Dona Sinha

Background: Anesthetic agents administered during surgery are one of the key perioperative factors affecting immune modulation in cancer patients. This comparative study elucidated the mechanisms by which the volatile anesthetic, isoflurane and the intravenous anesthetic, propofol impacted apoptosis signaling in CD4+ helper T (Th) cells. Methods: Flow cytometry was used to analyze apoptosis, mitochondrial function and reactive oxygen species (ROS) generation, while Western blotting, ELISA and RT-qPCR were employed to study protein/gene expression in sorted CD4⁺ Th cells from perioperative breast cancer female patients (anesthetized with isoflurane or propofol, n=15 per group) and Jurkat T cells. Results: Patient-derived CD4⁺ Th cells and Jurkat T cells exhibited that isoflurane at clinically relevant concentrations triggered apoptosis through mitochondrial depolarization, ROS generation, DNA damage, and activation of caspase-3/7. Specific use of caspase-3/7 inhibitor, Z-DEVD-FMK and antioxidant N-acetyl cysteine rescued isoflurane-induced apoptosis. Further, isoflurane relative to propofol, activated p38 mitogen-activated protein kinase (MAPK), and use of p38 inhibitor, SB203580 suppressed isoflurane-induced apoptosis. Collectively, these findings validated the involvement of the ROS-p38-caspase-3/7 axis in isoflurane-associated apoptosis signaling. On the other hand, propofol conserved mitochondrial integrity, reduced oxidative stress, and maintained higher proliferative capacity. Interestingly, isoflurane-associated apoptosis was transient, with postoperative recovery in patients and similar rescue from apoptosis was evident in Jurkat T cells within 24-48 h of drug removal. Conclusions: By integrating analyses of patient-derived CD4+ Th cells with mechanistic validations in Jurkat T cells, this study identified the ROS-p38-caspase-3/7 signaling axis and the reversible nature of isoflurane-induced apoptosis.

Molecular epidemiology targeting the impact of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM_2.5) on pro-oncogenic signaling has been sparsely reported from the Indian industrial belt. This study investigated the effect of seasonal variation in PM_2.5 on pro-oncogenic drivers in the pulmonary and systemic cellular environments of a thermal power plant participants in West Bengal, India during 2021–2022. PM_2.5 levels were significantly higher during spring than monsoon, coinciding with reduced hemoglobin and lung function indices. Linear Mixed-Effects Regression (LMER) confirmed that elevated PM_2.5 exposure was significantly associated with increased inflammatory response, enhanced matrix metalloproteinase-9 (MMP-9) activity, and upregulation of the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) cascade, along with downregulation of phosphatase and tensin homolog (PTEN). These molecular alterations reflected enhanced proliferative and pro-angiogenic signaling and reduced apoptosis in the airway cells and the leukocytes. Collectively, the findings indicate that short-term seasonal surges in PM_2.5, may induce subclinical molecular perturbations that predispose exposed individuals in industrial areas to activation of the EGFR/PI3K/AKT pro-oncogenic signaling.

Ambient particulate matters (PMs) are the most dreaded pollutants prevailing in the environment. PMs are not single entities but a conglomeration of several components, some of which are carcinogenic in nature. PMs are responsible for innumerable human diseases, and out of them, cardiovascular and respiratory disorders, including lung carcinogenesis, are the major causes of morbidity and premature mortality in the exposed populations. Reduced ambient air quality is a serious public health concern, especially in East and Southeast Asian countries. PMs may affect the lung environment by inducing mutations in several genes which often leads to cell proliferation, reduced apoptosis of affected cells, and increases the expression of stemness markers, leading to epithelial–mesenchymal transition and metastasis. With the alarming rise of the ambient PM concentration in the environment, women and children in the rural areas and elderly individuals in the urban areas are at a major risk of developing several pulmonary diseases, including lung cancer. Therefore, mass awareness, implementation of pollution abatement strategies, and enforcement of strict government policies for curbing ambient PM emissions from anthropogenic sources are urgently needed.

