[The Efficacy and Safety of Venetoclax Combined with Azacitidine in the Treatment of Adult Patients with Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy].

OBJECTIVE: To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. METHODS: The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively. RESULTS: After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred. CONCLUSION: VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.

BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.

The Effects of Abdominal Obesity and Sagittal Imbalance on Sacroiliac Joint Pain After Lumbar Fusion.

BACKGROUND: Postoperative sacroiliac joint pain (SIJP) is a common manifestation of failed back surgery syndrome after a posterior lumbar interbody fusion (PLIF). However, there is currently no consensus on the risk factors for SIJP after PLIF. OBJECTIVES: We explored the effects of abdominal obesity and sagittal imbalance on SIJP after PLIF. STUDY DESIGN: This is a prospective observational cohort study. SETTING: This study occurred at the Department of Spinal Surgery at a hospital affiliated with a medical university. METHODS: A total of 401 patients who underwent PLIF from June 2018 to June 2021 were enrolled in this study. 36 patients experienced postoperative SIJP. In contrast, a matched group comprised 72 non-SIJP patients. We used 1:2 propensity score matching to compare obesity features and sagittal spine parameters in the 2 groups. Inflammatory cytokines and visual analog scale (VAS) scores were measured in the SIJP group. RESULTS: A total of 36 patients (8.98%) experienced SIJP during the follow-up. Compared with the non-SIJP group, patients with postoperative SIJP had a higher body mass index (BMI), greater abdominal obesity, a higher incidence of pelvic incidence-lumbar lordosis greater than 10°, and a higher incidence of a sagittal vertical axis greater than 5 cm (P < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve for waist circumference was greater than that for BMI (0.762 vs. 0.650, P = 0.049). Logistic regression analysis revealed that the risk factors for SIJP were abdominal obesity, a pelvic incidence-lumbar lordosis of greater than 10°, and a sagittal vertical axis greater than 5 cm (P < 0.05). In patients with SIJP, interleukin 6, tumor necrosis factor-α, and VAS scores were higher in the abdominal obesity group than in the non-abdominal obesity group (P < 0.05). LIMITATIONS: There was no uniform diagnosis of SIJP, so the incidence rate of SIJP might not be accurate. CONCLUSIONS: The significant predictors of SIJP were abdominal obesity and sagittal imbalance. Patients with abdominal obesity showed higher levels of inflammatory markers and pain intensity. More attention should be paid to body shape and the angle of correction of lumbar lordosis before lumbar surgery.

Vitamin D delays intervertebral disc degeneration and improves bone quality in ovariectomized rats.

Known to be involved in bone-cartilage metabolism, Vitamin D (VD) may play a role in human's disc pathophysiology. Given that postmenopausal women are prone to suffer VD deficiency and intervertebral disc degeneration (IDD), this study is intended to investigate whether VD can delay IDD in ovariectomized rats by improving bone microstructure and antioxidant stress. Female Sprague-Dawley rats were randomly allocated into four groups: sham, oophorectomy (OVX)+VD deficiency (VDD), OVX, and OVX+VD supplementation (VDS). In vivo, after a 6-month intervention, imaging and pathology slice examinations showed that IDD induced by OVX was significantly alleviated in VDS and deteriorated by VDD. The expressions of aggrecan and Collagen II in intervertebral disc were reduced by OVX and VDD, and elevated by VDS. Compared with the OVX+VDD and OVX group vertebrae, OVX+VDS group vertebrae showed significantly improved endplate porosity and lumbar bone mineral density with increased percent bone volume and trabecular thickness. Furthermore, 1α,25(OH)2 D3 restored the redox balance (total antioxidant capacity, ratio of oxidized glutathione/glutathione) in the disc. The cocultivation of 1α,25(OH)2 D3 and nucleus pulposus cells (NPCs) was conducted to observe its potential ability to resist excessive oxidative stress damage induced by H2 O2 . In vitro experiments revealed that 1α,25(OH)2 D3 reduced the senescence, apoptosis, and extracellular matrix degradation induced by H2 O2 in NPCs. In conclusion, VDS exhibits protective effects in OVX-induced IDD, partly by regulating the redox balance and preserving the microstructure of endplate. This finding provides a new idea for the prevention and treatment of IDD.

