2023年 · 第136卷第19期

Cardiovascular diseases, including heart failure, coronary artery disease, atherosclerosis, aneurysm, thrombosis, and hypertension, are a great economic burden and threat to human health and are the major cause of death worldwide. Recently, researchers have begun to appreciate the role of microbial ecosystems within the human body in contributing to metabolic and cardiovascular disorders. Accumulating evidence has demonstrated that the gut microbiota is closely associated with the occurrence and development of cardiovascular diseases. The gut microbiota functions as an endocrine organ that secretes bioactive metabolites that participate in the maintenance of cardiovascular homeostasis, and their dysfunction can directly influence the progression of cardiovascular disease. This review summarizes the current literature demonstrating the role of the gut microbiota in the development of cardiovascular diseases. We also highlight the mechanism by which well-documented gut microbiota-derived metabolites, especially trimethylamine N-oxide, short-chain fatty acids, and phenylacetylglutamine, promote or inhibit the pathogenesis of cardiovascular diseases. We also discuss the therapeutic potential of altering the gut microbiota and microbiota-derived metabolites to improve or prevent cardiovascular diseases.

Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell therapy is the most widely applied cellular therapy. Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017, five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies. Moreover, clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing. Both China and the United States have contributed significantly to the development of clinical trials. However, CAR-T cell therapy has many limitations such as a high relapse rate, adverse side effects, and restricted availability. Various methods are being implemented in clinical trials to address these issues, some of which have demonstrated promising breakthroughs. This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that Janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of Janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.

Extreme temperature events, including extreme cold, are becoming more frequent worldwide, which might be harmful to pregnant women and cause adverse birth outcomes. We aimed to investigate the association between exposure to low ambient temperature in pregnant women and adverse birth outcomes, such as preterm birth, low birth weight, and stillbirth, and to summarize the evidence herein.

Relevant studies were searched in PubMed, Cochrane, and Embase electronic databases until November 2021. Studies involving low ambient temperature, preterm birth, birth weight, and stillbirth were included. The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses were followed to conduct this study risk of bias and methods for data synthesis.

A total of 34 studies were included. First, pregnant women exposed to low ambient temperature had an increased risk of preterm birth (risk ratio [RR] 1.08; 95% confidence interval [CI] 1.04–1.13). Subgroup analyses revealed that exposure during late pregnancy was more likely to induce preterm birth. In addition, only pregnant women exposed to <1st percentile of the mean temperature suffered increased risk of preterm birth. Moreover, pregnant women living in medium or hot areas were more prone to have preterm births than those in cold areas when exposed to low ambient temperatures. Asians and Blacks were more susceptible to low ambient temperatures than Caucasians. Second, pregnant women exposed to low ambient temperature had an increased risk of low birth weight (RR 1.07; 95% CI 1.03–1.12). Third, pregnant women had an increased risk of stillbirth while exposed to low ambient temperature during the entire pregnancy (RR 4.63; 95% CI 3.99–5.38).

Exposure to low ambient temperature during pregnancy increases the risk of adverse birth outcomes. Pregnant women should avoid exposure to extremely low ambient temperature (<1st percentile of the mean temperature), especially in their late pregnancy. This study could provide clues for preventing adverse outcomes from meteorological factors.

No. CRD42021259776 at PROSPERO (https://www.crd.york.ac.uk/PROSPERO/).

Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China.

Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders.

During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR= 0.78, 95% confidence interval [CI]: 0.71–0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m² ≤ BMI < 24.0 kg/m²); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68–0.89) and 0.69 (95% CI: 0.59–0.79) compared with their counterparts, respectively.

High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.

Vaccination has been shown effective in controlling the global coronavirus disease 2019 (COVID-19) pandemic and reducing severe cases. This study was to assess the flare and change in disease activity after COVID-19 vaccination in patients with stable rheumatoid arthritis (RA).

A prospective cohort of RA patients in remission or with low disease activity was divided into a vaccination group and a non-vaccination group based on their COVID-19 vaccination status. Each of them was examined every 3 to 6 months. In the vaccination group, disease activity was compared before and after vaccination. The rates of flare defined as disease activity scores based on 28-joint count (DAS28) >3.2 with ΔDAS28 ≥0.6 were compared between vaccination and non-vaccination groups.

A total of 202 eligible RA patients were enrolled. Of these, 98 patients received no vaccine shot (non-vaccination group), and 104 patients received two doses of vaccine (vaccination group). The median time interval from pre-vaccination visit to the first immunization and from the second dose of vaccine to post-vaccination visit was 67 days and 83 days, respectively. The disease activity scores at pre-vaccination and post-vaccination visits in the vaccination group patients were similar. At enrollment, gender, RA disease course, seropositivity, and disease activity were comparable across the two groups. Flare was observed in five (4.8%) of the vaccination group patients and nine (9.2%) of the non-vaccination group patients at post-vaccination assessment (P = 0.221). In terms of safety, 29 (27.9%) patients experienced adverse events (AEs) after vaccination. No serious AEs occurred.

