Cancer remains a major global health concern, ranking as the second leading cause of death worldwide. Within the tumor microenvironment proteases play a crucial role in cancer cell migration and progression. Their involvement in processes from tumor growth to metastasis has spurred extensive research into their therapeutic potential. This review explores the role of proteases in tumor biology and evaluates their therapeutic targeting through protease inhibitors. Proteases, ranging from metalloproteases to cysteine proteases, play pivotal roles in extracellular matrix degradation, angiogenesis, and the maintenance of cancer stem cell niches. Their involvement in cancer pathogenesis has led to development of protease inhibitors as potential anti-cancer agents, with matrix metalloprotease inhibitors (MMPIs) showing significance due to their enzymatic activity. The source for the development of these inhibitors may be derived either naturally or may be synthesized artificially based on principles of protein structure, peptide bonding, and molecular interactions. Additionally, drugs targeting protein pathways either directly or through epigenetic regulation have demonstrated therapeutic potential. Advancements in nanotechnology now offer promising drug delivery systems with reduced side effects compared to traditional methods. Targeting proteases represents a multidimensional approach to cancer therapy. Though challenges remain, protease inhibitors present a multifaceted approach to cancer treatment, holding the potential to transform the landscape of cancer therapeutics.
Lung cancer is one of the most prevalent cancers with a high mortality rate. While the prognosis of lung cancer remains challenging, advances in treatment strategies especially immunotherapy, targeted therapies, and personalized medicine improve outcomes for many patients. However, understanding antigen presentation machinery (APM) holds a crucial part in apprehending the disease and also immunotherapy response by its governing role in adaptive immunity. We aim to shed light on lung cancer APM mechanisms and debate therapeutic approaches to recover or elude the defects in antigen presentation. Cancer is a widely multifaceted disease with altered cellular processes, affecting APM and being affected by aberrant APM. Recent findings focus on revealing new mechanisms affecting antigen presentation as well as revisiting the discovered mechanisms in different cancer types, including lung cancer. Additionally, antigen presentation defects are associated with immune checkpoint inhibitor resistance and low immunogenicity in tumors. These issues currently are common focuses in immunotherapy research, which requires better understanding of APM defects. This review discusses the perturbations in APM, its impact on lung cancer progression and immune based compensatory treatment strategies for lung cancer.
The transcription factor and oncoprotein Ets-1 regulates the transcription of several target genes involved in several biological processes such as tumor progression. This activity of Ets-1 is mediated by its interaction with protein partners. The aim of this review is to summarize the interacting partners of Ets-1 and to provide an overview of their role in the regulation of Ets-1 transcriptional activity. A number of studies have shown that Ets-1 interacts with a large number of transcription factors, nuclear receptors, cofactors, and modifying enzymes that determine the final biological outcome. Most of these interactors activates Ets-1, while others repress it. This has improved our understanding of the role of Ets-1 in tumor progression. The identification of novel Ets-1 interactors will be important to complete the understanding of its regulatory networks and may help to develop therapeutic strategies that target protein-protein interaction.
Host defense peptides (HDPs) have emerged as promising candidates with multifaceted roles in enhancing host immunity against a variety of microbial threats. This review aims to examine the immunomodulatory potential and inducibility of HDPs, providing insights into their ability to enhance host immunity and address the challenge of multidrug-resistant bacteria. Data were extracted from a total of 31 publications. A total of nine (9) Host Defense Peptides (HDPs) were identified from various microorganisms, exhibiting diverse antimicrobial activities. Additionally, eight (8) HDPs were sourced from plants, while ten (10) experimental animal-derived HDPs were also documented. Data also showed that synergistic combinations of HDPs with antibiotics or antivirals enhanced efficacy, including a 50
Biogeographical ancestry (BGA) inference can generate valuable investigative leads when STR-based identification is not immediately available. However, the absence of suitable Filipino ancestry-informative markers (AIMs) and reference population databases poses challenges in developing and establishing a BGA inference capability to complement current forensic DNA analysis methods. Complex genetic relationships exist among Filipino groups resulting from ancient and recent migrations, admixture, and isolation driven by socio-cultural, economic, and geographical factors. Assessments of existing forensic BGA assays indicate limited informativeness in local investigations within the Asia Pacific, including the Philippines. This review highlights the need to identify more suitable AIMs and establish a suitable population database from different groups for more informative forensic BGA inference in the Philippines. This paper reviews considerations relevant to the application of forensic BGA inference in the Philippines. The challenges associated with establishing representative population datasets, identifying ancestry-informative markers and capability implementation are highlighted.