Molecular mechanisms of Chengshi Beixie Fenqing Decoction based on network pharmacology: pivotal roles of relaxin signaling pathway and its associated target proteins against Benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski's rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4'-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4'-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways.Communicated by Ramaswamy H. Sarma.

Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation.

CTCF plays an important role in 3D genome organization by adjusting the strength of chromatin insulation at TAD boundaries, where clustered CBS (CTCF-binding site) elements are often arranged in a tandem array with a complex divergent or convergent orientation. Here, using Pcdh and HOXD loci as a paradigm, we look into the clustered CTCF TAD boundaries and find that, counterintuitively, outward-oriented CBS elements are crucial for inward enhancer-promoter interactions as well as for gene regulation. Specifically, by combinatorial deletions of a series of putative enhancer elements in mice in vivo or CBS elements in cultured cells in vitro, in conjunction with chromosome conformation capture and RNA-seq analyses, we show that deletions of outward-oriented CBS elements weaken the strength of long-distance intra-TAD promoter-enhancer interactions and enhancer activation of target genes. Our data highlight the crucial role of outward-oriented CBS elements within the clustered CTCF TAD boundaries in developmental gene regulation and have interesting implications on the organization principles of clustered CTCF sites within TAD boundaries.

SARS-CoV-2 subgenomic RNA: formation process and rapid molecular diagnostic methods.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which caused coronavirus disease-2019 (COVID-19) is spreading worldwide and posing enormous losses to human health and socio-economic. Due to the limitations of medical and health conditions, it is still a huge challenge to develop appropriate discharge standards for patients with COVID-19 and to use medical resources in a timely and effective manner. Similar to other coronaviruses, SARS-CoV-2 has a very complex discontinuous transcription process to generate subgenomic RNA (sgRNA). Some studies support that sgRNA of SARS-CoV-2 can only exist when the virus is active and is an indicator of virus replication. The results of sgRNA detection in patients can be used to evaluate the condition of hospitalized patients, which is expected to save medical resources, especially personal protective equipment. There have been numerous investigations using different methods, especially molecular methods to detect sgRNA. Here, we introduce the process of SARS-CoV-2 sgRNA formation and the commonly used molecular diagnostic methods to bring a new idea for clinical detection in the future.

Identification and validation of ubiquitination-related signature and subgroups in immune microenvironment of tuberculosis.

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the bacterial pathogen responsible for causing tuberculosis (TB), a severe public health concern that results in numerous deaths worldwide. Ubiquitination (Ub) is an essential physiological process that aids in maintaining homeostasis and contributes to the development of TB. Therefore, the main objective of our study was to investigate the potential role of Ub-related genes in TB. METHODS: Our research entailed utilizing single sample gene set enrichment analysis (ssGSEA) in combination with several machine learning techniques to discern the Ub-related signature of TB and identify potential diagnostic markers that distinguish TB from healthy controls (HC). RESULTS: In summary, we used the ssGSEA algorithm to determine the score of Ub families (E1, E2, E3, DUB, UBD, and ULD). Notably, the score of E1, E3, and UBD were lower in TB patients than in HC individuals, and we identified 96 Ub-related differentially expressed genes (UbDEGs). Employing machine learning algorithms, we identified 11 Ub-related hub genes and defined two distinct Ub-related subclusters. Notably, through GSVA and functional analysis, it was determined that these subclusters were implicated in numerous immune-related processes. We further investigated these Ub-related hub genes in four TB-related diseases and found that TRIM68 exhibited higher correlations with various immune cells in different conditions, indicating that it may play a crucial role in the immune process of these diseases. CONCLUSION: The observed enrichment of Ub-related gene expression in TB patients emphasizes the potential involvement of ubiquitination in the progression of TB. These significant findings establish a basis for future investigations to elucidate the molecular mechanisms associated with TB, select suitable diagnostic biomarkers, and design innovative therapeutic interventions for combating this fatal infectious disease.

Lysosomal dysfunction in carbon black-induced lung disorders.

