Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory ...leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.
Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ...ribavirin for treating patients with COVID-19.
This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days IQR 5–11) than the control group (12 days 8–15; hazard ratio 4·37 95% CI 1·86–10·24, p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.
Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
In response to the rising importance of the climate agenda, many countries have restructured their electricity markets to facilitate the utilization of renewable energy. China is an interesting case ...because it has expanded its utilization of wind and solar energy with unmatched speed. This review starts with an analysis of the 2002 reforms that uncoupled electricity production from transmission. The investigation covers the period leading up to the 2022 proposal, which aimed to build a nationally integrated electricity market. The analysis suggests that a careful alignment of incentives for key market players to produce and consume renewable energy is vital during the process of energy transition. The introduction of feed-in tariffs in 2009 for wind energy, which were subsequently extended to solar energy, stimulated a high growth in installed capacity. However, a high electricity curtailment rate resulted. Since 2018, the Chinese government has resorted to curtailment caps and renewable portfolio standards to increase the utilization of renewable electricity. After the announcement of the “dual carbon goals” in 2020, the Chinese government launched a series of reforms that aimed to nurture growth in the green electricity market and the formation of a nationally integrated electricity market. The removal of interregional trade barriers is a key element of China’s current electricity market reforms and will be crucial to determining whether China can achieve its climate goals.
Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with ...familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln
mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln
mice. We then studied how minoxidil, an ATP-sensitive K
channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln
mice than in WT mice. Treatment of Eln
mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln
mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln)
mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K
channel opener increased Eln gene expression and altered 126 other matrix-associated genes.
BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. ...BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death. 89.6% of Baz1b
mice die within 24 h of birth without vascular anomalies or congenital heart disease (except for patent ductus arteriosus). Some (<50%) Baz1b
were noted to have prolonged neonatal cyanosis, patent ductus arteriosus, or reduced lung aeration, and none developed a milk spot. Meanwhile, 35.5% of Baz1b
mice die over the first three weeks after birth. Surviving Baz1b heterozygotes grow slowly (with variable severity). 66.7% of Baz1b
mice develop bowel dilation, compared to 37.8% of wild-type mice, but small bowel and colon transit studies were normal. Additionally, enteric neuron density appeared normal in Baz1b
mice except in distal colon myenteric plexus, where neuron density was modestly elevated. Combined with several rare phenotypes (agnathia, microphthalmia, bowel dilation) recovered, our work confirms the importance of BAZ1B in survival and growth and suggests that reduced copy number of BAZ1B may contribute to the variability in Williams syndrome phenotypes.
Lysyl oxidase (LOX) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox ...mutants had a mild phenotype and did not dilate without drug-induced provocation. Here, we present a new, more severe mutant, Loxb2b370.2Clo (c.G854T; p.Cys285Phe), whose mutation falls just N-terminal to the copper-binding domain. Unlike the other mutants, the C285F Lox protein was stably produced/secreted, and male C57Bl/6J Lox+/C285F mice exhibit increased systolic blood pressure (BP; p < 0.05) and reduced caliber aortas (p < 0.01 at 100mmHg) at 3 months that independently dilate by 6 months (p < 0.0001). Multimodal imaging reveals markedly irregular elastic sheets in the mutant (p = 2.8 × 10−8 for breaks by histology) that become increasingly disrupted with age (p < 0.05) and breeding into a high BP background (p = 6.8 × 10−4). Aortic dilation was amplified in males vs. females (p < 0.0001 at 100mmHg) and ameliorated by castration. The transcriptome of young Lox mutants showed alteration in dexamethasone (p = 9.83 × 10−30) and TGFβ-responsive genes (p = 7.42 × 10−29), and aortas from older C57Bl/6J Lox+/C285F mice showed both enhanced susceptibility to elastase (p < 0.01 by ANOVA) and increased deposition of aggrecan (p < 0.05). These findings suggest that the secreted Lox+/C285F mutants produce dysfunctional elastic fibers that show increased susceptibility to proteolytic damage. Over time, the progressive weakening of the connective tissue, modified by sex and blood pressure, leads to worsening aortic disease.
An increasing number of breast cancer patients in Asian countries has been found to consume dietary supplements including phytoestrogen-rich Chinese herbal medicines with an expectation to alleviate ...the side effects of conventional cancer therapies.
The question of whether estrogenic Chinese herbal medicines are beneficial or detrimental to the health of breast cancer patients remains uncertain.
The present study aimed at establishing a systematic approach to look at the safety profiles of estrogenic Chinese herbal medicines (CHM).
The effects of estrogenic CHM on the growth of human breast cancer cells as well as the progression of breast tumors in mice have been investigated.
