Despite decades of research dominated by the amyloid-beta hypothesis, clinical treatment of Alzheimer's disease (AD) has yet to achieve a decisive breakthrough. This editorial advances an alternative pathological paradigm: the collapse of endogenous hydrogen sulfide (H₂S) signaling represents a central failure point in the brain's intrinsic defense mechanisms against AD. We dissect the molecular cascade triggered by cystathionine γ-lyase (CSE) deficiency, focusing on how reduced persulfidation of glycogen synthase kinase 3β (GSK3β) directly promotes Tau hyperphosphorylation and subsequent neuronal injury. A critical message of this commentary is the need to dispel the oversimplified notion that sulfide supplementation alone can confer neuroprotection. Because H₂S works within a narrow therapeutic window and has complex hormetic effects, untargeted dietary or environmental exposure cannot match the spatiotemporal precision of endogenous signaling. Instead, it may increase the risk of toxicity. By integrating analyses of transsulfuration metabolism, mitochondrial function, and nutritional status, we propose a precision medicine framework centered on brain-targeted delivery technologies and metabolic correction strategies to selectively restore compromised H₂S signaling networks. This conceptual shift marks a new direction in AD research, shifting the focus from clearing toxic protein aggregates to restoring endogenous neuronal resilience.

Regenerative medicine holds substantial promise for restoring the function of damaged or lost organs and tissues. However, the development of effective small-molecule drugs in this field has been limited, partially owing to the lack of suitable regenerative animal models for drug discovery. Enchytraeus japonensis, a small annelid with exceptional regenerative capacity, is emerging as a valuable model for regeneration research. E. japonensis regenerates in a shorter period, in only 4 days, than other major regenerative animal models. Moreover, novel experimental systems have recently been developed to enhance the utility of E. japonensis, including a soaking RNA interference system for easy, non-invasive gene knockdown, an imaging system for quantifying cell distribution in the blastema, and soaking-based pharmacological inhibition using small-molecule compounds. This review highlights E. japonensis as a potential platform for chemical screening in regenerative medicine.

The feasibility of substituting traditional decoction pieces with Chinese herbal formula granules fundamentally hinges on the equivalence of their active components. Formula granules face complex compositional changes during manufacturing: volatile oils suffer substantial losses (retention rates below 30% in aromatic herbs), thermolabile glycosides undergo degradation during high-temperature processing, and Maillard reactions generate novel compounds whose pharmacological contributions remain unclear. Although advanced analytical technologies such as ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) can identify thousands of components, existing quality control standards still rely on 1-3 pharmacopeial markers, and fingerprint similarity criteria lack uniformity (0.80-0.95), inadequately reflecting the true quality of multi-component systems. Bioequivalence studies demonstrate that formula granules generally exhibit 60-90% performance of traditional decoctions in vitro, with comparable area under the curve (AUC) and Cmax values for certain components but significant discrepancies for others. Critically, high chemical similarity cannot guarantee clinical therapeutic equivalence—the logical chain from"component equivalence" to "therapeutic equivalence" remains unestablished. Clinical research is sparse, with high-quality randomized controlled trials (RCTs) representing less than 5% of studies and head-to-head comparisons particularly scarce. Future research must develop volatile component preservation technologies, establish comprehensive synergistic effect evaluation methodologies, and most importantly, conduct large-scale clinical trials. Without these efforts, the scientific credibility and international acceptance of formula granules will remain questionable.

The well-known medicinal plant ginger (Zingiber officinale Roscoe) has numerous health benefits, but its key bioactive compound, 6-gingerol, suffers from poor water solubility and stability. This study aimed to enhance the oral delivery of ginger extract by formulating a self-nanoemulsifying drug delivery system (SNEDDS) using a design of experiments (DoE) approach. Ginger rhizomes were extracted by ultrasound-assisted extraction, with a 10-min extraction time yielding the highest 6-gingerol content. An I-optimal mixture design was then applied to develop SNEDDS formulations using castor oil, Cremophor RH40, various co-surfactants (Span 20 or Span 80), and co-solvents (polyethyleneglycol 400 (PEG 400) or ethanol). The optimized SNEDDS readily self-emulsified in gastric medium, producing nano-sized droplets (42.5-78.1 nm) with low polydispersity (0.12-0.58) within 10 min. The ginger extract-loaded SNEDDS (G-SNEDDS) achieved high encapsulation efficiencies, exceeding 90% for both 6-gingerol and 6-shogaol, and significantly enhanced the in vitro release of 6-gingerol, reaching cumulative release levels of approximately 90-100% over 48 h, compared to only 67% from the unformulated extract. Transmission electron microscopy (TEM) confirmed the formation of uniform, spherical nanoemulsion droplets. Short-term stability testing indicated that the optimized formulation remained physically stable, as evidenced by minimal changes in droplet size, and preserved most of the 6-gingerol content under ambient storage conditions; however, exposure to elevated temperatures accelerated the conversion of 6-gingerol to 6-shogaol. Overall, the optimized SNEDDS significantly enhanced the solubility, dissolution, and storage stability of ginger extract, offering a promising strategy to improve the oral bioavailability of the therapeutically active constituents present in ginger.

