Biomedical Journal最新文献

The 2025 Nobel Prize in Physiology or Medicine, awarded to Shimon Sakaguchi, Mary E. Brunkow, and Fred Ramsdell, recognizes the discovery and molecular definition of regulatory T cells (Tregs) as the cornerstone of peripheral immune tolerance. This recognition honors a transformative journey marked by Sakaguchi's identification of CD4⁺CD25⁺ T cells as a regulatory population (1995), followed by Brunkow and Ramsdell's discovery that mutations in the FOXP3 gene cause both the scurfy mouse phenotype and human IPEX syndrome (2001), and culminating in the demonstration that FOXP3 governs Treg development and function (2003). This achievement crowns a turbulent half-century arc. The suppressor T-cell (Ts) hypothesis of the 1970s proposed an active T-cell brake on immunity but collapsed in the 1980s due to phenotypic ambiguity and reproducibility failures. Following this "dark age," the concept of active suppression was kept alive through functional studies in organ-specific autoimmunity (Parish, Kong, Rose) and transplantation tolerance (Waldmann). However, it was Sakaguchi's discovery of CD25 as a specific marker that finally provided the physical identity of these cells, bridging the gap between functional observation and cellular definition. The subsequent identification of FOXP3 as the lineage-defining transcription factor transformed a disputed concept into a reproducible, engineerable immune module. Today, this molecular precision drives broad clinical translation, ranging from Treg-based therapies in autoimmunity and transplantation to targeted Treg modulation in cancer immunotherapy. This Short Review traces the trajectory-from controversy to molecular definition-and frames a forward path for context-dependent modulation of Tregs in clinical medicine.

Background: Aging is associated with impaired muscle protein turnover, oxidative stress, and functional decline. Both renin-angiotensin system (RAS) inhibition and exercise modulate redox balance and anabolic-catabolic signaling; however, how aging influences their effects under physiological conditions remains unclear.

Methods: Middle-aged (50 weeks) and old (72 weeks) female C57BL/6 mice were randomly assigned to control (C), losartan (L; RAS inhibitor), exercise (E), or combined losartan plus exercise (LE) groups for a four-month intervention. Exercise capacity, cardiac function, oxidative stress markers [thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC)] in skeletal muscles, and key regulators of muscle protein turnover (Akt, mTOR, ERK1/2, Smad2, FoxO3a, and p38 MAPK) were evaluated. Two-way analysis of variance was used to determine whether age influences the effects of interventions.

Results: Exercise training (E and LE) improved exercise capacity in both age groups. The combined LE intervention significantly enhanced cardiac systolic function compared to exercise alone. Losartan exerted age-dependent, opposite redox effects. In middle-aged mice, losartan increased TBARS and reduced TAC. Conversely, in old mice, losartan significantly reduced TBARS and increased TAC. Most protein turnover regulators (Akt, mTOR, ERK, FoxO3a, and p38 MAPK) remained unchanged by interventions, while Smad2 activation exhibited age-dependent patterns. Smad2 activation levels increased in middle-aged LE mice but were reduced by exercise in old mice.

Conclusions: While exercise is a robust intervention, losartan's efficacy is critically dependent on the animal's baseline oxidative status. These findings highlight the importance of considering age as a critical factor when designing pharmacological interventions for age-related muscle atrophy.

Chikungunya virus (CHIKV), an alphavirus in the Togaviridae family, is transmitted to humans through mosquito bites and can lead to severe complications in newborns and elders. Its RNA genome functions as mRNA to produce viral nonstructural proteins, which assemble into replication complex for synthesizing new viral genomic and subgenomic RNA within the cytoplasm. Previous studies have established a CHIKV replicon system, that can express CHIKV replication complex from viral genomic RNA and an eGFP reporter from subgenomic RNA, to study viral RNA replication and screen antivirals against the CHIKV RNA replication. Additionally, researchers have discovered that BPR2-D2, which is classified to furanocoumarin, exhibits potential as a broad-spectrum antiviral drug. In this research, we applied the replicon system to evaluate the antiviral activity of BPR2-D2 against CHIKV RNA replication. The effective concentration was 10.47 ± 0.02297 nM for inhibiting 50% of CHIKV genomic RNA replication with high selective index. Moreover, we validated the antiviral effect of BPR2-D2 with the authentic infection of Sindbis virus, which is also an arthritogenic alphavirus. The molecular docking analysis was applied to suggest possible targets of BPR2-D2 among CHIKV nonstructural proteins. Taken together, this research demonstrated that BPR2-D2 can be a promising antiviral against CHIKV.

