Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.

Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-ß, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.

Design and Development of a Non-invasive Opto-Electronic Sensor for Blood Glucose Monitoring Using a Visible Light Source.

Background The management of diabetes is critically dependent on the continuous monitoring of blood glucose levels. Contemporary approaches primarily utilize invasive methods, which often prove to be uncomfortable and can deter patient adherence. There is a pressing need for the development of novel strategies that improve patient compliance and simplify the process of glucose monitoring. Aim and objectives The primary objective of this research is to develop a non-invasive blood glucose monitoring system (NIBGMS) that offers a convenient alternative to conventional invasive methods. This study aims to demonstrate the feasibility and accuracy of using visible laser light at a wavelength of 650 nm for glucose monitoring and to address physiological and technical challenges associated with in vivo measurements. Methods Our approach involved the design of a device that exploits the quantitative relationship between glucose concentration and the refraction phenomena of laser light. The system was initially calibrated and tested using glucose solutions across a range of concentrations (25-500 mg/dL). To get around the problems that come up when people's skin and bodies are different, we combined an infrared (IR) transmitter (800 nm) and receiver that checks for changes in voltage, which are indicative of glucose levels. Results The prototype device was compared with a commercially available blood glucose monitor (Accu-Chek active machine; Roche Diabetes Care, Inc., Mumbai, India). The results demonstrated an average linearity of 95.7% relative to the Accu-Chek machine, indicating a high level of accuracy in the non-invasive measurement of glucose levels. Conclusions The findings suggest that our NIBGMS holds significant promise for clinical application. It reduces the discomfort associated with blood sampling and provides reliable measurements that are comparable to those of existing invasive methods. The successful development of this device paves the way for further commercial translation and could significantly improve the quality of life for individuals with diabetes, by facilitating easier and more frequent monitoring.

Corrigendum to 'Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics' [Genes & Diseases 10 (2023) 1367-1401].

[This corrects the article DOI: 10.1016/j.gendis.2022.02.007.].

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Formulation of Carnosic-Acid-Loaded Polymeric Nanoparticles: An Attempt to Endorse the Bioavailability and Anticancer Efficacy of Carnosic Acid against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered to be one of the most difficult subtypes of breast cancer (BC) to treat. The sheer absence of certain receptors makes it very tough to target, leaving high-dose chemotherapy as probably the sole therapeutic option at the cost of nonspecific toxic effects. Carnosic acid (CA) has been established as a potential chemotherapeutic agent against a range of cancer cells. However, its in vivo chemotherapeutic potential is significantly challenged due to its poor pharmacokinetic attributes. In this study, poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were formulated to circumvent the biopharmaceutical limitations of CA. CA-loaded polymeric NPs (CA-PLGA NPs) have been evaluated as a potential therapeutic option in the treatment of TNBC. Different in vitro studies exhibited that CA-PLGA NPs significantly provoked oxidative-stress-mediated apoptotic death in MDA-MB-231 cells. The improved anticancer potential of CA-PLGA NPs over CA was found to be associated with improved cellular uptake of the nanoformulation by TNBC cells. In vivo studies also established the improvement in the chemotherapeutic efficacy of CA-nanoformulation over that of free CA without showing any sign of systemic toxicity. Thus, CA-PLGA NPs emerge as a promising candidate to fix two bugs with a single code, resolving biopharmaceutical attributes of CA as well as introducing a treatment option for TNBC.

Formulation of silver nanoparticles using Duabanga grandiflora leaf extract and evaluation of their versatile therapeutic applications.

The current research focused on the green synthesis of silver nanoparticles (AgNPs) using Duabanga grandiflora leaf extract. The green synthesis of AgNPs was confirmed by the surface plasmon resonance band at 453 nm in a UV-Visible analysis. The formulated AgNPs had a diameter of around 99.72 nm with a spherical shape. Fourier transform infrared (FTIR) spectrum revealed the bio-reducing potential of phytochemicals present in D. grandiflora, which fundamentally influenced the synthesis of AgNPs. Zeta potential, dynamic light scattering (DLS), scanning electron microscopic (SEM), energy-dispersive X-ray spectroscopic (EDX), X-ray diffraction (XRD), and transmission electron microscopic (TEM) analyses were executed to reveal the physicochemical attributes of the AgNPs. The AgNPs were further investigated for their antioxidant, antidiabetic, anticancer, and antibacterial potential. The DPPH free radical assay revealed the potential radical scavenging capacity (IC50 = 76.73 µg/ml) of green synthesized AgNPs. α-Amylase inhibitory assay displayed significant inhibitory potential (IC50 = 162.11 µg/ml) of this starch-breaking enzyme by AgNPs, revealing the antidiabetic potential of AgNPs. AgNPs exhibited potential cytotoxic activity (IC50 = 244.57 µg/ml) against malignant human kidney cells. In addition, AgNPs showed outstanding antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacterial strains. Interestingly, AgNPs showed cytotoxic and antimicrobial activities at much higher concentrations than radical scavenging and α-amylase inhibitory concentrations. Thus, our finding elaborated the scope of green synthesized AgNPs for diverse therapeutic applications (dose-dependent) for further clinical translation.

Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance.

The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.

Papaya peel extract-mediated green synthesis of zinc oxide nanoparticles and determination of their antioxidant, antibacterial, and photocatalytic properties.

This study describes an effective and eco-friendly approach to the synthesis of zinc oxide nanoparticles (ZnONPs) utilizing papaya fruit peel extract (PPE). The structural evaluation and morphological features of synthesized ZnONPs were examined using various physicochemical analyses. The formulated ZnONPs were spherical to hexagonal in shape with ⁓ 170 nm in diameter. ZnONPs exhibited improved antioxidant potential in terms of DPPH radical scavenging activity (IC50 = 98.74 µg/ml) and ferric-reducing potential compared with PPE. The antibacterial activity of ZnONPs was measured against pathogenic strains of Salmonella typhi, Bacillus subtilis, Staphylococcus aureus, and Escherichia coli. The biosynthesized ZnONPs showed potential antibacterial efficacy against all microbes. In addition, ZnONPs exhibited potential photocatalytic activity in rhodamine B degradation in the presence of sunlight. The results indicated that papaya peels, which are these fruit wastes, could be helpful for the green synthesis of ZnONPs with good dose-responsive antioxidant, antibacterial, and photocatalytic activities.

Nanomedicines for the management of diabetic nephropathy: present progress and prospects.

Diabetic nephropathy (DN) is a serious microvascular consequence of diabetes mellitus (DM), posing an encumbrance to public health worldwide. Control over the onset and progress of DN depend heavily on early detection and effective treatment. DN is a major contributor to end-stage renal disease, and a complete cure is yet to be achieved with currently available options. Though some therapeutic molecules have exhibited promise in treating DN complications, their poor solubility profile, low bioavailability, poor permeation, high therapeutic dose and associated toxicity, and low patient compliance apprehend their clinical usefulness. Recent research has indicated nano-systems as potential theranostic platforms displaying futuristic promise in the diagnosis and treatment of DN. Early and accurate diagnosis, site-specific delivery and retention by virtue of ligand conjugation, and improved pharmacokinetic profile are amongst the major advantages of nano-platforms, defining their superiority. Thus, the emergence of nanoparticles has offered fresh approaches to the possible diagnostic and therapeutic strategies regarding DN. The present review corroborates an updated overview of different types of nanocarriers regarding potential approaches for the diagnosis and therapy of DN.

Carbon Dots' Potential in Wound Healing: Inducing M2 Macrophage Polarization and Demonstrating Antibacterial Properties for Accelerated Recovery.

Bacterial infections and persistent inflammation can impede the intrinsic healing process of wounds. To combat this issue, researchers have delved into the potential use of carbon dots (CDs) in the regulation of inflammation and counteract infections. These CDs were synthesized using a microwave-assisted hydrothermal process and have demonstrated outstanding antibacterial and antibiofilm properties against Gram-positive and Gram-negative bacteria. Additionally, CDs displayed biocompatibility at therapeutic concentrations and the ability to specifically target mitochondria. CD treatment effectively nullified lipopolysaccharide-triggered reactive oxygen species production by macrophages, while simultaneously promoting macrophage polarization toward an anti-inflammatory phenotype (M2), leading to a reduction in inflammation and an acceleration in wound healing. In vitro scratch assays also revealed that CDs facilitated the tissue-repairing process by stimulating epithelial cell migration during reepithelialization. In vivo studies using CDs topically applied to lipopolysaccharide (LPS)-stimulated wounds in C57/BL6 mice demonstrated significant improvements in wound healing due to enhanced fibroblast proliferation, angiogenesis, and collagen deposition. Crucially, histological investigations showed no indications of systemic toxicity in vital organs. Collectively, the application of CDs has shown immense potential in speeding up the wound-healing process by regulating inflammation, preventing bacterial infections, and promoting tissue repair. These results suggest that further clinical translation of CDs should be considered.