Xuefu Zhuyu Capsule (XFZY) demonstrated potential in alleviating post-stroke depression (PSD), a condition whose underlying mechanisms may involve the gut–brain axis. This study aimed to explore the therapeutic effects of XFZY on PSD and its possible modulation of the gut microbiota–gut–brain axis in a rat model. Wistar rats were randomly assigned to sham, PSD, three XFZY dose (0.216, 0.432, 0.864 g/kg), and fluoxetine (1.80 mg/kg) groups (n = 12 per group). The PSD model was established using transient middle cerebral artery occlusion (t-MCAO) combined with chronic unpredictable mild stress (CUMS), followed by 28 days of XFZY administration. In a separate experiment, gut microbiota was depleted via antibiotic cocktails, with rats divided into sham, PSD, XFZY medium Dose (XFM), pseudo-germ-free (PGF) and PGF + XFM (PGFX) groups. Behavioral tests indicated that XFZY ameliorated depressive-like behaviors, with the medium dose (0.432 g/kg) showing the most significant effect. Histological analysis using hematoxylin and eosin (H&E) and Nissl staining revealed that XFZY alleviated colonic and neuronal damage. Furthermore, 16S rRNA sequencing and gas chromatography revealed that XFZY modulated gut microbiota composition, increased species richness, and elevated levels of short-chain fatty acids such as acetic acid, propionic acid, and butyric acid. Enzyme-Linked Immunosorbent Assay (ELISA) results showed that XFZY reduced pro-inflammatory cytokines — interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), while immunohistochemistry indicated enhanced intestinal barrier function and reduced neuroinflammation. Furthermore, after depletion of gut microbiota using antibiotic cocktails, these therapeutic effects of XFZY were abolished. In summary, XFZY may alleviate PSD by modulating the gut microbiota and regulating the gut–brain axis, offering a promising direction for future therapeutic research.

The importance of oral health has gained increasing recognition in the recent years owing to its association with numerous systemic diseases such as diabetes and cardiovascular disease. Dental checkups are crucial for maintaining and promoting oral health; however, in Japan, a relatively low uptake of dental checkups remains a challenge. Community pharmacists are expected to play a vital role in supporting the health and well-being of local residents; however, they have been observed to be reluctant to provide support in the oral health domain. This study aimed to develop and evaluate a blended learning training program on oral health support aimed at educating pharmacists working in health support pharmacies. The training, which involved online learning and on-site training, covered topics such as the importance of oral health, methods of oral health assessment, and the mechanisms of eating and swallowing. The participants, including a total of 39 pharmacists from across the country, completed surveys before and after the training, as well as at 9 months and 15 months posttraining. The results demonstrated a significant improvement in the pharmacists' knowledge, explanatory abilities, and confidence in providing oral health support, and these effects were observed to persist for up to 15 months after the training had ended. In addition, the variety of oral health-related products in pharmacies increased. This blended learning program demonstrates the potential to redefine the role of pharmacists in promoting oral health and contribute to the improvement of oral health among local residents.

Needle-insertion pain during dental local anesthesia remains one of the strongest triggers of dental anxiety. Conventional topical anesthetics show limited penetration through the thick palatal mucosa and often provide insufficient suppression of insertion pain. Microneedle (MN) patches have emerged as a minimally invasive drug-delivery platform capable of enhancing transmucosal permeability and topical anesthetic efficacy. This randomized, double-blind, crossover clinical trial evaluated the efficacy and safety of a benzocaine-loaded MN patch applied to the palatal mucosa prior to local anesthesia. Twenty adult patients requiring bilateral maxillary premolar scaling and root planing received MN or placebo patches in two study periods separated by a one-week washout. The primary outcome was the presence or absence of needle-insertion pain. Secondary outcomes included injection-phase pain assessed using a 100-mm visual analogue scale (VAS), numbness or discomfort at the application site, vital signs, and adverse events. Needle-insertion pain was reported in 2 of 20 cases (10%) under the MN patch condition, compared with 14 of 20 cases (70%) under the placebo patch condition, demonstrating a significantly lower incidence with the MN patch (p = 0.00049). In contrast, VAS scores for injection-phase pain did not differ significantly between conditions. No clinically relevant numbness, mucosal irritation, or MN-related adverse events were observed, and vital signs remained stable throughout both study periods. The benzocaine-loaded MN patch selectively attenuated superficial needle-insertion pain while maintaining an excellent safety profile. The absence of an effect on deeper injection-phase pain is likely attributable to the substantial thickness of the palatal mucosa. These findings support the clinical utility of MN-assisted transmucosal anesthesia as a novel drug-delivery modality in dentistry and provide a foundation for the development of minimally invasive analgesic systems.

