Impaired macrophage polarization is a key factor exacerbating osteoporosis (OP), influencing bone metabolism via modulating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Histone cell cycle regulator (HIRA), an epigenetic regulator, is downregulated in OP. However, its role in modulating macrophage polarization and BMSCs osteogenic differentiation remains unclear. Bone marrow-derived macrophages (BMDMs) and BMSCs were extracted from the bone marrow of SD rats, and identified using staining and flow cytometry. An ovariectomized (OVX) mouse model was established, and HIRA protein was detected via Western blot. A co-culture system of BMDMs and BMSCs was established, and BMDMs were transfected with an HIRA overexpression plasmid. Cytokine levels were measured by ELISA kits, bone structure was assessed via micro-CT, and histopathological staining evaluated femoral tissue pathology, calcium deposition, and osteoclast counts. The levels of proteins associated with osteogenic differentiation, osteoclast differentiation, macrophage polarization, and the YAP1/β-catenin pathway were detected using Western blot. HIRA is downregulated in BMSCs treated with dexamethasone and in the femoral tissues of OVX mice. Overexpression of HIRA effectively raised M2 polarization markers and reduced M1 polarization markers in BMDMs, and promoted BMSCs osteogenic differentiation. Following HIRA overexpression in OVX mice, femoral tissue damage was significantly reduced, osteoclast numbers decreased, and bone metabolic imbalance improved. Furthermore, HIRA overexpression also activated the YAP1/β-catenin axis in the femoral tissue of OVX mice, thereby suppressing bone loss and promoting macrophage M2 polarization. HIRA promotes M2 polarization of macrophages by activating the YAP1/β-catenin pathway, thereby enhancing BMSC osteogenic differentiation and ultimately reducing bone loss in OVX mice. Overexpression of histone cell cycle regulator (HIRA) promotes M2 polarization of BMDMs by activating the YAP1/β-catenin pathway, thereby promoting BMSCs osteogenic differentiation and declining bone loss in OVX mice.
Resveratrol (Res), a natural polyphenolic compound, exhibits multiple antitumor activities against acute myeloid leukemia (AML), though its mechanisms remain incompletely understood. In this study, CCK-8 assay, CFSE flow cytometry, Transwell assays, and flow cytometry assessed proliferation, invasion, migration, and programmed cell death in MV4-11 and MOLM-13 leukemic cell lines. Western blotting examined cell death regulatory factors (Cleaved-caspase 3/caspase 3, Bax, Bcl-2), aerobic glycolysis proteins (GLUT1, HK2, LDHA, PKM2), cuproptosis-related proteins (FDX1, DLAT, Lip-DLAT, DLST, Lip-DLST, HSP70, SDHB), and PI3K/AKT pathway proteins (p-PI3K/PI3K, p-AKT/AKT). Intracellular Cu2⁺ levels were measured colorimetrically, while glucose uptake, lactate, and ATP levels were quantified to evaluate cellular metabolism. Mechanistic investigations utilized PFKFB3 overexpression, PI3K activator (740 Y-P), and inhibitor (LY294002) intervention experiments. The antitumor efficacy of Res was validated in an AML xenograft mouse model. Res significantly inhibited AML cell proliferation, invasion, and migration while promoting apoptosis. It markedly downregulated FDX1, Lip-DLAT, Lip-DLST, and SDHB while upregulating HSP70 and intracellular Cu2⁺, inducing cuproptosis—an effect reversible by the cuproptosis inhibitor TTM. Res reduced glucose uptake, lactate production, ATP generation, and downregulated GLUT1, HK2, LDHA, and PKM2, thereby suppressing aerobic glycolysis-a process reversed by PFKFB3 overexpression. Furthermore, Res inhibited PI3K and AKT phosphorylation; the PI3K activator 740 Y-P counteracted Res-mediated effects while the PI3K inhibitor LY294002 enhanced them. In vivo experiments confirmed that Res treatment markedly diminished tumor size and mass, lowered Ki-67 proliferation marker, enhanced programmed cell death, suppressed PI3K/AKT signaling, decreased glycolytic enzyme levels, and elevated copper-dependent cell death mediators. Res exerts anti-AML effects by inhibiting the PI3K/AKT pathway while coordinately regulating aerobic glycolysis and cuproptosis in AML cells. Resveratrol effectively suppresses tumor progression by inhibiting the PI3K/AKT axis, downregulating aerobic glycolysis, and promoting cuproptosis.
