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Arterial blood pressure is controlled by vasodilatory factors such as nitric oxide (NO) that are released from the endothelium under the influence of fluid shear stress exerted by flowing blood. Flow-induced endothelial release of ATP and subsequent activation of Gq/G11-coupled purinergic P2Y2 receptors have been shown to mediate fluid shear stress-induced stimulation of NO formation. However, the mechanism by which fluid shear stress initiates these processes is unclear. Here, we have shown that the endothelial mechanosensitive cation channel PIEZO1 is required for flow-induced ATP release and subsequent P2Y2/Gq/G11-mediated activation of downstream signaling that results in phosphorylation and activation of AKT and endothelial NOS. We also demonstrated that PIEZO1-dependent ATP release is mediated in part by pannexin channels. The PIEZO1 activator Yoda1 mimicked the effect of fluid shear stress on endothelial cells and induced vasorelaxation in a PIEZO1-dependent manner. Furthermore, mice with induced endothelium-specific PIEZO1 deficiency lost the ability to induce NO formation and vasodilation in response to flow and consequently developed hypertension. Together, our data demonstrate that PIEZO1 is required for the regulation of NO formation, vascular tone, and blood pressure.

White adipose tissue (WAT) expansion in obesity occurs through enlargement of preexisting adipocytes (hypertrophy) and through formation of new adipocytes (adipogenesis). Adipogenesis results in WAT hyperplasia, smaller adipocytes and a metabolically more favourable form of obesity. How obesogenic WAT hyperplasia is induced remains, however, poorly understood. Here, we show that the mechanosensitive cationic channel Piezo1 mediates diet-induced adipogenesis. Mice lacking Piezo1 in mature adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed a high fat diet (HFD) resulting in larger adipocytes, increased WAT inflammation and reduced insulin sensitivity. Opening of Piezo1 in mature adipocytes causes the release of the adipogenic fibroblast growth factor 1 (FGF1), which induces adipocyte precursor differentiation through activation of the FGF-receptor-1. These data identify a central feed-back mechanism by which mature adipocytes control adipogenesis during the development of obesity and suggest Piezo1-mediated adipocyte mechano-signalling as a mechanism to modulate obesity and its metabolic consequences. Adipose tissue expansion occurs via enlargement of adipocytes as well as the generation of new fat cells, the latter being associated with more favorable metabolic outcomes. Here, the authors show that activation of adipocyte Piezo1 results in release of FGF1 and stimulates the differentiation of adipocyte precursor cells.

The expansion of the white adipose tissue (WAT) in obesity goes along with increased mechanical, metabolic and inflammatory stress. How adipocytes resist this stress is still poorly understood. Both in human and mouse adipocytes, the transcriptional co-activators YAP/TAZ and YAP/TAZ target genes become activated during obesity. When fed a high-fat diet (HFD), mice lacking YAP/TAZ in white adipocytes develop severe lipodystrophy with adipocyte cell death. The pro-apoptotic factor BIM, which is downregulated in adipocytes of obese mice and humans, is strongly upregulated in YAP/TAZ-deficient adipocytes under HFD, and suppression of BIM expression reduces adipocyte apoptosis. In differentiated adipocytes, TNFα and IL-1β promote YAP/TAZ nuclear translocation via activation of RhoA-mediated actomyosin contractility and increase YAP/TAZ-mediated transcriptional regulation by activation of c-Jun N-terminal kinase (JNK) and AP-1. Our data indicate that the YAP/TAZ signaling pathway may be a target to control adipocyte cell death and compensatory adipogenesis during obesity. The expansion of the white adipose tissue during obesity is accompanied by increased cellular stress, but factors that protect adipocytes from cell death are not well known. Here the authors report that the transcriptional co-activators YAP and TAZ are activated in adipocytes during obesity, which increases adipocyte survival through the proapoptotic factor BIM.

The El Niño/Southern Oscillation is characterized by irregular warm (El Niño) and cold (La Niña) events in the tropical Pacific Ocean, which have substantial global environmental and socioeconomic impacts. These events are generally attributed to the instability of basin-scale air–sea interactions in the equatorial Pacific. However, the role of sub-basin-scale processes in the El Niño/Southern Oscillation life cycle remains unknown due to the scarcity of observations and coarse resolution of climate models. Here, using a long-term high-resolution global climate simulation, we find that equatorial ocean eddies with horizontal wavelengths less than several hundred kilometres substantially inhibit the growth of La Niña and El Niño events. These submesoscale eddies are regulated by the intensity of Pacific cold-tongue temperature fronts. The eddies generate an anomalous surface cooling tendency during El Niño by inducing a reduced upward heat flux from the subsurface to the surface in the central-eastern equatorial Pacific; the opposite occurs during La Niña. This dampening effect is missing in the majority of state-of-the-art climate models. Our findings identify a pathway to resolve the long-standing overestimation of El Niño and La Niña amplitudes in climate simulations. Submesoscale ocean eddies inhibit the growth of La Niña and El Niño events, according to an analysis of long-term high-resolution global climate simulations.

Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including anti-proliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

El Niño-Southern Oscillation (ENSO) features strong warm events in the eastern equatorial Pacific (EP), or mild warm and strong cold events in the central Pacific (CP), with distinct impacts on global climates. Under transient greenhouse warming, models project increased sea surface temperature (SST) variability of both ENSO regimes, but the timing of emergence out of internal variability remains unknown for either regime. Here we find increased EP-ENSO SST variability emerging by around 2030 ± 6, more than a decade earlier than that of CP-ENSO, and approximately four decades earlier than that previously suggested without separating the two regimes. The earlier EP-ENSO emergence results from a stronger increase in EP-ENSO rainfall response, which boosts the signal of increased SST variability, and is enhanced by ENSO non-linear atmospheric feedback. Thus, increased ENSO SST variability under greenhouse warming is likely to emerge first in the eastern than central Pacific, and decades earlier than previously anticipated. Under global warming, increased variability in El Niño sea surface temperature was projected to be detectable by about 2070. Here the authors show that the increased variability of a type of more impactful El Niño events is likely detectable by 2030.

