Reverse transcriptase and integrase are key enzymes that play a pivotal role in HIV-1 viral maturation and replication. Reverse transcriptase consists of two active sites: RNA-dependent DNA polymerase and RNase H. The catalytic domains of integrase and RNase H share striking similarity, comprising two aspartates and one glutamate residue, also known as the catalytic DDE triad, and a Mg2+ pair. The simultaneous inhibition of reverse transcriptase and integrase can be a rational drug discovery approach for combating the emerging drug resistance problem. In the present review, the dual inhibition of RNase H and integrase is systematically discussed, including rationality of design, journey of development, advancement and future perspective.
Cancer involves cells' abnormal growth and ability to invade or metastasize to different body parts. Cancerous cells can divide uncontrollably and spread to other areas through the lymphatic or circulatory systems. Tumors form when malignant cells clump together in an uncontrolled manner. In this context, the cytokine interferon-gamma (IFN-γ) is crucial in regulating immunological responses, particularly malignancy. While IFN-γ is well-known for its potent anti-tumor effects by activating type 1 immunity, recent research has revealed its ability to suppress type 2 immunity, associated with allergy and inflammatory responses. This review aims to elucidate the intricate function of IFN-γ in inhibiting type 2 immune responses to cancer. We explore how IFN-γ influences the development and function of immune cells involved in type 2 immunity, such as mast cells, eosinophils, and T-helper 2 (Th2) cells. Additionally, we investigate the impact of IFN-mediated reduction of type 2 immunity on tumor development, metastasis, and the response to immunotherapeutic interventions. To develop successful cancer immunotherapies, it is crucial to comprehend the complex interplay between type 2 and type 1 immune response and the regulatory role of IFN-γ. This understanding holds tremendous promise for the development of innovative treatment approaches that harness the abilities of both immune response types to combat cancer. However, unraveling the intricate interplay between IFN-γ and type 2 immunity in the tumor microenvironment will be essential for achieving this goal.
According to the World Health Organization (WHO), cancer is the second-highest cause of mortality worldwide, killing nearly 9.6 million people annually. Despite the advances in diagnosis and treatment during the last couple of decades, it remains a serious concern due to the limitations of currently available cancer management strategies. Therefore, alternative strategies are highly required to overcome these glitches. In addition, many etiological factors such as environmental and genetic factors initiate the activation of the Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) pathway. This aberrant activation of the JAK-STAT pathway has been reported in various disease states, including inflammatory conditions, hematologic malignancies, and cancer. For instance, many patients with myeloproliferative neoplasms carry the acquired gain-of-function JAK2 V617F somatic mutation. This knowledge has dramatically improved our understanding of pathogenesis and has facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK-STAT pathway. Our aim is not to be expansive but to highlight emerging ideas towards preventive therapy in a modern view of JAK-STAT inhibitors. A series of agents with different specificities against different members of the JAK family of proteins is currently undergoing evaluation in clinical trials. Here we give a summary of how JAK-STAT inhibitors function and a detailed review of current clinical drugs for managing cancer as a new therapeutic approach.
Inflammation is an essential immune response that helps fight infections and heal tissues. However, chronic inflammation has been linked to several diseases, including cancer, autoimmune disorders, cardiovascular diseases, and neurological disorders. This has increased interest in finding natural substances that can modulate the immune system inflammatory signaling pathways to prevent or treat these diseases. Luteolin is a flavonoid found in many fruits, vegetables, and herbs. It has been shown to have anti-inflammatory effects by altering signaling pathways in immune cells. This review article discusses the current research on luteolin's role as a natural immune system modulator of inflammatory signaling mechanisms, such as its effects on nuclear factor-kappa B, mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and inflammasome signaling processes. The safety profile of luteolin and its potential therapeutic uses in conditions linked to inflammation are also discussed. Overall, the data point to Luteolin's intriguing potential as a natural regulator of immune system inflammatory signaling processes. More research is needed to fully understand its mechanisms of action and possible therapeutic applications.
Neurological disorders are possibly the most prevalent and have been identified to occur among individuals with autism beyond chance. These disorders encompass a diverse range of consequences with neurological causes and have been regarded as a major threat to public mental health. There is no tried-and-true approach for completely protecting the nervous system. Therefore, plant-derived compounds have developed significantly nowadays. Coumestrol (CML) is a potent isoflavone phytoestrogen with a protective effect against neurological dysfunction and has been discovered to be structurally and functionally similar to estrogen. In recent years, more research has been undertaken on phytoestrogens. This research demonstrates the biological complexity of phytoestrogens, which consist of multiple chemical families and function in various ways. This review aimed to explore recent findings on the most significant pharmacological advantages of CML by emphasising neurological benefits. Numerous CML extraction strategies and their pharmacological effects on various neurological disorders, including PD, AD, HD, anxiety, and cognitive impairments, were also documented.
