Signal transducer and activator of transcription 3 (STAT3) constitutively expresses in human liver cancer cells and has been implicated in apoptosis resistance and tumorigenesis. Alantolactone, a sesquiterpene lactone, has been shown to possess anticancer activities in various cancer cell lines. In our previous report, we showed that alantolactone induced apoptosis in U87 glioblastoma cells via GSH depletion and ROS generation. However, the molecular mechanism of GSH depletion remained unexplored. The present study was conducted to envisage the molecular mechanism of alantolactone-induced apoptosis in HepG2 cells by focusing on the molecular mechanism of GSH depletion and its effect on STAT3 activation. We found that alantolactone induced apoptosis in HepG2 cells in a dose-dependent manner. This alantolactone-induced apoptosis was found to be associated with GSH depletion, inhibition of STAT3 activation, ROS generation, mitochondrial transmembrane potential dissipation, and increased Bax/Bcl-2 ratio and caspase-3 activation. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine (NAC). The data demonstrate clearly that intracellular GSH plays a central role in alantolactone-induced apoptosis in HepG2 cells. Thus, alantolactone may become a lead chemotherapeutic candidate for the treatment of liver cancer.

Isoalantolactone, a sesquiterpene lactone compound possesses antifungal, antibacteria, antihelminthic and antiproliferative activities. In the present study, we found that isoalantolactone inhibits growth and induces apoptosis in pancreatic cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of reactive oxygen species, cardiolipin oxidation, reduced mitochondrial membrane potential, release of cytochrome c and cell cycle arrest at S phase. N-Acetyl Cysteine (NAC), a specific ROS inhibitor restored cell viability and completely blocked isoalantolactone-mediated apoptosis in PANC-1 cells indicating that ROS are involved in isoalantolactone-mediated apoptosis. Western blot study showed that isoalantolactone increased the expression of phosphorylated p38 MAPK, Bax, and cleaved caspase-3 and decreased the expression of Bcl-2 in a dose-dependent manner. No change in expression of phosphorylated p38 MAPK and Bax was found when cells were treated with isoalantolactone in the presence of NAC, indicating that activation of these proteins is directly dependent on ROS generation. The present study provides evidence for the first time that isoalantolactone induces ROS-dependent apoptosis through intrinsic pathway. Furthermore, our in vivo toxicity study demonstrated that isoalantolactone did not induce any acute or chronic toxicity in liver and kidneys of CD1 mice at dose of 100 mg/kg body weight. Therefore, isoalantolactone may be a safe chemotherapeutic candidate for the treatment of human pancreatic carcinoma.

High levels of stress are expected when crises affect people’s lives. Therefore, this web-based, cross-sectional study was conducted among university students from Pakistan to investigate the psychological impairment and coping strategies during COVID-19 pandemic. Google forms were used to disseminate the online questionnaire to assess anxiety (Generalized Anxiety disorder-7), depression (Patient Health Questionnaire-9) and the coping strategies (Brief-COPE). A total of 1134 responses (age 21.7±3.5 years) were included. The frequency of students having moderate-severe anxiety and depression (score ≥ 10) were ≍ 34% and 45%, respectively. The respondents’ aged ≥ 31 years had significantly lower depression score than those ≤ 20 years (p = 0.047). Males had significantly less anxiety (6.62 ± 5.70 vs 7.84 ± 5.60, p = 0.001) and depression (8.73 ± 6.84 vs 9.71 ± 7.06, p = 0.031) scores. Those having family member, friend or acquaintances infected with disease had significantly higher anxiety score (8.89 ± 5.74 vs 7.09 ± 5.56, p < 0.001). Regarding coping strategies, majority of respondents were found to have adopted religious/spiritual coping (6.45 ± 1.68) followed by acceptance (5.58 ± 1.65), self-distraction (4.97 ± 1.61) and active coping (4.81 ± 1.57). In conclusion, COVID-19 cause significant impairment on mental health of the students. The most frequent coping strategy adopted by students were religious/spiritual and acceptance coping. During epidemics mental health of students should not be neglected.

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