Patients with recurrent acute gout flares who are unable to use nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine have limited alternatives and remain at high risk of flare recurrence. Firsekibart is a fully human monoclonal antibody targeting interleukin-1βeta (IL-1β) The objective of this study is to evaluate the longer-term efficacy and safety of firsekibart through 48 weeks in patients with acute gout unsuitable for standard anti-inflammatory therapy. This was a multicenter, randomized, double-blind, positive-controlled phase 3 study of firsekibart with compound betamethasone. Followed by a 24-week open-label extension (OLE), conducted at hospitals in China. The double-blind phase was conducted from Week 0 to Week 24, followed by an OLE through Week 48 and a 12-week safety follow-up period after the last dose. Adults with ≥ 2 acute gout flares in the past year and a contraindication, intolerance, or inadequate response to NSAIDs and/or colchicine were enrolled. Patients completing the double-blind phase entered the OLE, during which firsekibart was administered for acute gout flares as needed. Efficacy included proportion of patients experiencing ≥ 1 gout flare recurrence, number of flares per patient, and time to first recurrence through Week 48, as well as rescue medication use during the OLE. Exploratory outcomes included health-related quality of life and flare-related pain. Safety included adverse events (AEs), laboratory tests, and immunogenicity. Of 313 patients (double-blind phase), 300 entered the OLE. By week 48, gout flare recurrence occurred in 70 patients (44.9
OBJECTIVES:To evaluate whether remimazolam besylate could provide noninferior sedation to dexmedetomidine in patients under mechanical ventilation (MV) in the ICU. DESIGN:A multicenter, single-blind, randomized, noninferiority trial. SETTING:Fifteen ICUs across China between October 2021 and November 2023. PATIENTS:Adults under endotracheal intubation MV who were expected to require sedation for 8-48 hours. INTERVENTIONS:Three hundred fourteen patients were randomly assigned at a 1:1 ratio to the remimazolam besylate or dexmedetomidine group. Analgesia was provided via a continuous IV infusion of remifentanil at 1.2-9.0 µg/kg/hr. Remimazolam besylate or dexmedetomidine was administered IV at an initial loading dose of 0.1 mg/kg followed by a maintenance dose of 0.10-0.30 mg/kg/hr or at an initial loading dose of 0.20 µg/kg followed by a maintenance dose of 0.2-0.70 µg/kg/hr to achieve the targeted sedation range on the Richmond Agitation-Sedation Scale of -2 to +1. MEASUREMENTS AND MAIN RESULTS:Of the 314 patients enrolled, 299 completed the study. The sedation efficacy rates, as the primary endpoint, were 82.6% and 83.2% in remimazolam besylate and dexmedetomidine groups, respectively, in the per-protocol set (PPS), whereas the rate was 72.9% in both groups in the intention-to-treat (ITT) set. The noninferiority margin was set as 10%, and the lower limits of the two-sided 95% CI for the intergroup difference were -3.0% and -2.6% in the PPS and ITT sets, respectively. The dexmedetomidine group had a higher incidence of bradycardia than the remimazolam besylate group (4.7% vs. 0.7%; p = 0.029), whereas no intergroup differences were noted for the remaining secondary endpoints and adverse events. CONCLUSIONS:Remimazolam besylate could provide noninferior sedation as dexmedetomidine with a lower risk of bradycardia for 48 hours in mechanically ventilated patients in the ICU.
BACKGROUND:Artemisia desertorum (desert mugwort) is widely planted in the Mu Us Desert of northwestern China for windbreak and sand fixation, but extensive cultivation has unexpectedly increased pollen-induced allergies. This study aims to perform allergen molecular diagnosis and evaluate its utility in characterizing immunoglobulin E (IgE) sensitization profiles linked to allergic phenotypes. METHODS:One hundred and thirty-five Artemisia-allergic patients from three regions differing in the Artemisia pollen exposure were examined. Eleven allergens were either purified naturally or recombinantly for IgE quantification using the ImmunoCAP assay. RESULTS:At least one allergen response was detected in 134 patients. Major allergens included Art d 1 (85.2%), Art d 2 (62.2%), Art d 3 (88.9%), Art d 7 (82.2%), and Art d 9 (54.1%). Patients from the high desert mugwort exposure region exhibited elevated serum-specific immunoglobulin E (sIgE) levels, increased sensitization to mugwort extract and allergen molecules, broader polysensitization, and higher asthma prevalence. Number of sensitized allergens and sIgE levels to mugwort extract and Art d 3 were independently associated with asthma in multivariable analysis. A predictive model was developed for asthma prediction with an AUC of 0.832. CONCLUSIONS:High environmental exposure to A. desertorum pollen increases pollen allergy prevalence and asthma risk in Mu Us Desert residents. Molecular allergy diagnostics with a comprehensive A. desertorum allergen panel enhanced diagnostic precision, supported disease severity prediction, and provided critical insights for improved clinical management.