COVID-19 vaccinations had no significant effect on disease activity or risk of flare in RA patients in remission or with low disease activity. Patients with stable RA should be encouraged to receive the COVID-19 vaccination.

Emergence delirium (ED) is a kind of delirium that occured in the immediate post-anesthesia period. Lower body temperature on post-anesthesia care unit (PACU) admission was an independent risk factor of ED. The present study was designed to investigate the association between intraoperative body temperature and ED in elderly patients undergoing non-cardiac surgery.

This study was a secondary analysis of a prospective observational study. Taking baseline body temperature as a reference, intraoperative absolute and relative temperature changes were calculated. The relative change was defined as the amplitude between intraoperative lowest/highest temperature and baseline reference. ED was assessed with the confusion assessment method for intensive care unit at 10 and 30 min after PACU admission and before PACU discharge.

A total of 874 patients were analyzed with a mean age of 71.8 ± 5.3 years. The incidence of ED was 38.4% (336/874). When taking 36.0°C, 35.5°C, and 35.0°C as thresholds, the incidences of absolute hypothermia were 76.7% (670/874), 38.4% (336/874), and 17.5% (153/874), respectively. In multivariable logistic regression analysis, absolute hypothermia (lowest value <35.5°C) and its cumulative duration were respectively associated with an increased risk of ED after adjusting for confounders including age, education, preoperative mild cognitive impairment, American Society of Anesthesiologists grade, duration of surgery, site of surgery, and pain intensity. Relative hypothermia (decrement >1.0°C from baseline) and its cumulative duration were also associated with an increased risk of ED, respectively. When taking the relative increment >0.5°C as a threshold, the incidence of relative hyperthermia was 21.7% (190/874) and it was associated with a decreased risk of ED after adjusting above confounders.

In the present study, we found that intraoperative hypothermia, defined as either absolute or relative hypothermia, was associated with an increased risk of ED in elderly patients after non-cardiac surgery. Relative hyperthermia, but not absolute hyperthermia, was associated with a decreased risk of ED.

Chinese Clinical Trial Registry (No. ChiCTR-OOC-17012734).

As one of the early discovered long non-coding RNAs (lncRNA), taurine upregulation gene 1 (TUG1) has been widely expressed in a variety of tumors. Moreover, it promotes cell proliferation, differentiation, apoptosis, and migration. However, our understanding of its importance in the pathogenesis of cataracts remains limited. This study aimed to explore the mechanism by which lncRNA TUG1 mediates lens epithelial cell apoptosis in age-related cataracts (ARC) by regulating the microRNAs (miR-29b)/second mitochondria-derived activator of caspases axis, and to identify more non-surgical strategies for cataract treatment.

The messenger RNA expression levels of TUG1, miR-29b, and Smac were detected using quantitative real-time polymerase chain reaction in vivo and in vitro. The expression of the Smac protein was analyzed by Western blotting and immunofluorescence. Flow cytometry and cell counting kit-8 assays were used to detect the cell apoptosis and proliferation rates, respectively. The targeted regulatory relationship between lncRNA TUG1, miR-29b, and Smac was verified by viral vector construction, co-transfection, nuclear and cytoplasmic separation, luciferase reporter assays, and RNA immunoprecipitation.

TUG1 and Smac were expressed at high levels in ARC and HLE-B3 cells treated with 200 μmol/L H₂O₂, whereas miR-29b expression was decreased. In vitro cell experiments confirmed that down-regulation of TUG1 could inhibit the apoptosis of lens epithelial cells. Mechanistically, Smac expression was negatively regulated by miR-29b. TUG1 competitively inhibited miR-29b expression and caused greater release of Smac. In addition, miR-29b partially reversed the effects of TUG1 on human lens epithelial cell line cells.

lncRNA TUG1 increases Smac expression and promotes apoptosis of lens epithelial cells in ARC by competitively inhibiting miR-29b. This mechanism is the cytological basis for ARC formation. Based on these results, the lncRNA TUG1/miR29b/Smac axis may be a new molecular pathway that regulates ARC development.