After eating a meal high in carbohydrates, beta cells in the islets of Langerhans of the pancreas secrete insulin in response to the metabolic fuels and neurohormonal inputs they receive. Insulin secretion must be kept under tight control in order to keep glucose levels from fluctuating. For example, the pathophysiology of type 2 diabetes is driven by a decline in insulin production, either absolute or relative, in the presence of insulin resistance. The mechanism that underlies how glucose increases the release of insulin has, for the most part, remained unaltered ever since it was discovered more than three decades ago. In reaction to glucose, the ratio of ATP to ADP that is found inside the cell rises, which causes the ATP-sensitive potassium (KATP) ion channels to close. These channels are the target of the medications known as sulfonylureas. As a consequence of this, the beta-cell membrane becomes depolarized, action potentials are induced, voltage-gated calcium ion channels are activated, and the amount of calcium ion that is present inside the cell rises, which ultimately leads to the exocytosis of insulin. The functions and molecular identities of the various significant channels that determine the electrical response in these cells have only recently been fully elucidated. Despite the fact that a large number of additional ion channels are known to contribute to the excitability of beta cells, it was not until recently that this information became available.
This review aims to synthesize the latest advances in immunotherapeutic cancer treatment approaches and spotlight groundbreaking discoveries and clinical trial outcomes. Immunotherapy represents a promising and transformative strategy for treating a variety of hematological malignancies and solid tumors. This therapeutic approach strives to bolster the body's inherent defense mechanisms to elicit enduring, specific, and individualized anti-tumor responses by harnessing the immune system's ability to identify and eradicate cancer cells. Various modes of immunotherapy—including monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, adoptive T-cell therapies, and oncolytic viruses—have achieved considerable success in clinical trials and patient results. Despite notable successes, challenges persist in the broader adoption of immunotherapy. Issues such as resistance mechanisms, tumor heterogeneity, and the complexity of the tumor microenvironment can weaken immune responses and constrain the efficacy of treatments. The current review is dedicated to understanding these obstacles and devising comprehensive strategies to surmount resistance and secure sustained responses.
Neuroblastoma is the most commonly seen extracranial tumor in children originating from the sympathetic nervous system. It is responsible for approximately 20
This review outlines NADPH oxidase structure and function in pancreatic β-cells. Furthermore, methods for detecting reactive oxygen species and NADPH oxidase inhibitors are discussed. NADPH oxidase–derived ROS regulates β-cell metabolism and insulin release. This review highlights new findings of the NADPH oxidase family, such as NOX4, in regulating β-cell function. For instance, NOX4-derived H2O2 and increased ATP levels promote the closure of ATP-sensitive K+ channels to induce insulin release. In addition, NOX2 inhibitors, such as the tetrahydroquinolines CPP11G and CPP11H, have been shown to interact with p47phox, preventing NOX2 assembly and activity. NADPH oxidase family is involved in the physiology and pathophysiology of pancreatic β-cells. However, more studies are necessary to fully understand when, where, and how NADPH oxidase–derived ROS regulate β-cell function. Better improved NADPH oxidase inhibitors are essential to tackle this problem and develop new strategies with in-depth research.
The discovery of insulin was a true landmark in biomedical research and provided a framework for the understanding of many pivotal mechanisms in cell biology throughout the twentieth century, as insulin for instance was the first major protein to have its amino acid sequence and 3D structure resolved. The elucidation of the processes that regulate and mediate insulin secretion has also contributed with crucial mechanistic insights on the pathways that lead to both type 1 and type 2 diabetes mellitus. More than 100 years after the discovery of this hormone, an overview of the present knowledge on insulin output from β-cells should be timely to the general researcher interested in the mechanisms that couple glucose stimulation to insulin secretion. Although the mechanisms underlying insulin secretion have been exhaustively studied and understood in animal models, the last decades have shown that important differences can be identified compared to human β-cells. Additionally, despite both reactive oxygen species as well as the immune system have been initially implicated in β-cell dysfunction and the progression to diabetes, increasing evidence indicates that both can also have physiological effects for proper insulin secretion. Given this background, this brief review focused on discussing various means by which glucose elicits insulin secretion by the β-cells, particularly on the modulatory role of redox balance and inflammation on β-cell function and/or demise, also drawing attention to the specific mechanisms connecting glucose stimulation to insulin secretion in humans.
