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Human adipose-derived mesenchymal stem cells (ADSCs) have the potential to be applied to solid organ treatments. However, tissue regeneration is limited by the death of transplanted cells. Ischemia is the main cause of the poor outcome. This study aimed to investigate the effect of berberine (BBR) on ADSCs after fat grafting. The antioxidant BBR on apoptosis and autophagy of ADSCs in vitro ischemia model was induced by hypoxia and serum deprivation (HY/SD). The autophagy promoter rapamycin and autophagy inhibitor 3-MA were incubated separately to investigate the crosstalk between autophagy and apoptosis. Pathway inhibitors further verified whether the autophagy and apoptosis were regulated by AMPK/mTor signaling pathway. Fat survival, fibrosis, level of inflammatory cell infiltration, and the effect of angiogenesis after BBR treatment were observed in vivo. BBR could reduce ROS production and reverse the decreasing cell survival rate. HY/SD would induce apoptosis and autophagy in ADSCs, and BBR could alleviate these processes. After interfering with the level of autophagy, we also proved that apoptosis was regulated by autophagy and changed accordingly. The results also indicated that BBR could protect against autophagy and apoptosis of ADSCs through AMPK/mTor pathway. The treated human-derived adipose tissue was transplanted into BALB/c nude mice, and with the intervention of BBR, the fat grafting had a higher survival rate, lower inflammatory cell infiltration and fibrosis level. Our present study revealed that BBR was a promising anti-autophagy and apoptosis agent for improving the survival rate of ADSCs during cell transplantation.

Diabetes mellitus (DM) and cancer are two major global public health challenges. Growing evidence shows that the core features of DM, including hyperactivated insulin/IGF-1 signaling axis, chronic hyperglycemia, and a persistent inflammatory microenvironment, are important factors driving tumorigenesis and progression. Currently available clinical antidiabetic drugs, such as chemically synthesized drugs, biological and natural products, have been proven to achieve a dual therapeutic effect of controlling blood glucose and regulating the tumor microenvironment (TME). However, these drugs face practical difficulties such as poor oral bioavailability, off-target side effects, and low drug accumulation at tumor sites in clinical application. To overcome these challenges, nanotechnology offers a highly promising solution. Thus, this review elucidates the mechanisms of DM-driven cancer development and the anti-tumor therapeutic mechanisms of current anti-diabetic drugs. Then, we highlight how tailor-made nanosystems overcome traditional delivery barriers, offering unique advantages in targeted delivery, integrated diagnostics, and the oral administration of fragile biologics. Finally, the clinical translatability, disadvantages, and future prospects of these nanosystems will be briefly discussed.

Inhibition of cellular adaptation to hypoxia can cause persistent inflammation, thereby increasing tissue damage and complicating wound healing in diabetes patients. Regulating cellular adaptation to hypoxic environments can help in effective wound repair. Hypoxia-inducible factor (HIF)-1 is a key regulator of cell hypoxia. Extracellular vesicles (EVs) regulate wound repair. This study investigated the mechanism of HIF-1α overexpression in adipose-derived stem cell extracellular vesicles (ADSCs-hEVs) in the repair of diabetic wounds. HIF-1α expression in diabetes patients and healthy participants was studied. High-throughput sequencing, GO, and KEGG analysis revealed that ADSCs small extracellular vesicle hypoxia environments may increase HIF-1α expression by affecting cell metabolism, differentiation, and TGF-β secretion, or by altering the PI3K/AKT pathway. Effect of addition of ADSCs-hEVs on cell proliferation and migration was investigated using Western blotting, EdU assay, transwell assay, and migration. In vivo, after 7, 14, and 21 days, important factors for diabetic wound healing were evaluated by immunohistochemistry, qRT-PCR, Masson staining, and H&E staining. HIF-1α expression decreased in the skin of diabetes patients; interleukin (IL)-6 expression increased, and growth factor-related indexes decreased. ADSCs-hEVs significantly increased the expression and secretion of growth factors, compared with ADSCs-EVs. In vivo, ADSC-hEV treatment accelerated the healing rate and improved the healing quality of diabetic wounds compared with ADSCs-EVs. Speed and quality of wound healing increased significantly in the ADSCs-hEVs group, which could inhibit early inflammation while promoting the secretion and expression of growth factors and extracellular matrix-related indexes.

