Cell-Penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery.

This review article discusses the challenges of delivering cargoes to the cytoplasm, for example, proteins, peptides, and nucleic acids, and the mechanisms involved in endosomal escape. Endocytosis, endosomal maturation, and exocytosis pose significant barriers to effective cytoplasmic delivery. The article explores various endosomal escape mechanisms, such as the proton sponge effect, osmotic lysis, membrane fusion, pore formation, membrane destabilization/ disruption, and vesicle budding and collapse. Additionally, it discusses the role of lysosomes, glycocalyx, and molecular crowding in the cytoplasmic delivery process. Despite the recent advances in nonviral delivery systems, there is still a need to improve cytoplasmic delivery. Strategies such as fusogenic peptides, endosomolytic polymers, and cell-penetrating peptides have shown promise in improving endosomal escape and cytoplasmic delivery. More research is needed to refine these strategies and make them safer and more effective. In conclusion, the article highlights the challenges associated with cytoplasmic delivery and the importance of understanding the mechanisms involved in endosomal escape. A better understanding of these processes could result in the creation of greater effectiveness and safe delivery systems for various cargoes, including proteins, peptides, and nucleic acids.

Drug Delivery System Approaches for Rheumatoid Arthritis Treatment: A Review.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that has traditionally been treated using a variety of pharmacological compounds. However, the effectiveness of these treatments is often limited due to challenges associated with their administration. Oral and parenteral routes of drug delivery are often restricted due to issues such as low bioavailability, rapid metabolism, poor absorption, first-pass effect, and severe side effects. In recent years, nanocarrier-based delivery methods have emerged as a promising alternative for overcoming these challenges. Nanocarriers, including nanoparticles, dendrimers, micelles, nanoemulsions, and stimuli-sensitive carriers, possess unique properties that enable efficient drug delivery and targeted therapy. Using nanocarriers makes it possible to circumvent traditional administration routes' limitations. One of the key advantages of nanocarrier-based delivery is the ability to overcome resistance or intolerance to traditional antirheumatic therapies. Moreover, nanocarriers offer improved drug stability, controlled release kinetics, and enhanced solubility, optimizing the therapeutic effect. They can also protect the encapsulated drug, prolonging its circulation time and facilitating sustained release at the target site. This targeted delivery approach ensures a higher concentration of the therapeutic agent at the site of inflammation, leading to improved therapeutic outcomes. This article explores potential developments in nanotherapeutic regimens for RA while providing a comprehensive summary of current approaches based on novel drug delivery systems. In conclusion, nanocarrier-based drug delivery systems have emerged as a promising solution for improving the treatment of rheumatoid arthritis. Further advancements in nanotechnology hold promise for enhancing the efficacy and safety of RA therapies, offering new hope for patients suffering from this debilitating disease.

Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective.

In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.

Structural Insights into N-heterocyclic Moieties as an Anticancer Agent against Hepatocellular Carcinoma: An Exhaustive Perspective.

Hepatocellular carcinoma (HCC) is rapidly spreading around the world with a high mortality rate. In the low- and middle-income nations most impacted by HCV and HBV infections, HCC places a significant strain on the healthcare system and leaches productive capability. An extensive study on HCC to create novel therapeutic approaches was motivated by the lack of adequate preventive or curative therapy methods. Several medications have been put forward and some drug molecules are under investigation by the Food and Drug Administration (FDA) for the treatment of HCC. However, these therapeutic choices fall short of the ideal due to toxicity and the rapid rise in drug resistance which decreases the efficacy of these therapeutics and leads to the severity of hepatocellular carcinoma. Therefore, concerning these problems, there is a critical need for novel systemic combination therapies as well as novel molecular entities that target various signalling pathways, reducing the likelihood that cancer cells may develop treatment resistance. In this review, we discuss the conclusions of several studies suggesting that the N-heterocyclic ring system is a key structural component of many synthetic drugs with a diverse range of biological activities. Following nuclei, such as pyridazine, pyridine, and pyrimidines, along with benzimidazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, quinolines, and quinazolines, have been included to provide a general overview of the link between structure and activity between heterocyclics and their derivatives against hepatocellular carcinoma. A comprehensive investigation of the structure-activity relationship between the series may be done by the direct comparison of anticancer activities with the reference.

Curcumin and its Derivatives Targeting Multiple Signaling Pathways to Elicit Anticancer Activity: A Comprehensive Perspective.

The uncontrolled growth and spread of aberrant cells characterize the group of disorders known as cancer. According to GLOBOCAN 2022 analysis of cancer patients in either developed countries or developing countries the main concern cancers are breast cancer, lung cancer, and liver cancer which may rise eventually. Natural substances with dietary origins have gained interest for their low toxicity, anti-inflammatory, and antioxidant effects. The evaluation of dietary natural products as chemopreventive and therapeutic agents, the identification, characterization, and synthesis of their active components, as well as the enhancement of their delivery and bioavailability, have all received significant attention. Thus, the treatment strategy for concerning cancers must be significantly evaluated and may include the use of phytochemicals in daily lifestyle. In the present perspective, we discussed one of the potent phytochemicals, that has been used over the past few decades known as curcumin as a panacea drug of the "Cure-all" therapy concept. In our review firstly we included exhausted data from in-vivo and in-vitro studies on breast cancer, lung cancer, and liver cancer which act through various cancer-targeting pathways at the molecular level. Now, the second is the active constituent of turmeric known as curcumin and its derivatives are enlisted with their targeted protein in the molecular docking studies, which help the researchers design and synthesize new curcumin derivatives with respective implicated molecular and cellular activity. However, curcumin and its substituted derivatives still need to be investigated with unknown targeting mechanism studies in depth.

Structural Insight on GPR119 Agonist as Potential Therapy for Type II Diabetes: A Comprehensive Review.

Diabetes Mellitus (DM) is a long-term metabolic condition that is characterized by excessive blood glucose. DM is the third most death-causing disease, leading to retinopathy, nephropathy, loss of vision, stroke, and cardiac arrest. Around 90% of the total cases of diabetic patients have Type II Diabetes Mellitus (T2DM). Among various approaches for the treatment of T2DM. G proteincoupled receptors (GPCRs) 119 have been identified as a new pharmacological target. GPR119 is distributed preferentially in the pancreas ß-cells and gastrointestinal tract (enteroendocrine cells) in humans. GPR119 receptor activation elevates the release of incretin hormones such as Glucagon-Like Peptide (GLP1) and Glucose Dependent Insulinotropic Polypeptide (GIP) from intestinal K and L cells. GPR119 receptor agonists stimulate intracellular cAMP production via Gαs coupling to adenylate cyclase. GPR119 has been linked to the control of insulin release by pancreatic ß-cells, as well as the generation of GLP-1 by enteroendocrine cells in the gut, as per in vitro assays. The dual role of the GPR119 receptor agonist in the treatment of T2DM leads to the development of a novel prospective anti-diabetic drug and is thought to have decreased the probability of inducing hypoglycemia. GPR119 receptor agonists exert their effects in one of two ways: either by promoting glucose absorption by ß-cells, or by inhibiting α-cells' ability to produce glucose. In this review, we summarized potential targets for the treatment of T2DM with special reference to GPR119 along with its pharmacological effects, several endogenous as well as exogenous agonists, and its pyrimidine nucleus containing synthetic ligands.