Three-dimensional (3D) imaging techniques enable accurate quantitative size measurement, and have been used to evaluate treatment effects on skin lesions such as ulcers, burns, and skin laxity. This study aimed to establish and validate a 3D imaging–based method to evaluate the surface area, area, and volume of cutaneous lesions associated with vascular anomalies (VA). We compared measurements obtained from two-dimensional (2D) photographs traced by three dermatologists with those obtained from 3D images traced by three company operators, and assessed inter- and intra-rater reliability. The procedure in the present study involves tracing lesion contours using photographs of VA captured by a 3D camera, followed by 3D processing of the images to measure lesion area, surface area, and volume. All patients provided written informed consent, and the study protocol was approved by the institutional review boards. Both 2D and 3D methods demonstrated high inter- and intra-rater reliability; however, better reliability was observed in the measurements obtained by company operators using 3D imaging. The findings indicate that 3D surface imaging provides more consistent and objective evaluation of lesion size than 2D photography and support the potential application of this method in clinical practice and clinical trials for VA. Accurate quantitative measurement of lesion size as an endpoint may facilitate the development of new treatment options for patients with VA.

Glossodynia-related pain refers to persistent, chronic pain occurring on the oral mucosal surface. Various medications are prescribed depending on symptom profiles and have demonstrated therapeutic benefits; however, these agents are often associated with adverse effects such as drowsiness or dizziness. Goreisan, a traditional Japanese Kampo medicine, has long been used empirically for glossodynia-related pain, particularly in patients reporting symptom fluctuation associated with weather changes. Nevertheless, high-quality clinical evidence supporting its efficacy remains limited. This multicenter, randomized, open-label preliminary exploratory study enrolled patients receiving treatment for glossodynia-related pain. Participants were assigned to receive either Goreisan (7.5 g/day for 12 weeks) in addition to standard therapy or standard therapy alone. Pain intensity was assessed using the visual analog scale (VAS) at baseline and at 4, 8, and 12 weeks. Salivary amylase activity was measured as an exploratory stress-related biomarker, and atmospheric pressure was recorded at each outpatient visit. Owing to insufficient enrollment, all analyses were descriptive and exploratory. Pain intensity improved from baseline in both groups. However, the proportion of patients achieving ≥ 20% improvement in VAS at week 12 was not higher in the Goreisan group than in the control group. Weak negative correlations between VAS scores and barometric pressure were observed in both groups (r ≈ − 0.2). No clinically relevant adverse events or hepatic dysfunction related to Goreisan were identified. This preliminary exploratory study did not confirm a clear analgesic efficacy of Goreisan for glossodynia. However, the findings provide descriptive data on pain trajectories, safety, and potential meteorological associations, supporting the need for future large-scale, double-blind, placebo-controlled trials.

The use of heat-not-burn (HNB) tobacco is rapidly increasing, particularly in Japan; however, its health effects, especially on innate immunity in the oral mucosa, remain unclear. This cross-sectional study aimed to compare the secretion levels of mucin 5B (MUC5B), a mucin that forms a protective barrier role on the oral mucosal surface, between HNB tobacco smokers and non-smokers. MUC5B levels in stored saliva samples from 208 males (147 in the non-smoking group, 32 in the HNB tobacco group, 15 in the paper cigarette group, and 14 in the dual-use group) were measured using enzyme-linked immunoassay (ELISA). The primary outcome was the MUC5B secretion rate (μg/min = MUC5B concentration × saliva secretion rate). Significant differences in MUC5B secretion rates were observed among the four groups, with multiple comparisons showing significantly lower rates in the HNB tobacco and dual-use groups than in the non-smoking group (p = 0.042 and p < 0.001, respectively). The observed decrease in salivary MUC5B secretion is a concern, as it may comprise oral hygiene and immune function. From a public health perspective, these findings provide a basis to discourage the use and combined use of HNB tobacco.