Background Endovascular therapy (EVT) is the standard of care for acute ischemic stroke due to large vessel occlusion. While predictors of 90-day functional outcome are well-established, the determinants of functional recovery remain less clearly defined in the post-discharge period for patients with initial disability. We aimed to identify the predictors of functional outcome at 3 months in patients who underwent EVT and were discharged with an unmet need for recovery (modified Rankin scale (mRS) score > 2). Methods A multi-center, observational cohort study was conducted using data from the Big Data Observatory Platform for Stroke in China. We included 836 patients from eight comprehensive stroke centers (August 2018 – December 2024) who received EVT, had a pre-stroke mRS of 0–2, and had an mRS > 2 at discharge. The primary outcome was functional outcome at 3 months post-EVT, defined as an mRS score of 0–2. Univariate and multivariate logistic regression analyses were performed to identify independent predictors. Results Of the 836 patients, 151 (18.1%) achieved a favorable functional outcome (mRS 0–2) at 3 months. In univariate analysis, the favorable outcome group was significantly younger, had a lower pre-EVT NIHSS, a lower rate of atrial fibrillation, a higher rate of intravenous thrombolysis, a higher rate of complete recanalization (mTICI 3), and a lower rate of parenchymal hematoma (PH) (all p  < 0.05). Multivariate regression confirmed four independent predictors: younger age (aOR: 0.973; 95% CI: 0.958–0.989; p  = 0.001), lower pre-EVT NIHSS (aOR: 0.940; 95% CI: 0.912–0.968; p  < 0.001), complete recanalization (aOR: 1.921; 95% CI: 1.305–2.826; p  = 0.001), and absence of PH (aOR: 0.424; 95% CI: 0.235–0.768; p  = 0.005). Conclusion A significant proportion of patients discharged with disability experiences meaningful functional recovery by 3 months post-EVT. The key predictors of this subsequent recovery are younger age, milder initial stroke severity, complete reperfusion, and the avoidance of hemorrhagic complications.

The prevalence of acute ischemic stroke (AIS) is increasing among people of working age, posing socioeconomic and healthcare challenges. Inability to return to work can have significant negative consequences and contribute to the economic burden of stroke. Endovascular treatment (EVT) has been established as the standard of care for large vessel occlusion AIS patients. In this study, we aimed to identify factors predicting favorable outcome among working age AIS patients undergoing EVT. We analyzed data from 309 patients from five comprehensive stroke centers between 2019 and 2023. All patients were working age (18<59) with symptoms onset of within 24 hours. Modified thrombolysis in cerebral infarction (mTICI) score of 2b-3 was considered as successful recanalization. We used 3-months mRS post-EVT to evaluate the outcome; mRS of 0-2 was defined as favorable outcome, whereas mRS of 3-6 was considered unfavorable outcome. The unfavorable outcome group consisted of 150 patients, and 159 patients were in the favorable outcome group. More people in the unfavorable outcome group had diabetes (29.33% vs 15.72%, p=0.004) and hypertension (61.33% vs 40.88, p<0.001). A multivariable regression analysis demonstrated that several factors, including successful recanalization (odds ratio (OR) 5.298, 95% confidence interval (CI) 1.735-16.174, p=0.003), pre-EVT NIHSS (OR 0.892, 95% CI 0.852-0.934, p=0.000), baseline Alberta stroke program early CT score (ASPECTS) (OR 1.609, 95% CI 1.274-2.032, p=0.000), hypertension (OR 0.477, 95% CI 0.270-0.845, p=0.011), diabetes mellitus (OR 0.413, 95% CI 0.208-0.820, p=0.011), and symptomatic intracerebral hemorrhage (sICH) (OR 0.045, 95% CI 0.006-0.359, p=0.003) can predict the outcome of patients undergoing EVT. Favorable outcome of working age patients with AIS undergoing EVT can be predicted using multiple factors, including hypertension, diabetes mellitus, successful recanalization, pre-EVT NIHSS, baseline ASPECTS, and sICH.