Long non-coding RNA colon cancer-associated transcript 1 (CCAT1) is involved in transforming multiple cancers into malignant cancer types. Previous studies underlining the mechanisms of the functions of CCAT1 primarily focused on its decoy for miRNAs (micro RNAs). However, the regulatory mechanism of CCAT1–protein interaction associated with tumor metastasis is still largely unknown. The present study aimed to identify proteome-wide CCAT1 partners and explored the CCAT1–protein interaction mediated tumor metastasis.

CCAT1–proteins complexes were purified and identified using RNA antisense purification coupled with the mass spectrometry (RAP-MS) method. The database for annotation, visualization, and integrated discovery and database for eukaryotic RNA binding proteins (EuRBPDB) websites were used to bioinformatic analyzing CCAT1 binding proteins. RNA pull-down and RNA immunoprecipitation were used to validate CCAT1–Vimentin interaction. Transwell assay was used to evaluate the migration and invasion abilities of HeLa cells.

RAP-MS method worked well by culturing cells with nucleoside analog 4-thiouridine, and cross-linking was performed using 365 nm wavelength ultraviolet. There were 631 proteins identified, out of which about 60% were RNA binding proteins recorded by the EuRBPDB database. Vimentin was one of the CCAT1 binding proteins and participated in the tumor metastasis pathway. Knocked down vimetin (VIM) and rescued the downregulation by overexpressing CCAT1 demonstrated that CCAT1 could enhance tumor migration and invasion abilities by stabilizing Vimentin protein.

CCAT1 may bind with and stabilize Vimentin protein, thus enhancing cancer cell migration and invasion abilities.

Serum hepatitis B virus deoxyribonucleic acid (HBV-DNA) load is a critical index used to reflect the degree of viral replication in hepatocytes and to evaluate host hepatitis viral status. The risk of hepatocellular carcinoma (HCC) incidence or recurrence varies depending on whether the HBV-DNA load is high or low.^[1]Consistent with previous studies and expert opinion, a HBV-DNA level >2000 IU/mL was defined as a high HBV-DNA load in the current study.^[2]

To the Editor:Vitiligo is a chronic disease that impacts many aspects of a patient’s life. The prevalence of vitiligo has been increasing, and currently involves up to 0.5% to 2% of all races worldwide.^[1]Although this condition very rarely produces any direct physical discomfort, the cosmetic problems and disfiguring appearance resulting from the depigmented lesions severely affect the quality of life (QoL) in these individuals.^[2]

To the Editor:Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are major causes of morbidity and mortality in older individuals, and their epidemiological link generates substantial challenges for the management of these devastating diseases. Abnormal glucose metabolism, accompanied by inhibition of the protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway, is a key factor in amyloid precursor protein (APP) accumulation and amyloid β (Aβ) formation in neuronal cells.^[1,2,3]Therefore, activation of the Akt/GSK-3β pathway may be a promising target for AD treatment.

To the Editor: The main cause for failed complex coronary lesions especially chronic total occlusion (CTO) revascularization is the inability of device delivery due to the lack of adequate guide support or the failure of guidewire manipulation, such as unsuccessful externalization of the retrograde guidewire and incapable reentry into the true lumen. Some devices and techniques have been used to deal with these problems, and the guide catheter extension system (GCES) is one of the effective solutions. Currently, five GCES devices are commercially available, the Proxis, Heartrail II (Terumo, Tokyo, Japan), GuideLiner (GL; Vascular Solutions, Charlotte, NC, USA), Guidezilla (GZ; Boston Scientific, Marlborough, MA, USA), and the Expressman Extension System (EES; APT Medical Inc., Hunan, China). GL and GZ have been reported to enable procedural success not only by providing extra backup support but also by accommodating multiple devices and facilitating device delivery.^[1]Besides, they also ensure little trauma to the ostium of CTO vessels.^[2,3]However, the rate of GZ- or GL-related events, including inaccessibility to the target lesions, device damage, or coronary artery dissection, became major obstacles in using GCES in CTO percutaneous coronary intervention (PCI).^[4,5]Moreover, the size of the radial artery guiding catheter limits the application of GCES in a guiding catheter that is no larger than 7 F, and it should be applied with more caution when delivering stents with a 4 mm diameter.

To the Editor: Diesel exhaust particles (DEPs) promote airway inflammation in asthma, but the mechanisms by which DEPs influence the onset and aggravation of asthma are complex. Standard DEPs have been used in many toxicological studies about DEPs and asthma. However, recent studies have shown that standard DEPs are unsuitable representatives of traffic-related emissions. The effects of regenerated DEPs and real-world DEPs on asthma have not been fully studied and more researches are urgently needed.

