Background: Upper respiratory infections (URIs) are among the most common diseases. However, the related burden has not been comprehensively evaluated. Thus, we designed the present study to describe the global and regional burden of URIs from 1990 to 2019. Methods: A secondary analysis was performed on the incidence, mortality, and disability-adjusted life years (DALYs) of URIs in different sex and age groups, from 21 geographic regions, 204 countries and territories, between 1990 and 2019, using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Countries and territories were categorized according to Socio-demographic Index (SDI) quintiles. Findings: Globally, the incident cases of URIs reached 17¢2 (95% uncertainty interval: 15¢4 to 19¢3) billion in 2019, which accounted for 42¢83% (40¢01% to 45¢77%) cases from all causes in the GBD 2019 study. The age-standardized incidence rate remained stable from 1990 to 2019, while significant decreases were found in the mortality and DALY rate. The highest age-standardized incidence rates from 1990 to 2019 and the highest age-standardized DALY rates after 2011 were observed in high SDI regions. Among all the age groups, children under five years old suffered from the highest incidence and DALY rates, both of which were decreased with increasing age. Fatal consequences of URIs occurred mostly in the elderly and children under five years old. Interpretation: The present study provided comprehensive estimates of URIs burden for the first time. Our findings, highlighting the substantial incidence and considerable DALYs due to URIs, are expected to attract more attention to URIs and provide future explorations in the prevention and treatment with epidemiological evidence.

Recently, autophagy has drawn more attention in cardiovascular disease as it has important roles in lipid metabolism. Mammalian target of rapamycin (mTOR) is a key regulator of autophagy; however, its effect on atherosclerosis and the underlying mechanism remains undefined. In this study, an obvious upregulation of mTOR and p-mTOR protein was observed in macrophage-derived foam cells. Blocking mTOR expression with specific small interference RNA (siRNA) dramatically suppressed foam cell formation, accompanied by a decrease of lipid deposition. Further mechanistic analysis indicated that suppressing mTOR expression significantly upregulated autophagic marker LC3 expression and downregulated autophagy substrate p62 levels, indicating that mTOR silencing triggered autophagosome formation. Moreover, blocking mTOR expression obviously accelerated neutral lipid delivery to lysosome and cholesterol efflux from foam cells, implying that mTOR could induce macrophage foam cell formation by suppressing autophagic pathway. Further, mTOR silencing significantly upregulated ULK1 expression, which was accounted for mTOR-induced foam cell formation via autophagic pathway as treatment with ULK1 siRNA dampened LC3-II levels and increased p62 expression, concomitant with lipid accumulation and decreased cholesterol efflux from foam cells. Together, our data provide an insight into how mTOR accelerates the pathological process of atherosclerosis. Accordingly, blocking mTOR levels may be a promising therapeutic agent against atherosclerotic complications.

Atherosclerotic plaque destabilization and rupture leads to acute coronary syndromes which cause serious damage to human health worldwide. However, there is currently a lack of efficient therapeutic methods. Mammalian target of rapamycin (mTOR) has been suggested to be involved in the development of atherosclerotic plaques and serves as a therapeutic target. The present study was performed to determine whether RNA interference (RNAi) of mTOR in vivo by LV‑mediated small hairpin RNA (shRNA) was capable of inhibiting the progression of atherosclerotic plaques. LV‑mediated shRNA against mTOR (LV‑shmTOR) was designed and obtained. Male apolipoprotein E‑deficient mice were fed a high‑fat diet and a constrictive collar was placed around the right carotid arteries of these mice to induce plaque formation. Eight weeks after surgery, mice were randomly divided into the mTOR RNA interference (LV‑shmTOR) group, receiving treatment with LV‑mTOR‑shRNA; the LV‑shCON group, receiving treatment with LV‑non‑specific‑shRNA; and the control group, receiving treatment with phosphate‑buffered saline. Following transfection, the mice were sacrificed to evaluate the effects of mTOR expression silencing on atherosclerosis. Transfection of LV‑mTOR‑shRNA markedly inhibited the mRNA and protein expression levels. Knockdown of mTOR ameliorated dysregulated blood lipid metabolism and stabilized aortic atherosclerotic plaques by decreasing the plaque area and increasing the fibrous cap and cap‑to‑core ratio. Furthermore, macrophages were decreased by silencing mTOR in atherosclerotic plaques. In addition, western blot analysis revealed that the knockdown of mTOR increased autophagy‑related protein 13 (Atg13) dephosphorylation and light chain 3‑I/light chain 3‑II (LC3‑I/LC3‑II) ratios, both of which were associated with a high activity of autophagy, suggesting an increase of autophagy in atherosclerotic plaques. Moreover, genes including matrix metalloproteinase 2, monocyte chemoattractant protein 1 and tissue factor, which promote plaque instability, were downregulated by silencing mTOR. These results demonstrate that LV‑mediated mTOR silencing by RNAi treatment induces macrophage autophagy and is a potential strategy for the treatment of atherosclerotic plaques.