Recent evidence suggests a crucial biological role for Circular RNAs (circRNAs) in keloid diseases, yet the underlying mechanisms remain unclear. This study explored the biological effects and molecular mechanisms of hsa_circ_0002198 in keloid formation. Real-time quantitative PCR (qRT-PCR) was employed to assess the expression of circ_0002198 in keloid tissues, normal skin tissues, keloid fibroblasts (KFs), and normal skin fibroblasts (NFs) from nine patients. To investigate the role of circ_0002198 in keloid pathogenesis, cell transfection technology was utilized to knock down circ_0002198. Various experiments including Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), Transwell, wound healing assay, flow cytometry, and others were conducted to explore the potential mechanisms associated with circ_0002198 expression. The RNA-binding protein Eukaryotic translation initiation factor 4A, isoform 3 (EIF4A3) binding to circ_0002198 was identified and confirmed through bioinformatics databases prediction and RNA immunoprecipitation (RIP) assay. Finally, the expression of EIF4A3 was assessed, and both silencing and overexpression were employed to verify its role in circ_0002198 regulation. The expression levels of circ_0002198 and EIF4A3 were notably elevated in keloid tissues and KFs compared to normal skin tissues and NFs. The reduction of circ_0002198 expression in KFs significantly impeded their proliferation, migration, and invasion. It also hindered the cell cycle process and the expression of associated proteins while concurrently promoting apoptosis in KFs. EIF4A3 was identified to bind to the flanks of circ_0002198, enhancing the occurrence of circ_0002198 and its role in regulating the progression of KFs. Our study offers insights into how Circular RNA may contribute to the pathogenesis of keloid formation, highlighting Circ_0002198 as a potential novel biomarker for keloids in association with EIF4A3. Further research, involving larger study cohorts, is necessary to broaden our understanding of keloid mechanisms and potential treatment approaches.

Background: Silicone implants are currently the most widely used artificial materials in plastic surgery. Capsule formation following implant application is unavoidable. When the capsule is excessively thick and strongly contracted, it can lead to obvious symptoms, clinically known as capsular contracture. Biological factors have always been the focus of research on the capsule formation. As a growth factor, progranulin (PGRN) plays an important regulatory role in wound healing, tissue fibrosis, tumor proliferation and invasion, and inflammation regulation. At present, the research on the capsule mainly involves the regulation of tissue healing and fibrosis under the influence of inflammation. Because PGRN has a regulatory role in these processes, we believe that the study of both can provide a new theoretical basis and intervention sites for monitoring and inhibiting the development of the capsule. Methods: In this experiment, the effects of different surgical operations on the content of PGRN in the surgical site and plasma of rats were detected. Sprague-Dawley (SD) rat dermal fibroblasts were co-cultured by recombinant PGRN. The effects of r-PGRN on fibroblasts were detected by 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing assay and Western blot assay. Finally, the effect of PGRN on capsule formation and contracture was studied by changing the content of PGRN in the prosthesis in rats after operation. Results: Surgical trauma and silicone implant increased plasma and local PGRN levels in SD rats. PGRN can activate the TGF-[beta]/ SMAD signaling pathway in a dose-dependent manner, thereby promoting fibroblast proliferation, differentiation and migration and inhibiting apoptosis and enhancing cell function, thereby promoting capsule formation and contracture. Conclusion: PGRN promotes the formation and contracture of the silicone implant capsule in SD rats by activating the TGF-[beta]/ SMAD signaling pathway. This discovery may provide new therapeutic targets and detection indicators. Keywords: fibrosis, fibroblast, silicone implants, implantation, TGF-[beta]