To the Editor:Myocardial fibrosis is a common pathological process of heart failure (HF). The methods for non-invasive diagnosis of myocardial fibrosis are finite. Currently, cardiac magnetic resonance (CMR) that serves as the gold standard for determining fibrotic lesions is able to offer high spatial resolution and validate myocardial fibrosis. However, the extracellular volume fraction measured with CMR can even increase in other pathologies such as inflammatory edema or protein deposition; thus, a new complementary imaging modality to detect cardiac fibrosis is necessary.

To the Editor:Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, with coronary heart disease (CHD) exhibiting the highest mortality rate. Obesity is an important risk factor for cardiometabolic complication and CVD. Visceral adipose (VA) and subcutaneous adipose (SA) tissues exert differential and possibly opposing effects on cardiometabolic outcomes.^[1,2]

To the Editor:In middle-aged and elderly individuals, intervertebral disc (IVD) degeneration (IVDD) can often cause low back pain (LBP). IVDD has a complex mechanism with many influencing factors. Biological changes in degenerative IVDs mainly include structural abnormalities of the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplate, as well as changes in the composition and amount of extracellular matrix (ECM). IVDD disease is treated conservatively, followed by surgery, but these are symptomatic treatments, with high complication rates.^[1]Gelatin-methacryloyl (GelMA) hydrogel system therapy reduces complications while treating the cause. Through minimally invasive surgery, GelMA hydrogels are used to deliver regenerative cells and/or biological factors to the target area to eliminate symptoms and promote IVD cell regeneration. Or, using three-dimensional (3D) printing technology, a bionic IVD can be constructed to replace a severely degenerated IVD. This is a research hotspot in the field of regenerative medicine and tissue engineering.

To the Editor:Patients with autoimmune diseases have increased risk of active cytomegalovirus (CMV) infection due to immune dysfunction or the application of glucocorticoid and immunosuppressants.^[1]Cuiet al^[2]found that compared with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (27%), post-transplant patients (14.8%), and hematological malignancies (5.1%), patients with autoimmune disease had the highest incidence of CMV antigenemia (35.1%). Monitoring CMV antigen-specific T cell immunity is helpful for understanding the protective immunity against CMV infection and identifing the risk of CMV-related complications. Currently, the CMV antigen-specific T cell immune responses in patients with autoimmune diseases remains unknown.

To the Editor:Unstable clinical conditions and complications make multiple laboratory tests and blood sampling inevitable in preterm infants, contributing to iatrogenic blood loss. Undoubtedly, iatrogenic blood loss is highly correlated with red blood cell transfusion (RBCT). A previous study on extremely low birth weight (BW) infants reported that the sampling blood loss was 30.0 mL/kg within the first week of life, leading to one or more RBCTs in 98% of patients.^[1]RBCTs are increasingly reported to cause inflammatory responses and increase the incidence of preterm complications. Therefore, reducing iatrogenic blood loss could not only decrease the need for transfusions but also reduce the risk of neonatal mortality and morbidity.

To the Editor:Post-operative cognitive dysfunction (POCD) is described as a series of changes in the neurocognitive conditions and behaviors of patients, which occur within several weeks or even months after anesthesia and surgery. POCD occurs in 20% to 50% of patients, resulting in burden on patients, and exerting a significant social and economic impact.^[1]Although an increased understanding of the effects of neuroinflammation and oxidative stress after surgery and anesthesia have clarified the underlying pathophysiology of POCD, many questions remain to be answered. At present, the treatment of POCD mainly focuses on prevention strategies, early identification, and perioperative risk factor management; and an effective treatment is still lacking. Dexmedetomidine (Dex) is a novel and highly selective α2 adrenergic receptor agonist. Perioperative Dex treatment can significantly reduce the incidence of POCD and inflammation, and it can improve post-operative neurocognitive function. Dex may inhibit the massive release of high mobility group protein B1 (HMGB1) by acting on the α2 adrenergic receptor to activate the PI3K/Akt signaling pathway, thus reducing the binding of HMGB1 with Toll-like receptor 4 and other membrane proteins, thus playing an anti-inflammatory role.^[2]Dex can also enhance HMGB1-induced cognitive decline in inflammatory mice via vagal nerve stimulation. HMGB1 is released extracellularly after cell activation, stress, injury, or death and can promote an inflammatory response. High HMGB1 expression is associated with the occurrence of POCD. The inflammatory immune response may play an important role in the pathogenesis of POCD. Regulatory T (Treg) cells are key regulatory cells involved in inflammation and play an important role in immune tolerance and homeostasis. HMGB1 can downregulate the immune function of Treg cells by decreasing the expression of marker molecules on their surface and inhibiting cytokine secretion. Extracellular HMGB1 also intensifies the autoimmune process by impairing the stability of Treg cells.^[3]In this study, we aimed to explore the effects and possible mechanisms of action of Dex in POCD.