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Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.

Human activities have led to a global temperature increase, and the primary objective of the Paris Agreement is to limit this rise to 1.5 °C of warming level. Understanding the impact of global warming beyond preindustrial conditions on precipitation intensity is crucial for devising effective adaptation and mitigation strategies, particularly in densely populated global land monsoon (GLM) regions. However, the time of emergence (ToE) of extreme summer monsoon precipitation and its dependency on global warming targets has rarely been investigated. Using large ensemble simulations forced by the SSP3–7.0 scenario, we reveal that the impacts of anthropogenic forcing on extreme precipitation intensity become evident in GLM regions before 2050, accompanied by a sudden expansion in areas where the ToE of extreme precipitation occurs. Furthermore, our study demonstrates that achieving the Paris Agreement goal at 1.5 °C of global warming level can prevent the ToE of extreme precipitation in Asian and African monsoon regions. This, in turn, has the potential to halve the number (over one billion) of individuals exposed to extreme precipitation. These findings highlight the urgent need for action to mitigate the risk associated with anthropogenic warming induced climate change.

A library of 24 congeners of the natural product sulfuretin were evaluated against nine panels representing nine cancer diseases. While sulfuretin elicited very weak activities at 10 µM concentration, congener 1t was identified as a potential compound triggering growth inhibition of diverse cell lines. Mechanistic studies in HCT116 colon cancer cells revealed that congener 1t dose-dependently increased levels of cleaved-caspases 8 and 9 and cleaved-PARP, while it concentration-dependently decreased levels of CDK4, CDK6, Cdc25A, and Cyclin D and E resulting in induction of cell cycle arrest and apoptosis in colon cancer HCT116 cells. Mechanistic study also presented MET receptor tyrosine kinase as the molecular target mediating the anticancer activity of compound 1t in HCT116 cells. In silico study predicted folded p-loop conformation as the form of MET receptor tyrosine kinase responsible for binding of compound 1t. Together, the current study presents compound 1t as an interesting anticancer lead for further development.

Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells’ death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a multifunctional agent that inhibits the oxidative catabolism of monoamine neurotransmitters and, hence, the detrimental production of ROS while enhancing neurotransmitter levels. Such a multifunctional agent might also inhibit acetylcholinesterase and neuroinflammation. To meet this end goal, a series of aminoalkyl derivatives of analogs of the natural product hispidol were designed, synthesized, and evaluated against both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Promising MAO inhibitors were further checked for the inhibition of acetylcholinesterase and neuroinflammation. Among them, compounds 3aa and 3bc were identified as potential multifunctional molecules eliciting submicromolar selective MAO-B inhibition, low-micromolar AChE inhibition, and the inhibition of microglial PGE2 production. An evaluation of their effects on memory and cognitive impairments using a passive avoidance test confirmed the in vivo activity of compound 3bc, which showed comparable activity to donepezil. In silico molecular docking provided insights into the MAO and acetylcholinesterase inhibitory activities of compounds 3aa and 3bc. These findings suggest compound 3bc as a potential lead for the further development of agents against neurodegenerative diseases.

Abstract Future change in summertime rainfall under a warmer climate will impact the lives of more than two-thirds of the world’s population. However, the future changes in the duration of the rainy season affected by regional characteristics are not yet entirely understood. We try to understand changes in the length of the rainy season as well as the amounts of the future summertime precipitation, and the related processes over regional monsoon domains using phase six of the Coupled Model Intercomparison Project archive. Projections reveal extensions of the rainy season over the most of monsoon domains, except over the American monsoon. Enhancing the precipitation in the future climate has various increasing rates depending on the subregional monsoon, and it is mainly affected by changes in thermodynamic factors. This study promotes awareness for the risk of unforeseen future situations by showing regional changes in precipitation according to future scenarios.

Direct growth inhibition of infectious organisms coupled with immunomodulation to counteract the immunosuppressive environment might be a beneficial therapeutic approach. Herein, a library of sulfuretin analogs were developed with potential capabilities to inhibit production of the immunosuppressive PGE2 and elicit direct growth inhibition against Leishmania donovani; the major causative agent of the fatal visceral leishmaniasis. Amongst explored library members bearing diverse methoxy and/or hydroxy substitution patterns at rings B and A, analog 1i retaining the C6-hydroxy moiety at ring-A, but possessing methoxy moieties in place of the polar dihydroxy moieties of sulfuretin ring-B, as well as analog 1q retaining the sulfuretin′s polar dihydroxy moieties at ring-B, but incorporating a C6-methoxy moiety instead of the C6-hydroxy moiety at ring-A, were the most promising hit compounds. Cytotoxicity evaluation suggested that analog 1i possesses a safety profile inducing the death of the parasite rather than host cells. In silico simulation provided insights into their possible binding with Leishmania donovani fumarate reductase. The current investigation presents sulfuretin analogs 1i and 1q as potential hit compounds for further development of multifunctional therapeutic agents against visceral leishmaniasis.

The Indo-Pacific warm pool (IPWP) is enclosed by a 28 °C isotherm and plays a vital role in controlling atmospheric circulations. However, the effects of changes in regional warm pool sea surface temperatures (SSTs) remain unexplored. We divided the IPWP into the Indian and Pacific sectors and distinguished their responses to natural variability and global warming. Furthermore, we examined the impacts of the interannual variability (IAV) in warm pool SST on the tropical Hadley, Walker, and monsoon circulations. The Hadley circulation was affected by warm pool SST warming, i.e., warmer SSTs over the warm pool strengthened the upward branch of Hadley circulation, whereas the downward branch was respectively weakened and strengthened in the Northern and Southern Hemispheres. Walker circulation was strengthened (weakened) in the warming (natural) mode. Consequently, the Walker circulation is weakened since the natural variability of warm pool SST plays a more dominant role rather than the warming trend of SSTs over the warm pool. Furthermore, our analysis displays that warm pool warming has little impact on the monsoon circulation. Our findings highlight the different roles of the IAV of warm pool regions in each tropical circulation as part of the warming trend and natural variability.

Summer monsoon frontal rainfall in East Asia (EA) is crucial for water resources and flood hazards in densely populated areas. Recent studies have documented the increasing intensity of summer frontal rainfall over recent decades. However, the extent of ongoing climate change on the intensification of the EA frontal precipitation system remains uncertain. Using an objective method for detecting frontal systems, we found a 17 ± 3% increase in observed frontal rainfall intensity during 1958 to 2015. Climate model simulations with and without greenhouse gases suggest that anthropogenic warming plays a key role in the intensification of EA summer frontal precipitation by 5.8% from 1991 to 2015. The analysis highlights that enhanced water vapor convergence and reinforced western North Pacific subtropical High collectively increased moisture transport to the region, resulting in intensified EA frontal precipitation. The results lend support to the anthropogenic warming-induced enhancement of the EA frontal precipitation and its persistence in the future. [ABSTRACT FROM AUTHOR]

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease. [ABSTRACT FROM AUTHOR]