The relationships and seasonal-to-annual variations among evapotranspiration (ET), precipitation (P), terrestrial water storage anomalies (TWSA), radiation (downward shortwave radiation, DSR), and phenology (leaf area index, LAI) are complex across the Amazon basin. To analyze how ET is controlled by these influencing factors, we used wavelet phase difference (WPD) to investigate the effects of P, TWSA, DSR, and LAI on ET at different spatiotemporal scales. The Amazon-scale averaged ET has strong correlations with these factors at the annual and multi-year periodicities. The patterns of WPDs have south-north and west-east divides due to the significant variation in climatic conditions. The results demonstrate that ET is mainly affected by water and energy availability while vegetation regulates both processes. The deep soil moisture/groundwater can provide strong subsidies to ET during the meteorological dry season in the water-limited area of Amazon. The WPD can well reflect the responses of ET to the variations of P, TWSA, DSR, and LAI, and the process of vegetation sustaining ET in the dry years in the water-limited area of the Amazon.

Aims

Myocardial injury after noncardiac surgery (MINS) is common in elderly patients and considered as an independent predictor of 30-day mortality after noncardiac surgery. Dexmedetomidine possesses cardiac-protective profile. Previous clinical studies have found that perioperative application of dexmedetomidine is associated with decreased 1-year mortality in patients undergoing cardiac surgery. The current study protocol aims to investigate the effects of dexmedetomidine on the incidence of MINS, complications, and 30-day mortality in elderly patients subjected to noncardiac surgery.

Methods

A multicenter, randomized, controlled, double-blind, prospective trial is designed to explore cardiac protection of dexmedetomidine in the elderly patients undergoing noncardiac surgery. A total of 960 patients aged over 65 years will be recruited and randomly assigned to dexmedetomidine group (group Dex) and normal saline placebo group (group NS) in a ratio of 1:1. Patients in group Dex will receive a bolus dose of 0.5 μg/kg dexmedetomidine within 10 min before surgical incision, followed by a consistent infusion at the rate of 0.3-0.5 μg/kg/h throughout the operation. Group NS patients will receive the same volume of normal saline. The primary outcome is the incidence of MINS via detecting the hs-TnT level within 3 days after the operation. The secondary outcome includes myocardial ischemic symptoms, the incidence of major adverse cardiovascular events (MACE) in hospital, length of ICU and postoperative hospital stay, the incidence of inhospital complications, and 30-day all-cause mortality.

Discussion

The results of the current study will illustrate the effect of dexmedetomidine on myocardial injury for elderly patients undergoing major noncardiac surgery.

Trial registration

The trial was registered with Chinese Clinical Trial Registry (CHICTR) on Aug 24, 2021 (ChiCTR2100049946, http://www.chictr.org.cn/showproj.aspx?proj=131804 ).

Multiple myeloma (MM), a plasma cell malignancy, is the second most prevalent hematologic malignancy in the US. Although much effort has been made trying to understand the etiology and the complexities of this disease with the hope of developing effective therapies, MM remains incurable at this time. Because of their antiproliferative and proapoptotic activities, interferons (IFNs) have been used to treat various malignancies, including MM. Although some success has been observed, the inherent toxicities of IFNs limit their efficacy. To address this problem, we produced anti-CD138 antibody fusion proteins containing either IFNα2 or a mutant IFNα2 (IFNα2(YNS)) with the goal of targeting IFN to CD138-expressing cells, thereby achieving effective IFN concentrations at the site of the tumor in the absence of toxicity. The fusion proteins inhibited the proliferation and induced apoptosis of U266, ANBL-6, NCI-H929, and MM1-144 MM cell lines. The fusion proteins decreased the expression of IFN regulatory factor 4 (IRF4) in U266. In addition, the fusion proteins were effective against primary cells from MM patients, and treatment with fusion proteins prolonged survival in the U266 murine model of MM. These studies show that IFNα antibody fusion proteins can be effective novel therapeutics for the treatment of MM.

Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1α signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1α and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1α prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1α expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1α signalling.

Soluble epoxide hydrolase (sEH) plays a critical role in inflammation by modulating levels of epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs). Here, we investigate the possible role of sEH in lipopolysaccharide (LPS)-mediated macrophage activation and acute lung injury (ALI). In this study, we found that a small molecule, wedelolactone (WED), targeted sEH and led to macrophage inactivation. Through the molecular interaction with amino acids Phe362 and Gln384, WED suppressed sEH activity to enhance levels of EETs, thus attenuating inflammation and oxidative stress by regulating glycogen synthase kinase 3beta (GSK3β)-mediated nuclear factor-kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) pathways in vitro. In an LPS-stimulated ALI animal model, pharmacological sEH inhibition by WED or sEH knockout (KO) alleviated pulmonary damage, such as the increase in the alveolar wall thickness and collapse. Additionally, WED or sEH genetic KO both suppressed macrophage activation and attenuated inflammation and oxidative stress in vivo. These findings provided the broader prospects for ALI treatment by targeting sEH to alleviate inflammation and oxidative stress and suggested WED as a natural lead candidate for the development of novel synthetic sEH inhibitors.

