has gained the faith of researchers for the delivery of therapeutics to the brain by targeting them to the specific target site. Polymeric nanoparticles (PNPs) emerge out to be an instrumental approach in drug targeting to the brain by overcoming the physiological barrier, biomedical barrier, and BBB. Preclinical discovery has shown the tremendous potential and versatility of PNPs in encapsulating several drugs and their targeting to the deepest regions of the brain, thus improving therapeutic intervention of CNS disorders. The current review will summarize advances in the development of PNPs for targeting therapeutics to the brain and the functional and molecular effects obtained in the preclinical model of most common CNS diseases. The advancement of PNPs in clinical practice and their prospect in brain targeting will also be discussed briefly.

Combinatorial delivery of Ribociclib and green tea extract mediated nanostructured lipid carrier for oral delivery for the treatment of breast cancer synchronising in silico, in vitro, and in vivo studies.

PURPOSE: The current research investigated the development and evaluation of dual drug-loaded nanostructure lipidic carriers (NLCs) of green tea extract and Ribociclib. METHOD: In silico study were performed to determine the effectiveness of combinational approach. The prepared NLCs were subjected to in vitro drug release, lipolysis, haemolysis and cell line studies to assess their in vivo prospect. RESULTS: In silico study was done to get docking score of EGCG (-8.98) close to Ribociclib (-10.78) in CDK-4 receptors. The prepared NLCs exhibited particle size (175.80 ± 3.51 nm); PDI (0.571 ± 0.012); and %EE [RBO (80.91 ± 1.66%) and GTE 75.98 ± 2.35%)] respectively. MCF-7 cell lines were used to evaluate the MTT assay, cellular uptake and antioxidant (ROS and SOD) of prepared NLCs. In vitro drug release showed the controlled release up to 72 h. In vitro lipolysis and in vitro haemolysis studies showed the availability of drugs at absorption sites and the greater in vivo prospects of NLCs respectively. Pharmacokinetic study revealed a 3.63-fold and 1.53-fold increment in RBO and GTE bioavailability in female Wistar rats respectively. CONCLUSION: The prominent potential of green tea extract and RBO-loaded NLCs in enhancing their therapeutic efficacy for better treatment of breast cancer.

An Overview of the Neuropharmacological Potential of Thymoquinone and its Targeted Delivery Prospects for CNS Disorder.

At present, people and patients worldwide are relying on the medicinal plant as a therapeutic agent over pharmaceuticals because the medicinal plant is considered safer, especially for chronic disorders. Several medicinal plants and their components are being researched and explored for their possible therapeutic contribution to CNS disorders. Thymoquinone (TQ) is one such molecule. Thymoquinone, one of the constituents of Plant Nigella Sativa, is effective against several neurodegenerative diseases like, Alzheimer's, Depression, Encephalomyelitis, Epilepsy, Ischemia, Parkinson's, and Traumatic. This review article presents the neuropharmacological potential of TQ's, their challenges, and delivery prospects, explicitly focusing on neurological disorders along with their chemistry, pharmacokinetics, and toxicity. Since TQ has some pharmacokinetic challenges, scientists have focused on novel formulations and delivery systems to enhance bioavailability and ultimately increase its therapeutic value. In the present work, the role of nanotechnology in neurodegenerative disease and how it improves the bioavailability and delivery of a drug to the site of action has been discussed. There are a few limitations to developing novel drug formulations, including solubility, pH, and compatibility of nanomaterials. Since here we are targeting CNS disorders, the bloodbrain barrier (BBB) becomes an additional challenge. Hence, the review summarized the novel aspects of delivery and biocompatible nanoparticles-based approaches for targeted drug delivery into CNS, enhancing TQ bioavailability and its neurotherapeutic effects.

Assessment of Combination Approaches of Phytoconstituents with Chemotherapy for the Treatment of Breast Cancer: A Systematic Review.

OBJECTIVE: Available conventional therapies are commonly used for the treatment of breast cancer, such as surgical procedures, hormonal therapy, radiation therapy, and chemotherapy. These therapies can be either given alone or in combination with other therapies. Various side effects associated with chemotherapies, including toxicity and multidrug resistance, have limited the use of chemotherapy, thus making it less effective than the above mentioned therapies. This review focus has been summarised as the application of anticancer with phytoconstituents that could be a promising and effective treatment strategy for breast cancer treatment. METHODS: This review is designed on relevant literature that was screened on the basis of in-scope criteria in the title, abstract, and keywords of the searched articles. The available literature was searched on PubMed, ScienceDirect, MedlinePlus, and Google scholar up to May 2021. A total of 47 articles were selected out of 168 articles based on inclusion and exclusion criteria. RESULTS: The major limitations accompanying available conventional treatment, mainly chemotherapy, include low bioavailability at the specific site of tumor cells, the occurrence of multidrug resistance, and high doserelated side effects. The phytoconstituents possessing anticancer properties and, when used in combination with chemotherapeutic agents, impart promising and potential therapeutic value. Many in vitro and in vivo studies showed that phytoconstituents could enhance the effectiveness of chemotherapy drugs for breast cancer treatment. CONCLUSION: The combination approaches of phytoconstituents with chemotherapeutic drugs provide less toxicity to normal cells, reduce side effects, and overcome multidrug resistance, thus making the combination approaches an effective strategy for the treatment of breast cancer.