It has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling. Treatment of PAH model with specific Notch inhibitor DAPT significantly reduced right ventricle systolic pressure to 26.6 ± 1.3 mmHg and right ventricle hypertrophy index to 33.5 ± 2.6% (P < 0.05 versus PAH), suppressed proliferation and enhanced apoptosis of pulmonary vascular cells as well as inhibited pulmonary arteries remodeling. Our results further indicated that level of Notch3 protein and NICD3 were increased in MCT-induced model of PAH, this was accompanied with elevation of Skp2 and Hes1 protein level and reduction of P27Kip1. Administration of rats with DAPT-prevented MCT induced these changes. Our results suggest that Notch3 signaling activation stimulated pulmonary vascular cells proliferation by Skp2-and Hes1-mediated P27Kip1 reduction, and Notch3 might be a new target to treat PAH.

Background Previous studies have suggested that sleep timing is associated with cardiovascular risk factors. However, there is no evidence on the relationship between sleep timing and congestive heart failure (CHF). We aimed to examine this relationship in this study. Methods and Results We recruited 4765 participants (2207 men; mean age, 63.6±11.0 years) from the SHHS (Sleep Heart Health Study) database in this multicenter prospective cohort study. Follow‐up was conducted until the first CHF diagnosis between baseline and the final censoring date. Sleep timing (bedtimes and wake‐up times on weekdays and weekends) was based on a self‐reported questionnaire. Cox proportional hazard models were constructed to investigate the association between sleep timing and CHF. During the mean follow‐up period of 11 years, 519 cases of CHF (10.9%) were reported. The multivariable Cox proportional hazards models revealed that participants with weekday bedtimes >12:00  am (hazard ratio [HR], 1.56; 95% CI, 1.15–2.11; P =0.004) and from 11:01  pm to 12:00  am (HR, 1.25; 95% CI, 1.00–1.56; P =0.047) had an increased risk of CHF compared with those with bedtimes from 10:01  pm to 11:00  pm . After stratified analysis, the association was intensified in participants with a self‐reported sleep duration of 6 to 8 hours. Furthermore, wake‐up times >8:00  am on weekdays (HR, 1.53; 95% CI, 1.07–2.17; P =0.018) were associated with a higher risk of incident CHF than wake‐up times ≤6:00  am . Conclusions Delayed bedtimes (>11:00  pm ) and wake‐up times (>8:00  am ) on weekdays were associated with an increased risk of CHF.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disorder with high morbidity and mortality, and is characterized by excessive growth of endothelial cells. Recently, the mammalian target of rapamycin (mTOR) has attracted increasing attention due to its potential as a therapeutic target against certain diseases associated with proliferative and metabolic abnormalities. However, the effect on mTOR on PAH has not yet been elucidated. In the present study, a marked downregulation of mTOR was observed in PAH patients. Following construction of a mouse model of PAH by chronic exposure to hypoxia, adenovirus-mediated upregulation of mTOR significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy and wall thickness of pulmonary arterioles, indicating a protective effect of mTOR on PAH. Further analysis confirmed that mTOR overexpression inhibited autophagy triggered by hypoxia through blocking light chain 3 II expression and increasing p62 levels. In vitro, hypoxia enhanced the proliferation of human pulmonary artery endothelial cells (PAECs), which was markedly abrogated by mTOR overexpression. Of note, upregulation of mTOR inhibited the hypoxia-induced autophagy pathway, which contributed to cell proliferation, while silencing of autophagy by RNA interference with ATG5 significantly inhibited cell proliferation. In conclusion, the results of the present study suggested a potential protective effect of mTOR on the progression of PAH by suppressing PAEC proliferation through blocking the autophagic pathway. Therefore, the present study suggested that mTOR is a promising therapeutic agent against PAH.

Here, we found that hernandezine, a novel AMPK activator, inhibited LPS-induced TNFα expression/production in human macrophage cells (THP-1 and U937 lines). Activation of AMPK is required for hernandezine-induced anti-LPS response. AMPKα shRNA or dominant negative mutation (T172A) blocked hernandezine-induced AMPK activation, which almost completely reversed anti-LPS activity by hernandezine. Exogenous expression of the constitutively activate AMPKα (T172D, caAMPKα) also suppressed TNFα production by LPS. Remarkably, hernandezine was unable to further inhibit LPS-mediated TNFα production in caAMPKα-expressing cells. Hernandezine inhibited LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NFκB) activation. Treatment of hernandezine in ex-vivo cultured primary human peripheral blood mononuclear cells (PBMCs) also largely attenuated LPS-induced TNFα production. Together, we conclude that AMPK activation by hernandezine inhibits LPS-induced TNFα production in macrophages/monocytes.

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