Background & objectives: The choice of anesthetic for better perioperative conservation of immune responses has always been contentious. This study investigated the differential impact of the intravenous anesthetic, propofol, and the volatile anesthetic, isoflurane on the T cell immune responses, if any, among individuals going through perioperative breast cancer. Methods: Perioperative blood samples (preoperative, intraoperative and postoperative) collected from participants with breast cancer in two arms namely isoflurane arm (n=50) and the propofol arm (n=50) were analyzed for T cell immune response using flow cytometry and ELISA. The interactions of anesthetics with CD4/CD8 were probed with molecular docking and molecular dynamic (MD) simulations. Results: Linear mixed model analysis showed that isoflurane in comparison to propofol inhibited CD4+ helper (Th) [β-coefficient: -8.75; 95% CI: -13.00 to -4.51] and CD19+ B cell (β: -7.51; 95% CI: -15.46 to 0.44) frequencies during the intraoperative period in perioperative breast cancer patients. Further, interleukin (IL)-10 and IL-12 were significantly increased during the intra- and postoperative periods in the isoflurane group as compared to the propofol group. Molecular docking (MD) validated propofol’s better binding energy with CD4/CD8 than isoflurane. MD simulations propagated that in contrast to isoflurane, propofol formed a more compact and stabilized structure with CD4/CD8, making the amino acid residues on the surface of CD4/CD8 inaccessible for any interaction. Interpretation & conclusions: The clinical observations and the in silico findings exhibited that propofol in comparison to isoflurane better regulated T cell immuno-inflammatory response in perioperative breast cancer patients.

: The dreadful scenario of cancer prevails due to the presence of cancer stem cells (CSCs), which contribute to tumor growth, metastasis, invasion, resistance to chemo- and radiotherapy, and recurrence. CSCs are a small subpopulation of cells within the tumor that are characterized by self-renewal capability and have the potential to manifest heterogeneous lineages of cancer cells that constitute the tumor. The major bioactive green tea polyphenol (-)-epigallocatechin gallate (EGCG) has been fruitful in downgrading cancer stemness signaling and CSC biomarkers in cancer progression. EGCG has been evidenced to maneuver extrinsic and intrinsic apoptotic pathways in order to decrease the viability of CSCs. Cancer stemness is intricately related to epithelial-mesenchymal transition (EMT), metastasis and therapy resistance, and EGCG has been evidenced to regress all these CSC-related effects. By inhibiting CSC characteristics EGCG has also been evidenced to sensitize the tumor cells to radiotherapy and chemotherapy. However, the use of EGCG in in vitro and in vivo cancer models raises concern about its bioavailability, stability and efficacy against spheroids raised from parental cells. Therefore, novel nano formulations of EGCG and adjuvant therapy of EGCG with other phytochemicals or drugs or small molecules may have a better prospect in targeting CSCs. However, extensive clinical research is still awaited to elucidate a full proof impact of EGCG in cancer therapy.

Lung cancer is a heterogeneous group of malignancies with high incidence worldwide. It is the most frequently occurring cancer in men and the second most common in women. Due to its frequent diagnosis and variable response to treatment, lung cancer was reported as the top cause of cancer-related deaths worldwide in 2020. Many aberrant signaling cascades are implicated in the pathogenesis of lung cancer, including those involved in apoptosis (B cell lymphoma protein, Bcl-2-associated X protein, first apoptosis signal ligand), growth inhibition (tumor suppressor protein or gene and serine/threonine kinase 11), and growth promotion (epidermal growth factor receptor/proto-oncogenes/phosphatidylinositol-3 kinase). Accordingly, these pathways and their signaling molecules have become promising targets for chemopreventive and chemotherapeutic agents. Recent research provides compelling evidence for the use of plant-based compounds, known collectively as phytochemicals, as anticancer agents. This review discusses major contributing signaling pathways involved in the pathophysiology of lung cancer, as well as currently available treatments and prospective drug candidates. The anticancer potential of naturally occurring bioactive compounds in the context of lung cancer is also discussed, with critical analysis of their mechanistic actions presented by preclinical and clinical studies.