Liver diseases, including viral hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), remain major global health burdens due to their high prevalence and limited therapeutic options. The need for safer and more effective hepatoprotective agents has renewed interest in traditional herbal medicines such as Radix Bupleuri. Its major bioactive constituents, saikosaponins (SSs), exhibit diverse pharmacological activities. This review synthesizes recent advances in the pharmacodynamics, molecular mechanisms, and toxicological characteristics of SSs, emphasizing their dual hepatoprotective and hepatotoxic properties. Relevant literature published from 2000 to 2025 was systematically retrieved from major scientific databases, including PubMed, Web of Science, Google Scholar, and other sources as appropriate, with emphasis on mechanistic studies and in vitro/in vivo evidence. SSs exert hepatoprotective effects through multiple mechanisms, including inhibition of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, activation of nuclear receptors, induction of hepatic stellate cell apoptosis and autophagy, and modulation of lipid metabolism via peroxisome proliferator-activated receptor α (PPARα)/sterol regulatory element-binding protein 1c (SREBP1c) signaling. SSs in HCC inhibit Cyclooxygenase-2 and STAT3, promote apoptosis and ferroptosis, suppress angiogenesis, and enhance chemotherapy and radiotherapy sensitivity. However, accumulating evidence indicates that SSs may induce dose-dependent hepatotoxicity through oxidative stress, apoptosis and autophagy injury. These dual pharmacological effects are influenced by CYP regulation, bioavailability, and potential drug-drug interactions. Overall, SSs represent promising yet complex therapeutic candidates. Optimization of dosing strategies, clarification of mechanistic determinants, and development of advanced delivery systems are essential for their safe clinical translation. Future research should incorporate multi-omics approaches, physiologically relevant liver models, and rigorously designed clinical trials to establish standardized Saikosaponin-based therapies for liver diseases.

Polypharmacy is prevalent among older adults with sarcopenia and may negatively impact clinical outcomes. Although sarcopenia is associated with polypharmacy, the effect of deprescribing on muscle health in hospitalized patients with sarcopenia remains poorly understood. This study aimed to investigate the association between deprescribing during hospitalization and muscle strength and mass at discharge in sarcopenic patients after stroke. This study retrospectively analyzed data from a cohort of sarcopenic patients aged ≥65 years admitted to a convalescent rehabilitation ward after stroke. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia 2019 criteria. Deprescribing was defined as a reduction in the number of medications during hospitalization. The primary outcome was handgrip strength at discharge, and the secondary outcome was skeletal muscle mass index (SMI) at discharge. Multiple linear regression analyses were performed to examine the association between deprescribing and outcomes, adjusting for potential confounders. Of the 970 patients enrolled, 217 older patients, with a mean age of 81.8 years (males, 45.6%), were diagnosed with sarcopenia and included in the analysis. The median number of medications at admission was 5 (interquartile range 3–8), and 23.0% of patients experienced deprescribing during hospitalization. Deprescribing during hospitalization was independently associated with higher handgrip strength (β = 0.122, p = 0.009) and SMI (β = 0.138, p = 0.009) at discharge. Deprescribing was positively associated with improved muscle strength and mass at discharge in sarcopenic patients after stroke. These findings suggest that medication review and deprescribing may be beneficial strategies in the rehabilitation of sarcopenic stroke patients.

Shear stress (SS) generated by blood flow elicits endothelial cell (EC) responses through mechanotransduction pathways. In particular, ATP released by SS is instrumental in regulating vascular dynamics. Cyclooxygenase-2 (COX-2), typically induced by inflammatory responses, is also constitutively expressed in vascular ECs under SS and exerts antithrombotic and vasodilatory effects. However, the mechanism whereby SS-induced ATP release regulates COX-2 expression remains incompletely understood. In this study, we investigated whether extracellular ATP released by SS under disturbed flow conditions promotes COX-2 expression in the mouse brain microvascular EC line bEnd.3. SS applied by disturbed flow via orbital shaking triggered ATP release and upregulated COX-2 expression. Moreover, stimulation by exogenous ATP and uridine 5'-triphosphate (UTP) increased COX-2 expression, which was suppressed by the P2Y₂ receptor antagonist AR-C118925XX. Disturbed flow-induced COX-2 expression was consistently attenuated by AR-C118925XX. Mechanistically, P2Y₂ receptor–mediated upregulation of COX-2 was dependent on the Gq/protein kinase C/extracellular signal-regulated kinases 1/2 signaling cascade. These findings suggest that SS-induced ATP released from ECs contributes to maintaining the expression of endothelial COX-2, highlighting the role of P2Y₂ receptor signaling in endothelial mechanotransduction.

