Uncovering the complex role of interferon-gamma in suppressing type 2 immunity to cancer.

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.

Designing therapeutic strategies to combat severe acute respiratory syndrome coronavirus-2 disease: COVID-19.

A highly contagious coronavirus disease COVID-19 caused by a recently identified severe acute respiratory syndrome CoV-2 (SARS-CoV-2) initially detected in Wuhan, China has spread worldwide and become a major health crisis in the absence of specific vaccine or antiviral drugs. SARS-CoV-2 infection has resulted in overwhelming number of reported deaths. Unfortunately it is still spreading uncontrollably despite implementing stringent protective measures. Rapid development of effective therapeutic strategies for treatment and prevention of infection is crucially required. Although genomic characterization has assisted in unfolding various aspects of SARS-CoV-2 but development of specific antiviral drugs and vaccine against COVID-19 is still a worldwide challenge. Understanding the disease pathological course underlying the clinical manifestations of COVID-19 is imperative to identify the vital targets for drug development. SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) receptor to enter the host cell and primarily target type II alveolar cells. COVID-19 disease progression is associated with distressed immune functions and hyper active inflammatory system leading to development of cytokine storm which is a vital factor involved in disease advancement. The current review elucidates the disease pathology and summarizes the possible therapeutic options to battle against COVID-19 on the basis of current state of understanding about SARS-CoV-2 pathogenic pathways and knowledge gained from previous SARS and MERS-CoV epidemics. Therapeutic strategies to treat and prevent infection as well as to suppress the disease progression to reduce severity and mortality rate is discussed. Drug candidates currently under consideration and undergoing clinical trials for COVID-19 treatment are highlighted.

Synthesis, biological evaluation and molecular modelling studies of 1,3,7,8-tetrasubstituted xanthines as potent and selective A2A AR ligands with in vivo efficacy against animal model of Parkinson's disease.

In the present study, an attempt has been made to develop a new series of 1,3,7,8-tetrasubstituted xanthine based potent and selective AR ligands for the treatment of Parkinson's disease. Antagonistic interactions between dopamine and A2A adenosine receptors serve as the basis for the development of AR antagonists as potential drug candidates for PD. All the synthesized compounds have been evaluated for their affinity toward AR subtypes using in vitro radioligand binding assays. 1,3-Dipropylxanthine 7a with a methyl substituent at N-7 position represents the most potent compound of the series and displayed highest affinity (A2A, Ki = 0.108 µM), however incorporation of a propargyl group at 7-positon of the xanthine nucleus seems to be the most appropriate substitution to improve selectivity towards the A2A subtype along with reasonable potency. Antiparkinsonian activity has been evaluated using perphenazine induced catatonia in rats. Most of the synthesized xanthines significantly lowered the catatonic score as compared to control and displayed antiparkinsonian effects comparable to standard drug. All the synthesized compounds were subjected to grid-based molecular docking studies to understand the key structural requirements for the development of new molecules well-endowed with intrinsic efficacy and selectivity as adenosine receptor ligands. In silico studies carried out on newly synthesized xanthines provided further support to the pharmacological results.

Synthesis and pharmacological characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activity.

The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the adenosine receptor (AR) binding affinities of the newly synthesized xanthines have also been studied. The compounds displayed moderate to potent binding affinities toward various adenosine receptor subtypes when evaluated through radioligand binding studies. However, most of the compounds showed the maximum affinity for the A2A subtype, some with high selectivity versus all other subtypes. Xanthine carboxylate amide 13b with a diethylaminoethylamino moiety at the para-position of the 8-phenylxanthine scaffold was identified as the most potent A2A adenosine receptor ligand with Ki=0.06µM. Similarly potent and highly A2A-selective are the isovanillin derivatives 16a and 16d. In addition, the newly synthesized xanthine derivatives showed good in vivo bronchospasmolytic activity when tested in guinea pigs.

Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands.

Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki = 1 µM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241-250, 2016. © 2016 Wiley Periodicals, Inc.

A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives.