Carbon black (CB), a component of environmental particulate pollution derived from carbon sources, poses a significant threat to human health, particularly in the context of lung-related disease. This study aimed to investigate the detrimental effects of aggregated CB in the average micron scale on lung tissues and cells in vitro and in vivo. We observed that CB particles induced lung disorders characterized by enhanced expression of inflammation, necrosis, and fibrosis-related factors in vivo. In alveolar epithelial cells, CB exposure resulted in decreased cell viability, induction of cell death, and generation of reactive oxidative species, along with altered expression of proteins associated with lung disorders. Our findings suggested that the damaging effects of CB on the lung involved the targeting of lysosomes. Specifically, CB promoted lysosomal membrane permeabilization, while lysosomal alkalization mitigated the harmfulness of CB on lung cells. Additionally, we explored the protective effects of alkaloids derived from Nelumbinis plumula, with a focus on neferine, against CB-induced lung disorders. In conclusion, these findings contribute to a deeper understanding of the pathophysiological effects of CB particles on the lungs and propose a potential therapeutic approach for pollution-related diseases.

[Risk Factors of Multiple Myeloma Complicated with Venous Thromboembolism].

OBJECTIVE: To analyze the clinical characteristics of venous thromboembolism (VTE) in patients with multiple myeloma (MM) and to identify the risk factors of VTE in MM patients. METHODS: 179 newly diagnosed MM (NDMM) patients admitted to The Second Hospital of Shanxi Medical University from January 2014 to December 2020 who were followed up for more than 6 months were collected, and they were divided into VTE group and control group according to whether combined with VTE. The clinical and laboratory data were compared between the two groups. Mann-whitney U test was used for inter-group comparison of measurement data, Chi-square test or Fisher's exact test was used for inter-group comparison of count data, and multivariate logistic regression analysis was performed to explore the risk factors of VTE in MM patients. RESULTS: Compared with control group, the serum albumin (ALB) level in VTE group was significantly lower (P =0.033), the fibrinogen (FIB) level was significantly higher (P =0.016), and the proportion of patients with D-dimer≥2 000 ng/ml was significantly higher than that in the control group (26.3% vs 4.4%, P =0.002). There was a significant difference in M-component type between the two groups (P =0.028), and the proportion of IgG type in VTE group was higher. There were no statistically significant differences between two groups in age, sex, body mass index (BMI), the proportions of patients with hypertension, diabetes, coronary heart disease and cerebral infarction, white blood cell (WBC) count, platelet (PLT) count, liver and kidney function, plasma cells ratio in bone marrow, serum globulin (GLO), lactate dehydrogenase (LDH), ß2-microglobulin (ß2-MG) level, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), prothrombin time (PT), activated partial thromboplastin time (APTT), disease stage, thrombosis prevention and the use of immunomodulators (P >0.05). Multivariate logistic regression analysis showed that FIB level (OR=1.578, 95%CI:1.035-2.407, P =0.034), D-dimer≥2 000 ng/ml (OR=5.467, 95%CI:1.265-23.621, P =0.023) and IgG type (OR=4.780, 95%CI: 1.221-18.712, P =0.025) were independent risk factors for VTE in MM patients. CONCLUSION: MM patients are prone to VTE, and FIB level, D-dimer≥2 000 ng/ ml and IgG type are independent risk factors for VTE in MM patients.

A retrospective analysis of coping competence among community health centers during the COVID-19 pandemic in Shanghai, China: Coping strategies for future public health emergency events.

This study aims to investigate the coping competence of 12 community health centers through nursing workforce, emergency preparation, emergency response training, and emergency support in a district of Shanghai during the coronavirus disease 2019 (COVID-19) pandemic in 2022 to propose coping strategies and implication for Future Public Health Emergency Events for community health centers. A cross-sectional survey was conducted on June 2022, and 12 community health centers (servicing a population of 104,472.67 ± 41,421.18, with 125 ± 36 health care providers per center) were then divided into group A (n = 5, medical care ratio ≥ 1:1) and group B (n = 7, medical care ratio < 1:1) according to collected data, and the nursing human resources management and coping competence of the centers with COVID-19 of both groups were retrospectively analyzed. Nursing shortages were obvious across all 12 centers. Certain deficiencies in the coping competence of community health centers with emergencies must be addressed (possession rate < 70% in both groups, p > 0.05). Community health centers need to enhance hospital-to-hospital collaboration and the ability to transport emergency staff to the post promptly during outbreaks. Emergency coping assessments, emergency drills at different levels, and mental health support need to be implemented regularly among community health centers, and effective donation management should be pursued as well. We expect that this study could support efforts by leaders of community health centers to conclude coping strategies including increasing nursing workforce, optimizing human recourse management, and identifying areas of improvement of centers for emergency coping during public health events.