Background: Mechanical irritation can lead to traumatic ulcers in the oral cavity and is a potential risk factor for oral cavity squamous cell carcinoma (OSCC). Habitual betel nut chewing reportedly has the potential to induce mechanical irritation and OSCC, but the details of the underlying mechanism(s) remain unknown.

Materials and methods: By integrating transcriptomic and proteomic data from 83 OSCC patients with our in vitro mechanical cell abrasion (MCA) model, we explored mechanical irritation-driven OSCC progression, including inflammasome activation, migration, invasion, and colony formation, and revealed underlying mechanisms via potassium efflux, ChIP-qPCR, co-IP, and immunofluorescence.

Results: We observed that the combination of betel nut alkaloid, arecoline, and MCA demonstrate a synergistic effect on inflammasome activation in OSCC cells. MCA could cause membrane injury, resulting in the efflux of lactate dehydrogenase and potassium ions; this could activate the NLRP3 inflammasome complex to facilitate the production of IL-1β and the nuclear translocation of the HIF-1α/NLRP3/ASC complex, which activated the HIF-1α oncogenic downstream target, ADAM8. Higher ADAM8 mRNA levels in tumors were correlated with poor prognosis in OSCC. Upon MCA treatment, the colocalization of HIF-1α, NLRP3, and ASC was enriched in the nucleus, leading to elevated inflammasome and tumorigenic responses, respectively, in OSCC cells.

Conclusions: Our MCA model simulating betel nut chewing induces membrane damage, activates the HIF-1α/NLRP3/ASC pathway, and enhances crosstalk between inflammation and HIF-1α signaling. Omics and clinical data reveal that ADAM8, a HIF-1α downstream target, may serve as a poor prognostic marker in OSCC.

Cellular senescence is a stress-induced cellular state that contributes to tissue dysfunction, chronic inflammation, and a broad range of aging-associated pathologies. The accumulation of senescent cells (SnCs) disrupt normal tissue function, positioning them as drivers of pathological decline and therapeutic targets for aging intervention. Accordingly, multiple senescence-targeted strategies have been developed, including senolytics, senomorphics, senescence immunotherapy, and restoration-oriented interventions. These approaches aim to mitigate senescence-driven pathology by eliminating senescent cells, modulating their secretory activity, or restoring cellular function. Ongoing advancements will require precise stratification of senescent states, careful assessment of long-term safety, and the integration of optimized delivery systems for targeted therapeutic outcomes.

Background: We aimed to establish the optimal value of the alanine aminotransferase (ALT)/quantitative HBsAg (qHBsAg) ratio and qHBsAg level at end of treatment (EOT) to predict HBsAg seroclearance following cessation of entecavir versus tenofovir disoproxil fumarate (TDF) in HBeAg-negative with chronic hepatitis B (CHB) patients.

Material and methods: This retrospective cohort study included 715 HBeAg-negative patients without cirrhosis who had previously received entecavir (n=438) or TDF (n=277).

Results: The cumulative incidences of HBsAg seroclearance at 5 and 10 years after cessation of entecavir or TDF were 13.0% and 33.8%, respectively. Both a qHBsAg level <100 IU/mL and an ALT/qHBsAg ratio ≥0.2 at EOT were independent predictors of HBsAg seroclearance (p <0.001). A qHBsAg of 100 IU/mL had significantly lower Akaike information criterion (AIC) and Bayesian information criterion (BIC) values than an ALT/qHBsAg ratio of 0.2 at EOT (AIC: 1273 vs. 1305, BIC: 1276 vs. 1308, both p <0.001). Additionally, patients who discontinued entecavir therapy had a higher rate of HBsAg seroclearance than patients who discontinued TDF therapy, regardless of qHBsAg ≥100 IU/mL (p=0.027) or ALT/qHBsAg ratio <0.2 (p=0.028). The optimal values for predicting HBsAg seroclearance were 300 and 100 IU/mL for qHBsAg and 0.1 and 0.2 for the ALT/qHBsAg ratio after stopping entecavir versus TDF, respectively.

Conclusions: A qHBsAg level <100 IU/mL at EOT is better predictor of HBsAg seroclearance than an ALT/qHBsAg ratio ≥0.2. Compared to TDF, entecavir was associated with higher rates of HBsAg seroclearance in patients with higher qHBsAg level or a lower ALT/qHBsAg ratio at EOT.