Background

Heat shock protein 70 (Hsp70) has been shown to exert cardioprotection. Intracellular calcium ([Ca²⁺]_i) overload induced by p38 mitogen-activated protein kinase (p38 MAPK) activation contributes to cardiac ischemia/reperfusion (I/R) injury. However, whether Hsp70 interacts with p38 MAPK signaling is unclear. Therefore, this study investigated the regulation of p38 MAPK by Hsp70 in I/R-induced cardiac injury.

Methods

Neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation for 6 h followed by 2 h reoxygenation (OGD/R), and rats underwent left anterior artery ligation for 30 min followed by 30 min of reperfusion. The p38 MAPK inhibitor (SB203580), Hsp70 inhibitor (Quercetin), and Hsp70 short hairpin RNA (shRNA) were used prior to OGD/R or I/R. Cell viability, lactate dehydrogenase (LDH) release, serum cardiac troponin I (cTnI), [Ca²⁺]_i levels, cell apoptosis, myocardial infarct size, mRNA level of IL-1β and IL-6, and protein expression of Hsp70, phosphorylated p38 MAPK (p-p38 MAPK), sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2), phosphorylated signal transducer and activator of transcription3 (p-STAT3), and cleaved caspase3 were assessed.

Results

Pretreatment with a p38 MAPK inhibitor, SB203580, significantly attenuated OGD/R-induced cell injury or I/R-induced myocardial injury, as evidenced by improved cell viability and lower LDH release, resulted in lower serum cTnI and myocardial infarct size, alleviation of [Ca²⁺]_i overload and cell apoptosis, inhibition of IL-1β and IL-6, and modulation of protein expressions of p-p38 MAPK, SERCA2, p-STAT3, and cleaved-caspase3. Knockdown of Hsp70 by shRNA exacerbated OGD/R-induced cell injury, which was effectively abolished by SB203580. Moreover, inhibition of Hsp70 by quercetin enhanced I/R-induced myocardial injury, while SB203580 pretreatment reversed the harmful effects caused by quercetin.

Conclusions

Inhibition of Hsp70 aggravates [Ca²⁺]_i overload, inflammation, and apoptosis through regulating p38 MAPK signaling during cardiac I/R injury, which may help provide novel insight into cardioprotective strategies.

Purpose

Intracellular calcium ([Ca²⁺]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca²⁺ signaling.

Methods

H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca²⁺]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed.

Results

Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca²⁺]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX.

Conclusion

This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca²⁺]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

PURPOSE: Intracellular calcium ([Ca2+]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca2+ signaling. METHODS: H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca2+]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed. RESULTS: Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca2+]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX. CONCLUSION: This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca2+]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

The RNA-binding protein, trans-active response DNA-binding protein 43 (TDP-43), is normally found in the nucleus, but in amyotrophic lateral sclerosis, frontal temporal dementia, and some cases of Alzheimer disease it is cleaved and mislocalized to the cytosol, leading to accumulation. The mechanisms contributing to this are largely unknown. Here, we show that part of the normal clearance cascade for TDP-43 involves the Cdc37/Hsp90 complex. An Hsp90 inhibitor that disrupts the Cdc37/Hsp90 complex reduced TDP-43 levels to a greater extent than a standard Hsp90 ATPase inhibitor. When Cdc37 was depleted, TDP-43 underwent proteolytic clearance that was dependent on nuclear retrotranslocation and autophagic uptake. Accumulation of the microtubule-associated protein tau prevented the clearance of cleaved TDP-43, but not its production. This caused cleaved TDP-43 to accumulate, a feature observed in the brain of persons with Alzheimer disease. Clearance of cleaved TDP-43 was also prevented by knockdown of the autophagic inducer beclin1. Thus, in cells where TDP-43 clearance is normally needed, a system that employs manipulation of the Hsp90 complex and autophagy exists. But when tau accumulation is occurring, cleaved TDP-43 can no longer be cleared, perhaps explaining the emergence of these co-pathologies.

Children with repeated inhalational anesthesia may develop cognitive disorders. This study aimed to investigate the transcriptome-wide response of hippocampus in young mice that had been exposed to multiple sevoflurane in the neonatal period. Mice received 3% sevoflurane for 2 h on postnatal day (PND) 6, 8, and 10, followed by arterial blood gas test on PND 10, behavioral experiments on PND 31-36, and RNA sequencing (RNA-seq) of hippocampus on PND 37. Functional annotation and protein-protein interaction analyses of differentially expressed genes (DEGs) and quantitative reverse transcription polymerase chain reaction (qPCR) were performed. Neonatal sevoflurane exposures induced cognitive and social behavior disorders in young mice. RNA-seq identified a total of 314 DEGs. Several enriched biological processes (ion channels, brain development, learning, and memory) and signaling pathways (oxytocin signaling pathway and glutamatergic, cholinergic, and GABAergic synapses) were highlighted. As hub-proteins, Pten was involved in nervous system development, synapse assembly, learning, memory, and behaviors, Nos3 and Pik3cd in oxytocin signaling pathway, and Cdk16 in exocytosis and phosphorylation. Some top DEGs were validated by qPCR. This study revealed a transcriptome-wide profile in mice hippocampus after multiple neonatal exposures to sevoflurane, promoting better understanding of underlying mechanisms and investigation of preventive strategies.