Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

ObjectiveThis study aimed to investigate the action mechanism by which Banxia Xiexintang （BXT） inhibits epithelial-mesenchymal transition （EMT） in chronic atrophic gastritis （CAG） rats by regulating the interleukin-17（IL-17）/extracellular regulated protein kinases（ERK）/CCAAT enhancer binding protein β（C/EBPβ）signaling pathway， thereby providing new theoretical evidence for the treatment of CAG with classic traditional Chinese medicine formulas. MethodsA CAG rat model was established by using the combined factor method. After successful modeling， the rats were randomly divided into the model group， low-， medium-， and high-dose groups （0.549， 1.098， 2.196 g·kg^-1， respectively） of BXT， and the positive drug group （vitacoenzyme， 0.3 g·kg^-1）. A normal control group was also set up. After 8 weeks of intervention， the pathological changes of gastric tissue were evaluated. The enzyme-linked immunosorbent assay （ELISA） was used to detect the contents of IL-17， tumor necrosis factor-α （TNF-α）， cyclooxygenase-2 （COX-2）， and C/EBPβ in serum， as well as the contents of EMT markers in gastric mucosal tissue including E-cadherin， N-cadherin， and vimentin. The immunohistochemistry method was employed to determine the localization and protein expression levels of IL-17， p-ERK， and C/EBPβ in gastric mucosal tissue. Western blot was used to detect the protein expressions of C/EBPβ， ERK， and its phosphorylated form （p）-ERK in gastric mucosa. Real-time polymerase chain reaction （Real-time PCR） was applied to measure the mRNA expression levels of ERK， COX-2， and C/EBPβ in gastric mucosa. ResultsCompared with those in the normal control group， the rats in the model group showed gastric mucosal glandular atrophy and inflammatory cell infiltration. The protein and their related mRNA expressions of C/EBPβ， ERK， and p-ERK in gastric mucosa were significantly increased （P<0.05，P<0.01）. The levels of IL-17， TNF-α， COX-2， and C/EBPβ in serum were significantly increased （P<0.01）. The contents of N-cadherin and vimentin in gastric mucosal tissue were significantly increased， while the content of E-cadherin was significantly decreased （P<0.01）. Compared with the model group， after intervention with different doses of BXT， the pathological damage of the gastric mucosa was improved to varying degrees. The protein and mRNA expressions of C/EBPβ， ERK， and p-ERK in gastric mucosa were significantly reduced （P<0.05，P<0.01）. The levels of IL-17， TNF-α， COX-2， and C/EBP β in serum were significantly decreased （P<0.01）. The contents of N-cadherin and vimentin in gastric mucosa tissue were decreased， while the content of E-cadherin was increased （P<0.05，P<0.01）. ConclusionBXT can effectively improve the pathological damage of gastric mucosal tissue in CAG rats. Its action mechanism may be related to reducing the levels of IL-17 and TNF-α in serum， regulating the IL-17/ERK/C/EBPβ signaling pathway and inhibiting the EMT process.

Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

OBJECTIVE To investigate the effects of calcitriol on sepsis-induced immunosuppression and its potential mechanism. METHODS A sepsis-induced immunosuppression mice model was established using cecal ligation and puncture （CLP）. The 7-day survival rate， serum levels of tumor necrosis factor- α （TNF- α）， interleukin-6 （IL-6）， and IL-1β were determined in sham operation group， CLP group and calcitriol group （1 μg/kg）； the morphological changes of lung tissue in mice were observed. Lipopolysaccharide （LPS） tolerance macrophage models （representing sepsis-induced immunosuppression） were established using mice macrophage cell line RAW264.7 cells. The levels of TNF-α and IL-6 in cell supernatants as well as mRNA expressions of IL-1β， nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 （NLRP3）， IL-18 and caspase-1 were assessed in culture medium group， LPS group， LPS tolerance group， and calcitriol （5 μmol/L） group. The following parameters were measured： propidium iodide （PI）-positive cell ratio， caspase-1 activity， lactate dehydrogenase （LDH） release， and Ca2+ levels. RESULTS Compared with CLP group， 7-day survival rate and serum levels of TNF-α， IL-6 and IL-1β were increased significantly in calcitriol group （P＜0.05）. Additionally， pulmonary tissue damage was markedly attenuated in calcitriol group. Compared with LPS tolerance group， the levels of TNF-α and IL-6 in cell supernatants， mRNA expressions of IL- 1β， NLRP3， IL-18 and caspase-1， PI-positive cell ratio， caspase-1 activity， LDH release， and Ca2+ levels were all increased significantly in calcitriol group （P＜0.05）. CONCLUSIONS Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be E-mail：yarfwy@163.com achieved by the binding of calcitriol to vitamin D receptor，which promotes the release of Ca2+ from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway.

OBJECTIVE: To observe the efficacy and safety of moxibustion in treating patients with central obesity of phlegm-dampness constitution. METHODS: A total of 66 patients with central obesity of phlegm-dampness constitution were randomly assigned to a moxibustion group (n=33, 3 cases dropped out) and a sham moxibustion group (n=33, 4 cases dropped out). The moxibustion group received mild moxibustion combined with lifestyle intervention; the moxibustion was applied at Shenque (CV8) and bilateral Zusanli (ST36), 30 min per session, maintaining a local skin temperature of (43±1) ℃. The sham moxibustion group received simulated moxibustion combined with lifestyle intervention; the simulated moxibustion was applied at the same acupoints, with the same session length, but with a maintained skin temperature of (37±1) ℃. Both groups were treated once every other day, three times per week for 8 consecutive weeks. Obesity-related physical indicators (waist circumference, hip circumference, body weight, body fat percentage, body mass index [BMI]), constitution evaluation indicators (phlegm-dampness constitution conversion score, symptom score), the impact of weight on quality of life-lite (IWQOL-Lite), the hospital anxiety and depression scale (HADS), and the incidence of adverse events were measured before and after treatment, and after 4 weeks of follow-up. RESULTS: Compared with before treatment, both groups showed significant reductions in waist circumference, hip circumference, body weight, body fat percentage, BMI, phlegm-dampness constitution conversion score and symptom score, IWQOL-Lite, and both anxiety and depression subscale scores of HADS after treatment and at follow-up (P<0.001). These improvements were significantly greater in the moxibustion group than those in the sham moxibustion group (P<0.001, P<0.01, P<0.05). One patient in the moxibustion group experienced a mild burn that resolved with routine care; the incidence of adverse reactions was 3.0% (1/33) in the moxibustion group and 0% (0/33) in the sham moxibustion group, with no statistically significant difference (P>0.05). CONCLUSION On the basis of lifestyle intervention, moxibustion effectively improves obesity-related physical indicators, enhances quality of life, alleviates anxiety and depression, and improves the phlegm-dampness constitution in patients with central obesity. These benefits persist for at least 4 weeks after treatment.
Humans ; Moxibustion ; Male ; Female ; Middle Aged ; Adult ; Obesity, Abdominal/psychology* ; Acupuncture Points ; Treatment Outcome ; Aged ; Quality of Life ; Young Adult ; Body Mass Index

BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*