Cancer immune evasion is still a major obstacle in elimination of cancer cells and current cancer treatment. This review focuses on immune evasion mechanisms at each step of the cancer immune cycle to better understand the escape of the tumor cells from the immune system and to provide insight to guide the design of effective anticancer therapeutic strategies. There are a number of factors that contribute to immune escape, including restriction of antigen recognition, inhibition of immune system cells, immunosuppressive effects, and accumulation of specific metabolites in TME. However, identification of immune escape mechanisms in cancer still remains an active area of research, as both tumor and immune response in individuals are heterogeneous and diverse. A better understanding of immune escape mechanisms in cancer can provide the development of clinically applicable therapeutic options in a range of cancers and contribute to the management of the disease.
Purpose of Review Mitochondrial DNA (mtDNA) plays an essential role in forensic science, aiding in human identification especially when dealing with degraded DNA samples or cases devoid of paternal family reference samples. Yet, the nuances of isolated populations, shaped by a small number of founders that separate from general populations due to factors such as cultural or geographic differences, and as such, often exhibit very different allele frequencies, pose challenges to its applicability. Recent Findings Recent investigations have determined that ignoring the presence of genetic isolates when performing forensic genetic analysis can introduce significant bias into the results ultimately leading to incorrect match probability estimates, increased false positives or false negatives, miscalculation of familial relationships, ethical and legal concerns, loss of public trust, and mistaken convictions or acquittals. Summary This paper offers a comprehensive review of the challenges and implications for human identification using mtDNA in isolated populations, focusing on population history and social factors; homogeneity of mtDNA; lack of representation in reference databases; and data interpretation and appropriate statistical methods.
Non-exhaustively and critically discuss recent advances in the understanding of fructose-induced dysmetabolism with a focus on the gut. We also highlight key knowledge gaps and present novel research perspectives on this topic. Excess fructose is detrimental to metabolic health and risk for metabolic diseases, but the elements connecting excess fructose to dysmetabolism remain ill-defined. The liver is seen as the key organ in the pathophysiology of fructose-driven metabolic disease. However, new evidence positions the gut as another important contributor. The gut shields the liver from fructose. When fructose exceeds intestinal clearance capacity, it overflows to the liver and distal gut. How fructose buildup in the gut lumen contributes to metabolic disease is not well-understood. Shedding light onto the enteric determinants of fructose-driven dysmetabolism can lead to new strategies to alleviate metabolic diseases.
This review discusses the characteristics of different in vivo experimental immunologic models for the development of immunotherapies and the role of immunology in cancer. According to recent studies, different immunologic mouse models are being created using diverse strains and customized according to cancer type. Cancer immunology and immunotherapy offer important therapeutic opportunities to develop new cancer treatments and improve patient survival. Unfortunately, immunotherapies do not always produce positive results. More studies, including patient-derived animal models, are needed to find new therapeutics and achieve positive immune responses against cancer. In particular, differentiated, humanized immunological mouse models, despite their limitations, facilitate the understanding of the mechanism of cancer therapeutics, the development of treatment modalities, drug administration, and the development of preclinical studies.
In this review, the role of inflammation on tumorigenesis with the scope of its tumor-promoting role as an enabling characteristic of cancer will be discussed along with promising therapeutical strategies that target inflammatory microenvironment of tumors. The hallmarks of cancer conceptualized by Hanahan and Weinberg in 2000 structured our understanding of the common features of cancer better, yet new emerging hallmarks and enabling characteristics are being considered within this concept in recent years. Tumor-promoting inflammation is one of these characteristics that opened a new era in cancer therapy with promising results. Recent studies revealed that targeting inflammation directly or as an adjuvant therapy is a clinically significant approach to increase the efficiency of cancer treatments. The presence of inflammatory cells in tumor development and the influence of inflammation on several cellular mechanism such as cell proliferation, invasion, and metastasis make this feature an important mediator between several hallmarks of cancer as well as a promising therapeutical target.