Molecular hybridization is a rational design strategy used to create new ligands or pro-totypes by identifying and combining specific pharmacophoric subunits from the molecular struc-tures of two or more known bioactive derivatives. Molecular hybridization is a valuable technique in drug discovery, enabling the modulation of unwanted side effects and the creation of potential dual-acting drugs that combine the effects of multiple therapeutic agents. Indole-triazole conju-gates have emerged as promising candidates for new drug development. The indole and triazole moieties can be linked through various synthetic strategies, such as click chemistry or other cou-pling reactions, to generate a library of diverse compounds for biological screening. The achieva-ble structural diversity with indole-triazole conjugates offers avenues to optimize their pharmaco-kinetic and pharmacodynamic attributes, amplifying their therapeutic efficacy. Researchers have extensively tailored both indole and triazole frameworks with diverse modifications to compre-hend their impact on the drug's pharmacokinetic and pharmacodynamic characteristics. The cur-rent review article endeavours to explore and discuss various research strategies to design indole-triazole hybrids and elucidate their significance in a variety of pathological conditions. The in-sights provided herein are anticipated to be beneficial for the researchers and will likely encour-age further exploration in this field.

Synthesis, Molecular Docking, and Biological Evaluation of Novel Indole--triazole Conjugates.

BACKGROUND: Indole-triazole conjugates have emerged as promising candidates for new drug development. Their distinctive structural characteristics, coupled with a wide array of biological activities, render them a captivating and promising field of research for the creation of novel pharmaceutical agents. OBJECTIVE: This study aimed to synthesize indole-triazole conjugates to investigate the influence of various substituents on the functional characteristics of indole-triazole hybrids. It also aimed to study the binding modes of new hybrids with the DNA Gyrase using molecular docking studies. METHODS: A new set of indole-triazole hybrids was synthesized and characterized using various physicochemical and spectral analyses. All hybrids underwent in-silico pharmacokinetic prediction studies. The antimicrobial efficacy of the hybrids was assessed using tube dilution and agar diffusion methods. Additionally, the in-vitro antioxidant activity of synthesized compounds was determined using the 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging assay. Furthermore, in silico molecular docking studies were performed to enhance our comprehension of how the synthesized compounds interact at the molecular level with DNA gyrase. RESULTS: Pharmacokinetic predictions of synthesized hybrids indicated favourable pharmacokinetic profiles, and none of the compounds violated the Lipinski rule of five. Notably, compound 6, featuring a cyclohexanol substituent, demonstrated superior antimicrobial and antioxidant activity (EC50 value = 14.23 µmol). Molecular docking studies further supported the in vitro antioxidant and antimicrobial findings, revealing that all compounds adeptly fit into the binding pocket of DNA Gyrase and engaged in interactions with crucial amino acid residues. CONCLUSION: In summary, our research underscores the efficacy of molecular hybridization in shaping the physicochemical, pharmacokinetic, and biological characteristics of novel indole-triazole derivatives.

Emerging Applications of Plant Antimicrobials in the Food Industry.

Food safety is a global concern with significant public health implications. Improper food handling can harbor a wide range of pathogenic organisms. Antimicrobial agents are crucial for controlling microbes and ensuring food safety and human health. The growing demand for natural, safe, and sustainable food preservation methods has driven research into using plant antimicrobials as alternatives to synthetic preservatives. The food industry is now exploring innovative approaches that combine various physical methods with multiple natural antimicrobials. This review aims to outline the evolving applications of plant antimicrobials in the food industry. It discusses strategies for managing bacteria and categorizes different plant antimicrobials, providing insights into their mechanisms of action and structures. This review offers a comprehensive overview of antimicrobial peptides (AMPs), detailing their structural characteristics, mechanisms of action, various types, and applications in food packaging fabrication and explaining how they contribute to food preservation. It highlights the synergistic and additive benefits of plant antimicrobials and their successful integration with food technologies like nanotechnology, which enhances the hurdle effect, improving food safety and extending shelf life. The review also emphasizes the importance of antimicrobial peptides and the need for further research in this area. Safety assessment and regulatory considerations are discussed as well. By addressing these gaps, plant antimicrobials have the potential to pave the way for more effective, safe, and sustainable food preservation strategies in the future.

Piperidine Nucleus as a Promising Scaffold for Alzheimer's Disease: Current Landscape and Future Perspective.