Non-small cell lung carcinoma (NSCLC): Implications on molecular pathology and advances in early diagnostics and therapeutics.

Continuous revision of the histologic and stage-wise classification of lung cancer by the World Health Organization (WHO) provides the foundation for therapeutic advances by promoting molecular targeted and immunotherapies and ensuring accurate diagnosis. Cancer epidemiologic data provide helpful information for cancer prevention, diagnosis, and management, supporting health-care interventions. Global cancer mortality projections from 2016 to 2060 show that cancer will overtake ischemic heart diseases (IHD) as the leading cause of death (18.9 million) immediately after 2030, surpassing non-small cell lung cancer (NSCLC), which accounts for 85 percent of lung cancers. The clinical stage at the diagnosis is the main prognostic factor in NSCLC therapies. Advanced early diagnostic methods are essential as the initial stages of cancer show reduced mortality compared to the advanced stages. Sophisticated approaches to proper histological classification and NSCLC management have improved clinical efficiency. Although immune checkpoint inhibitors (ICIs) and targeted molecular therapies have refined the therapeutic management of late-stage NSCLC, the specificity and sensitivity of cancer biomarkers should be improved by focusing on prospective studies, followed by their use as therapeutic tools. The liquid biopsy candidates such as circulating tumor cells (CTCs), circulating cell-free tumor DNA (cfDNA), tumor educated platelets (TEP), and extracellular vesicles (EVs) possess cancer-derived biomolecules and aid in tracing: driver mutations leading to cancer, acquired resistance caused by various generations of therapeutic agents, refractory disease, prognosis, and surveillance.

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics.

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer.

Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.

Clinical Strategies and Therapeutics for Human Monkeypox Virus: A Revised Perspective on Recent Outbreaks.

An enveloped double-stranded DNA monkeypox virus (MPXV) is a causative agent of the zoonotic viral disease, human monkeypox (HMPX). MPXV belongs to the genus Orthopoxviridae, a family of notorious smallpox viruses, and so it shares similar clinical pathophysiological features. The recent multicountry HMPX outbreak (May 2022 onwards) is recognized as an emerging global public health emergency by the World Health Organization, shunting its endemic status as opined over the past few decades. Re-emergence of HMPX raises concern to reassess the present clinical strategy and therapeutics as its outbreak evolves further. Keeping a check on these developments, here we provide insights into the HMPX epidemiology, pathophysiology, and clinical representation. Weighing on its early prevention, we reviewed the strategies that are being enrolled for HMPX diagnosis. In the line of expanded MPXV prevalence, we further reviewed its clinical management and the diverse employed preventive/therapeutic strategies, including vaccines (JYNNEOS, ACAM2000, VIGIV) and antiviral drugs/inhibitors (Tecovirimat, Cidofovir, Brincidofovir). Taken together, with a revised perspective of HMPX re-emergence, the present report summarizes new knowledge on its prevalence, pathology, and prevention strategies.

CRISPR-Cas9 in Alzheimer's disease: Therapeutic trends, modalities, and challenges.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no known cure, which has prompted the exploration of novel therapeutic approaches. The clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) tool has generated significant interest for its potential in AD therapeutics by correcting faulty genes. Our report comprehensively reviews emerging applications for CRISPR-Cas9 in developing in vitro and in vivo models for AD research and therapeutics. We further assess its ability to identify and validate genetic markers and potential therapeutic targets for AD. Moreover, we review the current challenges and delivery strategies for the in vivo application of CRISPR-Cas9 in AD therapeutics.

Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies.

Diabetes mellitus (DM) and cardiovascular complications are two unmet medical emergencies that can occur together. The rising incidence of heart failure in diabetic populations, in addition to apparent coronary heart disease, ischemia, and hypertension-related complications, has created a more challenging situation. Diabetes, as a predominant cardio-renal metabolic syndrome, is related to severe vascular risk factors, and it underlies various complex pathophysiological pathways at the metabolic and molecular level that progress and converge toward the development of diabetic cardiomyopathy (DCM). DCM involves several downstream cascades that cause structural and functional alterations of the diabetic heart, such as diastolic dysfunction progressing into systolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, and subsequent heart failure over time. The effects of glucagon-like peptide-1 (GLP-1) analogues and sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular (CV) outcomes in diabetes have shown promising results, including improved contractile bioenergetics and significant cardiovascular benefits. The purpose of this article is to highlight the various pathophysiological, metabolic, and molecular pathways that contribute to the development of DCM and its significant effects on cardiac morphology and functioning. Additionally, this article will discuss the potential therapies that may be available in the future.