Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways.

Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.

E-Z Isomerization in Guanidine: Second-order Saddle Dynamics, Non-statisticality, and Time-frequency Analysis.

Our recent work on the E-Z isomerization reaction of guanidine using ab initio chemical dynamics simulations [Rashmi et al., Regul. Chaotic Dyn. 2021, 26, 119] emphasized the role of second-order saddle (SOS) in the isomerization reaction; however, we could not unequivocally establish the non-statistical nature of the dynamics followed in the reaction. In the present study, we performed thousands of on-the-fly trajectories using forces computed at the MNDO level to investigate the influence of second-order saddle in the E-Z isomerization reaction of guanidine and the role of intramolecular vibrational energy redistribution (IVR) on the reaction dynamics. The simulations reveal that while majority of the trajectories follow the traditional transition state pathways, 15 % of the trajectories follow the SOS path. The dynamics was found to be highly non-statistical with the survival probabilities of the reactants showing large deviations from those obtained within the RRKM assumptions. In addition, a detailed analysis of the dynamics using time-dependent frequencies and the frequency ratio spaces reveal the existence of multiple resonance junctions that indicate the existence of regular dynamics and long-lived quasi-periodic trajectories in the phase space associated with non-RRKM behavior.

Effect of different levels of gibberellic acid and kinetin on quality and self-life of banana (Musa spp.) fruits.

Artificial fruit ripening agents have become increasingly popular in recent years. During the off-seasons, various ripening agents are used for the ripening of banana fruits. The effects of various ripening agents of banana fruits (variety: Malbhog) were studied. Seven treatments consisting of distilled water, Gibberellic acid (GA3) @ 100 ppm, GA3 @ 200 ppm, GA3 @ 300 ppm, kinetin @ 3 ppm, kinetin @ 5 ppm, and kinetin @ 7 ppm were laid out in a Completely Randomized Design with three replications. The maximum loss in weight (9.195%), Total Soluble Solids (20.33˚B), the highest color score (6), pH (4.767), Total Soluble Solids/Titratable Acidity TA (34.23), and Pulp peel ratio (2.84) were observed in banana sprayed with distilled water whereas the minimum value for TSS (12.67˚B), pulp peel ratio (1.813), peel color rating (2.67), TSS/TA (15.32) were observed in GA3 @ 300 ppm treated fruits. The maximum (32.67 days) and the minimum (18.33 days) shelf-life was observed in GA3 @ 300 ppm and distilled water respectively. This research will help in the regulation of ripening as per the needs of consumers and the distance of the market. In horticulture, it will help to extend storage life and reduce quality and economic loss.

Stable chaos and delayed onset of statisticality in unimolecular dissociation reactions.

Statistical models provide a powerful and useful class of approximations for calculating reaction rates by bypassing the need for detailed, and often difficult, dynamical considerations. Such approaches invariably invoke specific assumptions about the extent of intramolecular vibrational energy flow in the system. However, the nature of the transition to the statistical regime as a function of the molecular parameters is far from being completely understood. Here, we use tools from nonlinear dynamics to study the transition to statisticality in a model unimolecular reaction by explicitly visualizing the high dimensional classical phase space. We identify generic features in the phase space involving the intersection of two or more independent anharmonic resonances and show that the presence of correlated, but chaotic, intramolecular dynamics near such junctions leads to nonstatisticality. Interestingly, akin to the stability of asteroids in the Solar System, molecules can stay protected from dissociation at the junctions for several picoseconds due to the phenomenon of stable chaos.

Breaking of a bond: when is it statistical?

Unimolecular dissociation dynamics of a model three degree of freedom triatomic molecule is studied in order to understand the mechanisms for deviations from statisticality. Performing a wavelet based time-frequency analysis of the dynamics allows for the dynamics to be followed on the network of nonlinear resonances, also called as the Arnold web. The results indicate that the long lifetime trajectories spend a considerable amount of time trapped near junctions in the web. It is argued that characterizing the dynamics near such junctions might lead to deeper insights into the origins of nonstatistical dynamics.

Sinonasal Neoplasia - Clinicopathological Profile And Importance of Computed Tomography.

BACKGROUND: Nasal cavity and Paranasal sinus malignancies are very rare, in which maxillary sinus is the commonest, followed by ethmoid, frontal and sphenoid sinus. Computed Tomography (CT) & Magnetic Resonance Imaging (MRI) play a key role in diagnosis, staging and management of paranasal sinuses and nasal pathologies. Multiplanar imaging in CT helps better imaging of critical anatomical areas. Aim of our study was to study the incidence, clinical features, CT features and its importance in the management of sinonasal neoplasms. MATERIALS AND METHODS: This prospective study was carried out in a tertiary care hospital of MP, India. Consecutive 40 histologically proven cases of sinonasal neoplasia who visited the Department of Otorhinolaryngology and Radiotherapy are included in our study. Demography and clinical features were recorded. Cases of nasal and paranasal sinus masses diagnosed on CT attending ENT and Radiotherapy OPD or admitted in the Radiotherapy ward forms the material of this study. This included patients of both sexes and all ages. Histopathological examination was asked to confirm the diagnosis made on CT. RESULTS: There were total 40 cases of sinonasal neoplasia among which 24 were benign. Almost all the benign cases were seen in the age group <40 y with mean age of 20 y and most of the malignant cases were seen in the age group above 40 y with mean age of 55 y. In our study we found male preponderance with male female ratio of 4:1 in both benign and malignant conditions. The commonest presenting symptoms of the patients with sinonasal masses in our study was nasal obstruction (75%) and nasal discharge (67.5%) followed by nasal mass (65%), epistaxis (62.5%) and headache (60%). Angiofibroma and papilloma were the commonest benign lesions. Commonest malignant lesion was squamous cell carcinoma. Of the malignant Sinonasal tumours studied in our series, maxillary sinus was involved in 13, ethmoid sinuses and nasal cavity in 10 cases each, and frontal sinuses in 2 cases. CONCLUSION: Contrast enhanced computed tomography with multiplanar reconstruction is an excellent modality for imaging sinonasal masses. CT can define the character of the sinonasal mass, thus differentiating benign from malignant. CT helps better imaging of critical anatomical areas and helpful in planning treatment procedures such as surgery and radiotherapy.