ObjectivesThis study aimed to explore the changes of four major inflammasomes in adult-onset Still’s disease (AOSD) and preliminarily evaluate the therapeutic effect of carboxyamidotriazole (CAI), which has previously been reported to have the significant anti-inflammatory activity.MethodThe mRNA expressions of proinflammatory cytokines and inflammasome components in peripheral blood mononuclear cells (PBMCs) from AOSD patients and healthy controls (HC) were determined by reverse transcription-quantitative PCR. Poly(dA:dT)-induced AIM2 inflammasome and flagellin-induced NLRC4 inflammasome activation models were established in bone marrow–derived macrophages (BMDMs). The levels of cytokines in serum and culture supernatants were measured by ELISA method.ResultsThe serum levels of IL-1β, IL-6, and TNF-α in AOSD patients were significantly higher than those in HC. However, the mRNA expressions of IL-1β, IL-6, IL-18, and TNF-α in PBMCs did not differ markedly in AOSD patients in comparison with HC. Significantly increased mRNA levels of AIM2, NLRC4, ASC, and caspase-1 were observed in patients with AOSD when compared with HC, while NLRP1 and NLRP3 showed no change in AOSD samples. In addition, CAI treatment could significantly reduce the levels of IL-1β, IL-6, and TNF-α secreted by AOSD PBMCs and inhibit AIM2 and NLRC4 inflammasomes activation in BMDMs.ConclusionsIncreased levels of proinflammatory cytokines in AOSD might be associated with NLRC4 and AIM2 inflammasomes activation. CAI is likely to have the therapeutic potential for AOSD by inhibiting NLRC4 and AIM2 inflammasomes activation and reducing the proinflammatory cytokines and worthy of further investigation. These results provide new ideas for elucidating the pathogenesis of AOSD and providing specific targeted therapy.Key points• Significantly higher mRNA levels of AIM2 and NLRC4 inflammsome signaling were observed in AOSD patients compared with health controls, indicating that AIM2 and NLRC4 inflammsome activation might be related to the increased proinflammatory cytokines in AOSD.• CAI treatment markedly reduced the secretion levels of cytokines IL-1β, IL-6, and TNF-α in AOSD PBMCs and inhibited AIM2 and NLRC4 inflammasome activation.

IntroductionEndovascular treatment (EVT) is an effective treatment for patients with acute ischemic stroke (AIS); however, it remains to be determined if treatment with intravenous thrombolysis (IVT) prior to EVT confers any benefit in octogenarians and older. This study aimed to address if bridging tPA has improved functional outcomes or complications in patients 80 years and older.MethodsThis multicentre retrospective cohort study included patients 80 years old and above who underwent endovascular therapy for large vessel occlusion acute ischaemic stroke in 10 compressive stroke centres across China and Singapore between 2018 and 2024. Clinical and procedural factors of patients in Singapore and China were compared using multivariate binary logistic regression. The primary outcome measured was 3-month functional independence defined as modified rankin scale (mRS) 0–2. Secondary outcomes included 3-month independent ambulation as defined as mRS 0–3, 3-month mortality rates and achieving successful recanalization. Data on intracranial haemorrhage was also collected.ResultsBridging IVT was not associated with improvement in 3-month functional independence (24.47% vs. 20.97%; p = 0.505), improvement in 3-month independent ambulation (32.80% vs. 41.49%; p = 0.512), 3-month mortality rates (36.17% vs. 33.33%; p = 0.637) or increased rates of successful recanalisation (89.36% vs. 87.63%; p = 0.672),. Instead, patients who underwent bridging IVT had higher rates of haemorrhage compared to patients who did not undergo bridging IVT even after adjusting for confounding factors (OR = 1.921; 95% CI 1.026–3.596; p = 0.041).ConclusionThe findings of this study suggest that bridging IVT prior to EVT may not improve functional outcomes or mortality rates. However, it appears to be associated with an increase in risk of intracranial haemorrhage.

IntroductionParenchymal haematoma (PH) is a potentially serious complication post endovascular treatment (EVT) and is associated with poor functional outcomes. It is unknown if modifiable factors can improve the outcomes of patients with PH. This study aimed to determine whether successful reperfusion is associated with favourable outcome in patients with ischemic stroke despite this complication.Methods In an international multi-centre study, favourable outcomes (mRS0-2) of patients achieving successful reperfusion (TICI 2b/3) were compared with outcomes of those with unsuccessful reperfusion. Results 346 patients were included in the final analysis. 36 patients had unsuccessful reperfusion (10.4%) while 310 had successful reperfusion (89.6%). Amongst patients with PH post-EVT, successful reperfusion conferred better 3-month favourable outcomes (20.32% vs 5.56%; p=0.032) and lower mortality rates (40.32% vs 72.22%; p <0.001) compared with patients who had unsuccessful reperfusion. Conclusion Successful reperfusion remains a strong predictor of favourable outcome and reduced mortality in ischemic stroke patients with parenchymal haematoma post endovascular treatment.