Discovery of Novel Diesters Incorporating Kojic Acid With NSAIDs and Palmitic Acid as Dual Inhibitor of Melanogenesis and Inflammation.

Our study focuses on creating hybrid compounds and assessing their suitability for use in skincare products. The synergistic combination of Kojic acid, NSAIDs, and Palmitic acid proved to be an effective approach in inhibiting melanin production, making it a promising solution for individuals with hyperpigmentation concerns with Kojic acid (KA) Ibuprofen monoester (IBUM) and Ibuprofen-Kojic acid-Palmitic acid diester (IBUD) exhibiting a potential tyrosinase (38 % and 49 % inhibition at 200 µM) and anti-melanogenesis activity (77 % and 79 % inhibition at 100 µM). Furthermore, these compounds exhibited potent anti-inflammatory effects, Kojic acid-Diclofenac monoester (DICM) and Diclofenac-Kojic acid-Palmitic acid diester (DICD) offering potential benefits for inflammation by lowering the paw volume.

Correction: Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes.

[This corrects the article DOI: 10.1371/journal.pone.

Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes.

Metastatic dissemination following successful treatment of the primary tumour remains a common cause of death. There is mounting evidence that therapeutic interventions themselves may promote development of metastatic disease. We earlier reported that cell-free chromatin particles (cfChPs) released from dying cancer cells are potentially oncogenic.

Cell-free chromatin particles released from dying cancer cells activate immune checkpoints in human lymphocytes: implications for cancer therapy.

Immune checkpoint blockade is the exciting breakthrough in cancer, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in blood of cancer patients, or those that are released locally from dying cancer cells, are readily internalized by healthy cells with biological consequences. Here we report that treatment of human lymphocytes with cfChPs isolated from sera of cancer patients led to marked activation of the immune checkpoints PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3.

Cell-free chromatin particles released from dying cells inflict mitochondrial damage and ROS production in living cells.

Mitochondrial damage and the resultant oxidative stress are associated with neurodegenerative diseases, ageing, and cancer. However, the triggers of mitochondrial damage remain unclear. We previously reported that cell-free chromatin particles (cfChPs) released from the billions of cells that die in the body every day can readily enter healthy cells and damage their DNA.

Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models.

Background And Objectives: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants.

Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as anti-infectious agents: , synthesis, and biological approach.

Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)--(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of dihydrofolate reductase (DHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis.

Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization.

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by H & C NMR and mass spectrometry.

Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents.

Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry.

A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration in mice.

Billions of cells die in the body every day, and cell-free chromatin particles (cfChPs) which are released from them enter into the extracellular compartments of the body, including into the circulation. cfChPs are known to readily enter into healthy cells to damage their DNA and activate apoptotic and inflammatory pathways. We have hypothesized that lifelong assault on healthy cells by cfChPs is the underlying cause of ageing, and that ageing could be retarded by deactivating extra-cellular cfChPs.

A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004).

Background: Our earlier studies have shown that cell-free chromatin particles (cfChPs) that are released from dying cancer cells are readily internalised by bystander cells leading to activation of two hallmarks of cancer viz. genome instability and inflammation. These hallmarks could be down-regulated by deactivating cfChPs medium of oxygen radicals generated upon admixing small quantities of the nutraceuticals resveratrol (R) and copper (Cu).

A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001).

Background: Transplant related toxicity is a major therapeutic challenge. We have previously reported that the toxicity of chemotherapy is largely not directly because of the drugs themselves; rather it is mainly due to DNA damage, apoptosis and hyper-inflammation triggered by cell-free chromatin particles that are released because of drug-induced host cell death. Cell-free chromatin particles can be inactivated by free-radicals which are generated when the nutraceuticals resveratrol and copper are administered orally.

Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer's disease.

Development of multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for Alzheimer's disease (AD). Herein, we reported a new series of deoxyvasicinone analogues as dual inhibitor of acetylcholinesterase (AChE) and tau aggregation that function as multitargeted ligands for AD. All the multitargeted ligands 11(a-j) and 15(a-g) were designed, synthesized, and validated by HNMR, CNMR and mass spectrometry.

Design, synthesis, crystal structure and anti-plasmodial evaluation of tetrahydrobenzo[4,5]thieno[2,3-]pyrimidine derivatives.

Effective chemotherapy is essential for controlling malaria. However, resistance of to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against .

Discovery of new phenyl sulfonyl-pyrimidine carboxylate derivatives as the potential multi-target drugs with effective anti-Alzheimer's action: Design, synthesis, crystal structure and in-vitro biological evaluation.

Alzheimer's disease (AD) is multifactorial, progressive neurodegeneration with impaired behavioural and cognitive functions. The multitarget-directed ligand (MTDL) strategies are promising paradigm in drug development, potentially leading to new possible therapy options for complex AD. Herein, a series of novel MTDLs phenylsulfonyl-pyrimidine carboxylate (BS-1 to BS-24) derivatives were designed and synthesized for AD treatment.

A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing.

It is estimated that 10-50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day.

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice.

We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component.

The CD200-CD200R cross-talk helps Leishmania donovani to down regulate macrophage and CD4CD44 T cells effector functions in an NFκB independent manner.

The lacuna in the knowledge of immunobiology, especially in visceral infections that are fatal if left untreated, are a major hurdle in getting a vaccine candidate for leishmaniasis. Till date, only a few drugs are available to combat human leishmaniasis and a vaccine candidate either prophylactic or preventive is still awaited. Therefore, identification of host and parasitic factors involved in the regulation of specific immune mechanisms are essentially needed.

Suppression of aspirin-mediated eosinophil activation by prostaglandin E: Relevance to aspirin and nonsteroidal anti-inflammatory drug hypersensitivity.

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by severe, sometimes life-threatening reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Mechanisms driving the disease include overproduction of leukotrienes and loss of anti-inflammatory prostaglandin E (PGE) production. Many cell types contribute to the disease; however, eosinophils are markedly elevated and are important drivers of pathologic findings.

Rabies Encephalitis With Myocarditis Mimicking ST-Elevation Myocardial Infarction.

Rabies virus infection remains a significant public health threat particularly in developing countries without effective canine vaccination programs. After symptoms develop, there is no effective treatment and mortality approaches 100%. In countries such as the United States where human rabies remains rare, initial diagnosis is often delayed.

Prevention of radiation-induced bystander effects by agents that inactivate cell-free chromatin released from irradiated dying cells.

Radiation-induced bystander effect (RIBE) is a poorly understood phenomenon wherein non-targeted cells exhibit effects of radiation. We have reported that cell-free chromatin (cfCh) particles that are released from dying cells can integrate into genomes of surrounding healthy cells to induce DNA damage and inflammation. This raised the possibility that RIBE might be induced by cfCh released from irradiated dying cells.