Polymeric Nanoparticles: Exploring the Current Drug Development and Therapeutic Insight of Breast Cancer Treatment and Recommendations.

This manuscript aims to provide the latest update on polymeric nanoparticle drug delivery system for breast cancer treatment after 2015 and how research-oriented it is based on the available research data. Therefore, the authors have chosen breast cancer which is the most frequent and common reason for mortality in women worldwide. The first-line treatment for breast cancer treatment is chemotherapy, apart from surgery, radiation and hormonal therapy. Chemotherapy is associated with lesser therapeutics and undesirable side effects and hence. In addition, drug resistance affects the therapeutic dose to the target site. Although various nano-based formulations have been developed for effective treatment, the polymeric nanoparticles effectively avoid the lacunae of conventional chemotherapy. There has been an effort made to understand the chemotherapy drugs and their conventional formulation-related problems for better targeting and effective drug delivery for breast cancer treatment. Thus, the polymeric nanoparticles as a strategy overcome the associated problems with resulting dose reduction, enhanced bioavailability, reduced side effects, etc. This present review has compiled the research reports published from 2015 to 2021 from different databases, such as PubMed, Google Scholar, ScienceDirect, which are related to breast cancer treatment in which the drug delivery of numerous chemotherapeutic agents alone or in combination, including phytoconstituents formulated into various polymer-based nanoparticles.

Nanomedicine: A Promising Avenue for the Development of Effective Therapy for Breast Cancer.

PURPOSE: Breast cancer is the most probable cancer among women. However, the available treatment is based on targeting different stages of breast cancer viz., radiation therapy, hormonal therapy, chemotherapy, and surgical interventions, which have some limitations. The available chemotherapeutics are associated with problems like low solubility, low permeability, high first-pass metabolism, and P-glycoprotein efflux. Hence, the aforementioned restrictions lead to ineffective treatment. Multiple chemotherapeutics can also cause resistance in tumors. So, the purpose is to develop an effective therapeutic regimen for the treatment of breast cancer by applying a nanomedicinal approach. METHODS: This review has been conducted on a systematic search strategy, based on relevant literature available on Pub Med, MedlinePlus, Google Scholar, and Sciencedirect up to November 2019 using keywords present in abstract and title of the review. As per our inclusion and exclusion criteria, 226 articles were screened. Among 226, a total of 40 articles were selected for this review. RESULTS: The significant findings with the currently available treatment is that the drug, besides its distribution to the target-specific site, also distributes to healthy cells, which results in severe side effects. Moreover, the drug is less bioavailable at the site of action; therefore, to overcome this, a high dose is required, which again causes side effects and lower the benefits. Nanomedicinal approaches give an alternative approach to avoid the associated problems of available chemotherapeutics treatment of breast cancer. CONCLUSION: The nanomedicinal strategies are useful over the conventional treatment of breast cancer and deliver a target-specific drug-using different novel drug delivery approaches.

Paediatric Urinary Tract Infection: A Hospital Based Experience.

INTRODUCTION: Paediatric Urinary Tract Infection (UTI) is one of the commonly encountered entities by paediatricians. Studies have shown easy vulnerability of paediatric urinary tract in any acute febrile illness and a miss in diagnosis could have long term consequences like renal scaring with its adverse effects. Bearing these evidence based preludes in view we designed our study to know the prevalence of UTI in Kashmir province. AIM: Aim of the present study was to know the prevalence of UTI in febrile children and to know the sensitivity of different imaging modalities like Renal and Urinary Bladder Ultrasonography (RUS), Voiding Cystourethrography (VCUG) and Dimercaptosuccinic Acid (DMSA) scan in diagnosing UTI. MATERIALS AND METHODS: A total of 304 patients, between 2 months to 10 years, with axillary temperature of ≥ 100.4oF (38oC), who did not have a definite source for their fever and who were not on antibiotics were included in the study. Detailed history and through clinical examination was done to rule out any potential or definite focus of infection as per the predesigned proforma. Routine urine examination with culture and sensitivity, followed by RUS and VCUG was done in all patients where routine urine examination was suggestive of UTI. DMSA was done in only culture proven cases after 6 months to document the renal scarring. RESULTS: Out of 304 children, 140 were males and 164 were females, UTI was present in 40 patients who had fever without any apparent cause giving a prevalence of 13.2%. Escherichia coli (E. coli) were the commonest isolated organism, followed by Klebsiella and Citrobacter species. Renal and Urinary Bladder Ultrasonography (RUS) detected Vesicoureteral Reflux (VUR) in 25% (10/40) while VCUG showed VUR in 55% (22/40) giving a RUS sensitivity of 45% for detecting VUR. DMSA done only after 6 months in UTI diagnosed patients showed a renal scarring in 25% (10/40) patients. CONCLUSION: Missing a febrile paediatric UTI, can prove a future catastrophe if not timely diagnosed and treated.