An understanding of epigenetic marks on chromatin and their roles in development and disease has been a highlight of the past few years of biological research. Acetylated lysine is one such chromatin mark that is specifically read by modules called bromodomains. Proteins that harbor bromodomain modules have been implicated in cancer and other disease conditions and developmental abnormalities. This review looks into recent findings about all known bromodomain-containing proteins in higher eukaryotes based on their family and enzymatic function. It further evaluates the consequences of mutations in these proteins resulting in diseased conditions. Finally, this review delves into potential bromodomain-based therapeutics that are under investigation or approved by the FDA. Epigenetic readers such as bromodomains that are present in few mammalian proteins impart them the ability to identify acetylated lysine marks on chromatin and functionally translate them into gene expression or repression affecting overall cellular and tissue phenotypes. We have summarized the latest updates in this field.
As the primary process involved in regulating cellular hemostasis, autophagy has dual functions in cancer by either promoting or suppressing tumor growth. This article reviews recent research on the role of autophagy in cancer therapy, and discusses several novel anti-cancer agents developed in the past 5 years that target autophagy. “How do these compounds affect autophagy?” and “what are their mechanisms of action?” are the two main questions answered in the present review. Two distinct and somewhat polar therapeutic strategies have proven effective in combating cancer development and progression which work by either inhibiting or inducing autophagy. Recent studies suggest that autophagy-based therapies sensitize some tumor cells to chemotherapy but not others. However, determining which cancer types are most likely to benefit from autophagy manipulation remains an active area of research. Improved understanding of tumor-specific autophagy mechanisms can pave the way for the development of anti-cancer agents that can serve as clinically feasible therapeutic options in a range of human cancers.
Immune exclusion and dormancy in cancer pose hurdles in successful cancer therapy. The review details the role played by discoidin domain receptor 1 (DDR1) in accumulation of collagen in the extracellular matrix of cancer. DDR1 contributes to immune exclusion and dormancy by specific alignment of collagen in extracellular matrix. Therapeutic targeting of DDR1 is thus evaluated as a viable option in cancer treatment. For many years, researchers believed that the intracellular kinase domain of DDR1 is the major contributing factor in cancer development and progression. The extracellular domain (ECD) of DDR1 that holds the collagen binding pocket is responsible for collagen alignment at the cancer matrix. The ECD-DDR1 alone determines the specific alignment of collagen that decides the various determinants of cancer that includes dormancy, immune exclusion, and metastasis. Many cancer types attain increased expression of collagen contributing to density and high-order alignment that can be associated to poor prognosis. Discoidin domain receptors (DDRs) are collagen binding receptors which on activation initiate various cellular responses. Overexpression of DDR1 in cancer cells is correlated to lesser infiltration of immune cells into tumor and also linked to dormant state of tumors.
Identified as a specific biomarker of the cholinergic neurons, choline acetyltransferase enzyme (ChAT) [EC number 2.3.1.6] catalyzes the synthesis of neurotransmitter acetylcholine (ACh). Acetylcholine has an essential role in the normal functioning of the brain and body. ChAT is involved in the recycling of choline for the synthesis of ACh. Choline is recycled following its metabolism by the cholinesterase enzyme. The homeostatic imbalance of choline acetyltransferase activity leads to neurodegenerative disorders. Localization and distribution of ChAT in the neuronal and non-neuronal tissues are of significance. The presence of ChAT in non-neuronal tissue is related to its role in the immune response cascade. ChAT enzyme has been explored as a potential biomarker for marking of initial stages of neurodegenerative disorders. Here we discuss the structure, active site required for substrate binding, different forms of ChAT enzyme, and its role in neuronal/non-neuronal tissues. The neurological disorders that are treated symptomatically, but the underlying cause is imbalance or deficiency of ChAT enzyme, are also reviewed. Various stimulators of the ChAT enzyme, which can be of potential importance for treatment therapies of neurodegenerative diseases, are discussed. We hope that the review will help interested researchers to explore ChAT as a potential target for treating one of the causative factors of several related neurodegenerative diseases.
