non-invasive-endotracheal-administration-lipopolysaccharide-to-induce

Non-Invasive Endotracheal Administration of Lipopolysaccharide to Induce Acute Lung Injury in Rodents

Acute Lung Injury (ALI) is a life-threatening inflammatory condition characterized by arterial hypoxemia, alveolar edema, compromised ...

CSIR-Indian Institute of Integrative Medicine

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.

Synthesis of Ofornine mimics from natural product l-vasicine as anti-hypertensive agents.

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.

Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception.

Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).

Targeting redox regulation and autophagy systems in cancer stem cells.

Transient receptor potential vanilloid type 4 (TRPV4) is a versatile ion channel with diverse roles in immune cells, including macrophages. While its function in inflammation remains debated, we investigated its role in regulating IL-10 production and its impact on macrophage reprogramming during inflammation.

TRPV4 facilitates the reprogramming of inflamed macrophages by regulating IL-10 production via CREB.

Colchicine binds to tubulin and destabilizes microtubules, stopping cell division and causing apoptosis. Its anti-cancer property affects microtubule integrity despite its reported toxicity. A series of novel colchicine derivatives were synthesized using the multi-component reaction method and evaluated for their antiproliferative properties, aiming to enhance their efficacy as anti-cancer agents compared to the parent compound, colchicine. With the SRB assay, we tested these derivatives for their anti-cancer efficacy against lung, breast, and melanoma using several human cancer cell lines, including A549, MCF-7, MDAMB-231, and A375. The study identified a derivative, , as notably more effective against melanoma cells, with a selectivity index about two times higher than colchicine. We further investigated the anti-cancer efficacy of compound  on human melanoma cells using additional  models, including the wound healing assay and colony formation assay. Compound  inhibited colony formation by up to 62.5% and reduced the migration potential of melanoma cells by 69%. The  studies reveal the probable interactions with the colchicine binding sites that have a comparable pose to colchicine.  formed a hydrogen bond with Cys241, Asn258 and a salt bridge with Lys352, which is important for its tubulin polymerization inhibitory activity. These findings suggest that  could selectively target melanoma cells, minimizing toxicity to healthy cells and potentially providing a safer and more effective treatment option with improved therapeutic outcomes.

Article	Year
Synthesis of Ofornine mimics from natural product l-vasicine as anti-hypertensive agents. Bioorganic & medicinal chemistry\| PubMed ID: 28110819	2017
Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception. Regulatory toxicology and pharmacology : RTP\| PubMed ID: 29108848	2017
Targeting redox regulation and autophagy systems in cancer stem cells. Clinical and experimental medicine\| PubMed ID: 36473988	2023
TRPV4 facilitates the reprogramming of inflamed macrophages by regulating IL-10 production via CREB. Inflammation research : official journal of the European Histamine Research Society ... [et al.]\| PubMed ID: 39101955	2024
Design, synthesis and antiproliferative activity of novel colchicine derivatives: selective inhibition of melanoma cell proliferation. Frontiers in pharmacology\| PubMed ID: 40657636	2025

Sheikh Rayees

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