Comparison of outcomes of self-expanding versus balloon-expandable valves for transcatheter aortic valve replacement: a meta-analysis of randomized and propensity-matched studies.

BACKGROUND: The postoperative outcomes of transcatheter aortic valve replacement (TAVR) with the new generation of self-expanding valves (SEV) and balloon-expandable valves (BEV) remain uncertain. METHODS: We conducted a meta-analysis based on randomized controlled trials (RCTs) and propensity score-matched (PSM) studies to evaluate the performance of the new generation TAVR devices, with a focus on Edwards SAPIEN 3/Ultra BEV, Medtronic Evolut R/PRO SEV, and Boston ACURATE neo SEV. Our primary endpoints were mortality and complications at both 30 days and one year post-operation. RESULTS: A total of 4 RCTs and 14 PSM studies were included. Our findings showed no significant difference between SEV and BEV regarding 30-day and 1-year mortality rates. ACURATE SEV required less permanent pacemaker implantation (PPI) at 30-day as compared to SAPIEN BEV, while Evolut SEV required a higher rate of PPI than SAPIEN BEV. The incidence of stroke, major or life-threatening bleeding (MLTB), major vascular complications (MVC), coronary artery obstruction (CAO) and acute kidney injury (AKI) did not differ significantly between the two groups. SEV had a larger effective orifice area (EOA) and lower mean transvalvular gradients (MPG) compared to BEV. However, there was an increased risk of paravalvular leakage (PVL) associated with SEV. CONCLUSIONS: In terms of 30-day mortality, stroke, bleeding, MVC, AKI, CAO, and one-year mortality, there was comparability between the two valve types following TAVR. SEV was associated with better hemodynamic outcomes, except for a higher incidence of PVL. Compared to SAPIEN BEV, ACURATE SEV had a lower risk of PPI at 30 days, while Evolut SEV was associated with a higher risk of PPI. These findings underscore the importance of personalized valve selection.

Classification and characterisation of extracellular vesicles-related tuberculosis subgroups and immune cell profiles.

Around the world, tuberculosis (TB) remains one of the most common causes of morbidity and mortality. The molecular mechanism of Mycobacterium tuberculosis (Mtb) infection is still unclear. Extracellular vesicles (EVs) play a key role in the onset and progression of many disease states and can serve as effective biomarkers or therapeutic targets for the identification and treatment of TB patients. We analysed the expression profile to better clarify the EVs characteristics of TB and explored potential diagnostic markers to distinguish TB from healthy control (HC). Twenty EVs-related differentially expressed genes (DEGs) were identified, and 17 EVs-related DEGs were up-regulated and three DEGs were down-regulated in TB samples, which were related to immune cells. Using machine learning, a nine EVs-related gene signature was identified and two EVs-related subclusters were defined. The single-cell RNA sequence (scRNA-seq) analysis further confirmed that these hub genes might play important roles in TB pathogenesis. The nine EVs-related hub genes had excellent diagnostic values and accurately estimated TB progression. TB's high-risk group had significantly enriched immune-related pathways, and there were substantial variations in immunity across different groups. Furthermore, five potential drugs were predicted for TB using CMap database. Based on the EVs-related gene signature, the TB risk model was established through a comprehensive analysis of different EV patterns, which can accurately predict TB. These genes could be used as novel biomarkers to distinguish TB from HC. These findings lay the foundation for further research and design of new therapeutic interventions aimed at treating this deadly infectious disease.

Exploring the inhibition mechanism of interleukin-1-beta in gouty arthritis by polygonum cuspidatum using network pharmacology and molecular docking: A review.