Heterocycles and their derivatives hold an important place in medicinal chemistry due to their vast therapeutic and pharmacological significance and wider implications in drug design and development. Piperidine is a nitrogen-containing heterocyclic moiety that exhibits an array of pharmacological properties. This review discusses the potential of piperidine derivatives against the neurodegenerative disease Alzheimer's. The incidences of Alzheimer's disease are increasing nowadays, and constant efforts are being made to develop a medicinal agent for this disease. We have highlighted the advancement in developing piperidine-based anti-neuronal disease compounds and the profound activities of some major piperidine-bearing drug molecules with their important target site. This review focuses on advancements in the field of natural and synthetic occurring piperidines active against Alzheimer's disease, with emphasis on the past 6 years. The discussion also includes the structure-activity relationship, the structures of the most promising molecules, and their biological activities against Alzheimer's disease. The promising activities revealed by these piperidinebased scaffolds undoubtedly place them at the forefront of discovering prospective drug candidates. Thus, it would be of great interest to researchers working on synthesizing neuroprotective drug candidates.

Exploring the Mechanical Perspective of a New Anti-Tumor Agent: Melatonin.

Melatonin is a serotonin-derived pineal gland hormone with many biological functions like regulating the sleep-wake cycle, circadian rhythm, menstrual cycle, aging, immunity, and antioxidants. Melatonin synthesis and release are more pronounced during the night, whereas exposure to light decreases it. Evidence is mounting in favor of the therapeutic effects of melatonin in cancer prevention, treatment and delayed onset in various cancer subtypes. Melatonin exerts its anticancer effect through modification of its receptors such as melatonin 1 (MT1), melatonin 2 (MT2), and inhibition of cancer cell proliferation, epigenetic alterations (DNA methylation/demethylation, histone acetylation/deacetylation), metastasis, angiogenesis, altered cellular energetics, and immune evasion. Melatonin performs a significant function in immune modulation and enhances innate and cellular immunity. In addition, melatonin has a remarkable impact on epigenetic modulation of gene expression and alters the transcription of genes. As an adjuvant to cancer therapies, it acts by decreasing the side effects and boosting the therapeutic effects of chemotherapy. Since current treatments produce drug-induced unwanted toxicities and side effects, they require alternate therapies. A recent review article attempts to summarize the mechanistic perspective of melatonin in different cancer subtypes like skin cancer, breast cancer, hepatic cancer, renal cell cancer, non-small cell lung cancer (NSCLC), colon oral, neck, and head cancer. The various studies described in this review will give a firm basis for the future evolution of anticancer drugs.

Recent Developments and Challenges in Molecular-Targeted Therapy of Non-Small-Cell Lung Cancer.

Treatment of lung cancer with conventional therapies, which include radiation, surgery, and chemotherapy results in multiple undesirable adverse or side effects. The major clinical challenge in developing new drug therapies for lung cancer is resistance, which involves mutations and disturbance in various signaling pathways. Molecular abnormalities related to epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) Kirsten rat sarcoma virus (KRAS) mutations, translocation of the anaplastic lymphoma kinase (ALK) gene, mesenchymal-epithelial transition factor (MET) amplification have been studied to overcome the resistance and to develop new therapies for non-small cell lung cancer (NSCLC). But, inevitable development of resistance presents limits the clinical benefits of various new drugs. Here, we review current progress in the development of molecularly targeted therapies, concerning six clinical biomarkers: EGFR, ALK, MET, ROS-1, KRAS, and B-RAF for NSCLC treatment.

A New Series of 1,3-Dimethylxanthine Based Adenosine A2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson's Disease.

BACKGROUND: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson's disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson's disease due to their potent A2A AR antagonistic properties. OBJECTIVE: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. METHODS: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. RESULTS: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly long-lasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. CONCLUSION: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

Unraveling dual feeding associated molecular complexity of salivary glands in the mosquito Anopheles culicifacies.

Mosquito salivary glands are well known to facilitate meal acquisition, however the fundamental question on how adult female salivary gland manages molecular responses during sugar versus blood meal uptake remains unanswered. To investigate these responses, we analyzed a total of 58.5 million raw reads generated from two independent RNAseq libraries of the salivary glands collected from 3-4 day-old sugar and blood fed Anopheles culicifacies mosquitoes. Comprehensive functional annotation analysis of 10,931 contigs unraveled that salivary glands may encode diverse nature of proteins in response to distinct physiological feeding status. Digital gene expression analysis and PCR validation indicated that first blood meal significantly alters the molecular architecture of the salivary glands. Comparative microscopic analysis also revealed that first blood meal uptake not only causes an alteration of at least 12-22% of morphological features of the salivary glands but also results in cellular changes e.g. apoptosis, confirming together that adult female salivary glands are specialized organs to manage meal specific responses. Unraveling the underlying mechanism of mosquito salivary gene expression, controlling dual feeding associated responses may provide a new opportunity to control vector borne diseases.