Circular RNAs (circRNAs) have emerged as pivotal regulators of gene expression and cellular processes in various physiological and pathological conditions. In recent years, there has been a growing interest in investigating the role of circRNAs in inflammatory lung diseases, owing to their potential to modulate inflammation-associated pathways and contribute to disease pathogenesis. Inflammatory lung diseases, like asthma, chronic obstructive pulmonary disease (COPD), and COVID-19, pose significant global health challenges. The dysregulation of inflammatory responses demonstrates a pivotal function in advancing these diseases. CircRNAs have been identified as important players in regulating inflammation by functioning as miRNA sponges, engaging with RNA-binding proteins, and participating in intricate ceRNA networks. These interactions enable circRNAs to regulate the manifestation of key inflammatory genes and signaling pathways. Furthermore, emerging evidence suggests that specific circRNAs are differentially expressed in response to inflammatory stimuli and exhibit distinct patterns in various lung diseases. Their involvement in immune cell activation, cytokine production, and tissue remodeling processes underscores their possible capabilities as therapeutic targets and diagnostic biomarkers. Harnessing the knowledge of circRNA-mediated regulation in inflammatory lung diseases could lead to the development of innovative strategies for disease management and intervention. This review summarizes the current understanding of the role of circRNAs in inflammatory lung diseases, focusing on their regulatory mechanisms and functional implications.
One of the main causes of death worldwide is lung cancer, which is largely caused by cigarette smoking. The crucial transcription factor NF-κB, which controls inflammatory responses and various cellular processes, is a constitutively present cytoplasmic protein strictly regulated by inhibitors like IκB proteins. Upon activation by external stimuli, it undergoes phosphorylation, translocates into the nucleus, and modulates the expression of specific genes. The incontrovertible association between pulmonary malignancy and tobacco consumption underscores and highlights a public health concern. Polycyclic aromatic hydrocarbons and nitrosamines, potent carcinogenic compounds present in the aerosol emitted from combusted tobacco, elicit profound deleterious effects upon inhalation, resulting in severe perturbation of pulmonary tissue integrity. The pathogenesis of smoking-induced lung cancer encompasses an intricate process wherein NF-κB activation plays a pivotal role, triggered by exposure to cigarette smoke through diverse signaling pathways, including those associated with oxidative stress and pro-inflammatory cytokines. Unraveling the participation of NF-κB in smoking-induced lung cancer provides pivotal insights into molecular processes, wherein intricate crosstalk between NF-κB and pathways such as MAPK and PI3K-Akt amplifies the inflammatory response, fostering an environment conducive to the formation of lung cancer. This study reviews the critical function of NF-κB in the complex molecular pathways linked to the initiation and advancement of lung carcinogenesis as well as potential treatment targets. See also the graphical abstract(Fig. 1).
CAR T cell therapy has revolutionized how we deliver cancer treatment, most notably for hematologic cancers, by compelling T cells to recognize and kill tumor cells. Nevertheless, current obstacles to utilizing this therapy in solid tumors and overcoming cancer resistance include radicalization. This review discusses how CD95 modulation can boost CAR T cell efficacy. Traditionally, CD95 was known to execute apoptosis induction, but it plays a dual role in induced cell death or in supporting cancer cell survival. Recent data have demonstrated that cancer cells escape CD95-mediated apoptosis via the downregulation of CD95, caspase 8 mutation, or the expression of the inhibition protein cFLIP. Additionally, the immunosuppressive tumor microenvironment, containing CD95L expressing immune cells, explains CAR T cell therapy resistance. Furthermore, we characterize the therapeutic potential of CD95 targeted approaches, including CD95L inhibition (APG101) and alterations in CAR T cell manufacturing (tyrosine kinase inhibitors to mitigate fratricide). In this review, we highlight the importance of multi-path way strategies combining CD95 modulation with CAR T cell engineering to overcome resistance, specifically to target tumor cells better and sustain CAR T cell persistence to enhance treatment efficacy in solid tumors.
Lung inflammatory disorders are a major global health burden, impacting millions of people and raising rates of morbidity and death across many demographic groups. An industrial chemical and common environmental contaminant, formaldehyde (FA) presents serious health concerns to the respiratory system, including the onset and aggravation of lung inflammatory disorders. Epidemiological studies have shown significant associations between FA exposure levels and the incidence and severity of several respiratory diseases. FA causes inflammation in the respiratory tract via immunological activation, oxidative stress, and airway remodelling, aggravating pre-existing pulmonary inflammation and compromising lung function. Additionally, FA functions as a respiratory sensitizer, causing allergic responses and hypersensitivity pneumonitis in sensitive people. Understanding the complicated processes behind formaldehyde-induced lung inflammation is critical for directing targeted strategies aimed at minimizing environmental exposures and alleviating the burden of formaldehyde-related lung illnesses on global respiratory health. This abstract explores the intricate relationship between FA exposure and lung inflammatory diseases, including asthma, bronchitis, allergic inflammation, lung injury and pulmonary fibrosis.