Polygonum cuspidatum (Huzhang, HZ) is one of the commonly used traditional Chinese medicines for treating gouty arthritis (GA), but the specific mechanism is not clear. This study employed network pharmacology and molecular docking techniques to examine the molecular mechanisms underlying the therapeutic effects of HZ on GA. The network pharmacology approach, including active ingredient and target screening, drug-compound-target-disease network construction, protein-protein interaction (PPI) networks, enrichment analysis, and molecular docking, was used to explore the mechanism of HZ against GA. Ten active ingredients of HZ were predicted to interact with 191 targets, 14 of which interact with GA targets. Network pharmacology showed that quercetin, physovenine, luteolin, and beta-sitosterol are the core components of HZ, and IL (interleukin)-1ß, IL-6, and tumor necrosis factor (TNF) are the core therapeutic targets. The mechanism of HZ in GA treatment was shown to be related to the IL-17 signaling pathway, NOD-like receptor signaling pathway, and Toll-like receptor signaling pathway, and is involved in the inflammatory response, positive regulation of gene expression, cellular response to lipopolysaccharide, and other biological processes. Molecular docking showed that all four core compounds had good binding properties to IL-1ß, with luteolin and beta-sitosterol showing better docking results than anakinra, suggesting that they could be used as natural IL-1ß inhibitors in further experimental studies. The mechanism of action of HZ against GA has multi-target and multi-pathway characteristics, which provides an important theoretical basis for the study of the active ingredients of HZ as natural IL-1ß inhibitors.

Oral pathogen aggravates atherosclerosis by inducing smooth muscle cell apoptosis and repressing macrophage efferocytosis.

Periodontitis imparting the increased risk of atherosclerotic cardiovascular diseases is partially due to the immune subversion of the oral pathogen, particularly the Porphyromonas gingivalis (P. gingivalis), by inducing apoptosis. However, it remains obscure whether accumulated apoptotic cells in P. gingivalis-accelerated plaque formation are associated with impaired macrophage clearance. Here, we show that smooth muscle cells (SMCs) have a greater susceptibility to P. gingivalis-induced apoptosis than endothelial cells through TLR2 pathway activation. Meanwhile, large amounts of miR-143/145 in P.gingivalis-infected SMCs are extracellularly released and captured by macrophages. Then, these miR-143/145 are translocated into the nucleus to promote Siglec-G transcription, which represses macrophage efferocytosis. By constructing three genetic mouse models, we further confirm the in vivo roles of TLR2 and miR-143/145 in P. gingivalis-accelerated atherosclerosis. Therapeutically, we develop P.gingivalis-pretreated macrophage membranes to coat metronidazole and anti-Siglec-G antibodies for treating atherosclerosis and periodontitis simultaneously. Our findings extend the knowledge of the mechanism and therapeutic strategy in oral pathogen-associated systemic diseases.

Enantioselective Divergent Syntheses of Cephalotaxus Alkaloids: (-)-Cephalotaxine, (-)-Cephalotine B, and (-)-Fortuneicyclidins A and B.

A new strategy focusing on the last-stage asymmetric assembly of the ring D, which inherently possesses the densest part of stereogenic centers and functional groups in the A/B/C/D ring system of (-)-cephalotaxine, has been developed, in which a novel Rh-catalyzed asymmetric (2 + 3) annulation of tertiary enamides with enoldiazoacetates is designed and explored for enantioselective construction of the crucial cyclopentane ring D bearing a unique spirocyclic aza-quaternary stereocenter. Based on the expeditious access of chiral functionalized building block with the tetracyclic A/B/C/D ring system, a concise enantioselective total synthesis of (-)-cephalotaxine starting from readily available homopiperonyl alcohol has been achieved in nine steps with only two column chromatography purifications. Following the tactical introduction of the Meinwald rearrangement, enantioselective divergent syntheses of (-)-cephalotine B with an additional C3-O-C11 oxo-bridged bond (14 steps), (-)-fortuneicyclidin B with an unprecedented C3-C10 bond (14 steps), and its 2-epimer (-)-fortuneicyclidin A (16 steps) have been also accomplished for the first time.

Corrigendum: Association between diagnostic efficacy of acoustic radiation force impulse for benign and malignant thyroid nodules and the presence or absence of non-papillary thyroid cancer: A meta-analysis.

[This corrects the article DOI: 10.3389/fonc.2023.1007464.].