Upwelling along oceanic eastern boundaries has attracted significant attention due to its profound effects on ocean productivity and associated biological and socioeconomic implications. However, uncertainty persists regarding the evolution of coastal upwelling with climate change, particularly its impact on future biological production. Here, using a series of state-of-the-art climate models, we identify a significant seasonal advancement and prolonged duration of upwelling in major upwelling systems. Nevertheless, the upwelling intensity (total volume of upwelled water) exhibits complex changes in the future. In the North Pacific, the upwelling is expected to attenuate, albeit with a minor magnitude. Conversely, in other basins, coastal upwelling diminishes significantly in equatorward regions but displays a slight decline or even an enhancement at higher latitudes. The climate simulations also reveal a robust connection between changes in upwelling intensity and net primary production, highlighting the crucial impact of future coastal upwelling alterations on marine ecosystems. Utilizing high-resolution climate models under a high emission scenario, this study demonstrates an anticipated advancement and extension of the coastal upwelling season, accompanied by intricate variations in intensity along oceanic eastern boundaries.

The Atlantic Niño/Niña is a leading mode of tropical climate variability with profound global environmental and socioeconomic impacts. Conventionally, its variability is projected to weaken under greenhouse warming, primarily attributed to suppressed basin‐scale air–sea interactions. However, the modulating role of sub‐basin‐scale ocean dynamical processes remains largely unexplored. Here, using an ensemble of high‐resolution climate simulations, we show that submesoscale ocean eddies substantially dampen Atlantic Niño/Niña variability by regulating vertical heat transport. Under greenhouse warming, this eddy‐induced damping is projected to diminish due to the suppressed Atlantic cold tongue and enhanced upper‐ocean stratification. Consequently, this attenuation of damping buffers approximately one‐third of the variability weakening driven by basin‐scale processes. This mechanism is corroborated by comparison with standard‐resolution climate simulations, which fail to resolve submesoscale eddies, and is further supported by CMIP6 model outputs. These findings highlight the critical importance of resolving fine‐scale ocean processes to improve the fidelity of future climate projections.

The risk of ulcerative colitis (UC) is increasing worldwide with limited success using classical drugs, which has underscored the development of novel agents. Recently, carrier-free molecular assembly has been proven to be an effective drug delivery system, but it has yet to be examined for UC drug development using phytochemicals. Based on traditional Chinese medicine compatibility and potential medicinal uses, a pair of natural compounds, berberine (BBR) and magnolol (MAG), were found to self-assemble into nanostructures in aqueous solutions. Spectral analysis revealed that the assembly mechanisms of BBR and MAG were mediated through charge interactions and π-π stacking. Pharmacokinetic studies and animal imaging showed that BBR-MAG self-assembly (BM) effectively promoted the oral bioavailability and biodistribution of BBR in the colon. BM exhibited superior effects in regulating inflammatory factors, maintaining colon barrier integrity, and regulating gut microbiota in a dextran sulfate sodium salt-induced colitis mouse model. Additionally, no apparent signs of toxicity were observed, suggesting that BM has a favorable safety profile. This study presents a new strategy for UC management and highlights the cooperative effects of combined phytochemicals. Graphical Abstract

The response of upwelling in the eastern boundary upwelling systems (EBUSs) to anthropogenic climate change has attracted much scientific attention due to its core role in nourishing marine ecosystems. A decade‐old hypothesis suggests that greenhouse warming may intensify upwelling‐favorable winds and subsequently the upwelling in EBUSs, but the impact of greenhouse warming on the seasonal cycle of upwelling remains unknown. Using the recent generation of global climate simulations under a high carbon emission scenario, we show a universal weakening of the upwelling seasonal cycle in the major EBUSs. This is mainly ascribed to the projected weakened seasonal cycle of the upwelling‐favorable winds. In addition, long‐term changes in geostrophic transport exert a nonnegligible contribution to the changes in the upwelling seasonal cycle. Our study suggests that the upwelling in the EBUSs is likely to have a more complicated response to greenhouse warming than previously thought. Plain Language Summary The eastern boundary upwelling systems (EBUSs), along the eastern boundaries of the Pacific and Atlantic basins, contain the most diverse marine ecosystems and provide competitive commercial industries. Thus, the potential changes of EBUSs to anthropogenic climate change are of concern for the associated ecosystem and coastal communities. Greenhouse warming threatens the ecosystems by changing the mean‐state eastern boundary upwelling and its seasonal cycle, with the latter being limitedly discussed in previous studies. Using a series of state‐of‐the‐art climate simulations, we show that the seasonal cycle of the upwelling in the major EBUSs will be weakened under a high carbon emission scenario. This attenuated seasonal cycle of upwelling is majorly caused by the weakened seasonal cycle of the equatorward alongshore winds. Moreover, we further investigate the role of geostrophic transport in upwelling seasonality's changes under global warming. We find that the cross‐shore geostrophic transport also plays a nonnegligible role in the response of upwelling seasonality to greenhouse warming, counteracting the wind‐driven changes in the Chile Current System but enhancing upwelling changes in other EBUSs. Key Points The seasonal cycle of upwelling in the major eastern boundary upwelling systems is weakened under greenhouse warming The weakened eastern boundary upwelling seasonal cycle is mainly attributed to the projected alongshore wind changes Geostrophic transport changes are nonnegligible to the changes in the eastern boundary upwelling seasonal cycle