Our results demonstrated that among 10 selected estrogenic CHM, the aqueous extracts of Cistanche deserticola (CD) and Dioscorea opposita (DO) at 0.4 to 1.6 mg/ml significantly stimulated cell viability in both estrogen receptor (ER)-positive (MDA-MB-361 and MCF-7) and ER-negative (SKBR3 and MDA-MB-231) breast cancer cells. However, results from animal studies showed that no significant difference was found on the size of mouse 4T1 breast tumors in CD- and DO-treated mice when compared with the control group, while the number of proliferative cells were found to be increased in DO-treated group. Besides, CD and DO treatments induced significant immunomodulatory effects on 4T1 tumor-bearing mice by increasing the production of cytokines IL-2 and IFN-γ and modulation of regulatory T-cells. Furthermore, CD and DO treatments did not stimulate, but in fact suppressed human triple-negative MDA-MB-231 breast xenografts growth in immunodeficiency mice.
The considerable concerns on the use of CD and DO in breast cancer patients could be relieved to some extents upon the findings of this pre-clinical study. The potential harmful effects of estrogenic Chinese herbal medicines on breast cancer growth should be verified in both cell-based and tumor-bearing mice models.
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(AS, Danggui) has long been regarded to stimulate breast cancer growth; hence, the use of AS in breast cancer patients remains a major concern for both patients and practitioners. Since safety ...studies of herbs would be unethical to carry out in patients, the present study aimed to investigate the potential unsafe effects of AS in a systematic pre-clinical approach. Human breast cancer cells, breast orthotopic tumor-bearing mouse models, as well as primary breast cancer cells from patients' tumors were used to evaluate the effect of AS hot water extract on the progression of breast tumors and/or growth of breast cancer cells. We showed that AS is not that stimulatory in breast cancer both
and
, though AS should still be used with caution in estrogen receptor-positive breast cancer patients. This novel approach of applying breast cancer cell lines, xenograft, and syngeneic tumors models, as well as primary breast cancer cells from patients' tumors in Chinese medicines safety evaluation was proven feasible. Our finding is important information for patients, Chinese medicine practitioners, and clinicians on the safety use of AS in breast cancer, which will affect future clinical practice.
Phellinus noxius is a pathogenic fungus that causes brown root rot disease, resulting in a widespread tree and crop mortality in the tropics and subtropics. Early stages of this disease are largely ...asymptomatic, hindering early diagnosis and effective treatment. We hypothesized that P. noxius infection would alter the rhizosphere microbiome of infected trees, based on which diagnostic biomarkers could be developed. Here, we examined for the first time the bacterial, archaeal, and fungal rhizosphere microbiome in four species of healthy and P. noxius‐infected trees (Ficus microcarpa, Celtis sinensis, Mallotus paniculatus, and Cinnamomum camphora) using high‐throughput amplicon sequencing. Results revealed the dominance of Proteobacteria and Actinobacteria in bacteria, Crenarchaeota and Euryarchaeota in archaea, and Ascomycota and Basidiomycota in fungi. Phellinus noxius infection did not affect the alpha diversity of the bacterial rhizosphere microbiome in all four tree species but affected that of archaea and fungi in a tree species‐dependent manner. Infection with P. noxius only affected the bacterial rhizosphere composition in M. paniculatus but not the other three tree species. By contrast, P. noxius infection affected the composition of the archaeal and fungal rhizosphere microbiome in all four tree species. Collectively, these results suggest that potential diagnostic biomarkers for brown root rot disease are tree species‐specific and should be developed based on different taxonomic groups. Our study has provided insights into the rhizosphere microbiome in healthy and P. noxius‐infected trees and laid a solid foundation for future comprehensive studies.
Phellinus noxius is a pathogenic fungus that causes the devastating brown root rot disease. We examined the bacterial, archaeal, and fungal rhizosphere microbiome in healthy and P. noxius‐infected trees of four species commonly found in Hong Kong using high‐throughput amplicon sequencing. Our results revealed distinct effects of P. noxius infection on the diversity and composition of the rhizosphere microbiome across host tree species, suggesting that potential diagnostic biomarkers for brown root rot disease are tree species‐specific.
Compared with the rich knowledge in the West, studies of the impact of wives’ relative income on marital quality during the fast socioeconomic change period in urban China have surprisingly fallen ...far behind. This study attempted to examine the impact of relative income on marital happiness among urban Chinese women. Using an urban Beijing sample of 763 married women, this study found that a woman married to a husband with lower income tended to be less happy with her marriage, but this effect will be countered if there is more love in the sense of a genuine concern about the well-being of the partner and a willing to make sacrifice for him. The results were interpreted from theoretical verification and possible mechanisms linking personal commitment and marital happiness.
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