This study aimed to elucidate the association between mid-regional pro-adrenomedullin (MR-proADM) levels at the onset of febrile neutropenia (FN) and clinical outcomes in patients with hematological malignancy undergoing hematopoietic stem cell transplantation (HSCT), and the prognostic performance of MR-proADM compared with established infection-related biomarkers comprising presepsin (P-SEP), procalcitonin (PCT), and C-reactive protein (CRP). We analyzed 26 patients (28 FN episodes) who underwent HSCT for hematological malignancy at Oita University Hospital. For each patient, time-dependent profiles of MR-proADM, P-SEP, PCT, and CRP from FN onset until clinical stabilization were evaluated. Correlation analysis was conducted among the four biomarkers. Multivariate analyses were performed to examine associations between peak biomarker levels and clinical outcomes. MR-proADM exhibited an early increase after FN onset, similar to other biomarkers. However, correlation analyses revealed no significant association between MR-proADM and P-SEP (r_s = 0.087, p = 0.290), PCT (r_s = 0.026, p = 0.791), or CRP (r_s = 0.073, p = 0.332). Multivariate analysis identified MR-proADM (p = 0.049) as a significant predictor of fever duration, while CRP (p = 0.032) was significantly associated with the number of organs affected by acute graft-versus-host disease (aGVHD). This study is the first to evaluate MR-proADM at FN onset in HSCT recipients. Elevated MR-proADM may predict prolonged fever, whereas CRP may reflect the severity of aGVHD. These findings suggest that these biomarkers may serve as complementary biomarkers for predicting different clinical outcomes.

This study aimed to explore the possibility of using a novel eye drop for ocular pain in dry eyes by examining the effect of tramadol eye drops on nocifensive behavior in normal and dry eye rats. Dry eye model rats were generated by the unilateral surgical excision of the extraorbital lacrimal glands. The effect of tramadol eye drops on ocular pain in normal and dry eye model rats was assessed using the eye closure time induced by a hyperosmolar (5 M NaCl) solution and the transient receptor potential vanilloid 1 (TRPV1) agonist (1 mM capsaicin). The current response induced by 1 μM capsaicin in the primary sensory neurons was measured by whole-cell recording using cultured trigeminal ganglion neurons. Extraorbital lacrimal gland excision (LGE) significantly enhanced the ocular nocifensive response induced by a 5 M NaCl solution. Pretreatment with tramadol eye drops transiently suppressed nocifensive behavior on the ocular surface in sham-operated and dry eye rats. The suppressive effect of tramadol was only effective on the ipsilateral eye and was not canceled by a μ-opioid receptor antagonist. Furthermore, the capsaicin-induced nocifensive behavior and current responses in primary sensory neurons were suppressed by tramadol treatment. Tramadol eye drops have been shown to temporarily relieve ocular pain in normal and hyperalgesic conditions, such as dry eye. The underlying mechanism may be a decrease in TRPV1-mediated responses at the peripheral sensory nerves on the ocular surface, not primarily mediated by μ-opioid receptor activation.

Bacterial genome-derived oligodeoxynucleotides (ODNs) are recognized as pathogen-associated molecular patterns by Toll-like receptors. They induce inflammatory responses by activating the innate immune response. Recently, ODNs reported to regulate stem cell differentiation have garnered attention owing to the discovery of new functions. In this study, we aimed to investigate the effects of a myogenic ODN (iSN04), derived from the Lactobacillus genome sequence and reported to enhance myoblast differentiation, on the differentiation of vascular endothelial cells and other mesodermal lineages derived from the human induced pluripotent stem cell lines iMR90-4 and 201B7. The addition of iSN04 to the differentiation induction medium increased the proportion of CD31⁺CD144⁺ endothelial cells in the cell population. Furthermore, quantitative RT-PCR showed that the addition of iSN04 increased the gene expression of vascular endothelial cell markers such as von Willebrand factor. Analysis of cells on Day 3 after the addition of iSN04 revealed an increase in the expression of Brachyury-T, a marker of the mesoderm. These results suggest that iSN04 may improve the differentiation efficiency of cells, such as vascular endothelial cells, into other mesodermal cells by promoting mesoderm differentiation.

Cancer cachexia is associated with poor clinical outcomes in lung cancer patients; however, its economic impact in Japan remains largely uncharacterized. This study quantified the incremental healthcare costs associated with cachexia in Japanese lung cancer patients using nationwide claims data. We conducted a retrospective cohort study using the Japan Medical Data Center Claims Database. Deceased lung cancer patients were classified into cachexia (n = 447) and control (n = 10464) groups based on International Classification of Diseases, 10th Revision diagnosis codes. Between-group cost differences were assessed using generalized linear models with a gamma distribution, adjusting for survival time, demographics, histology, metastasis, and comorbidities. Within-patient cost changes were analyzed using fixed-effects regression, comparing 6-month periods before and after cachexia diagnosis. Cachexia was independently associated with 13.5% higher total medical costs (rate ratio: 1.14, 95% confidence interval [CI]: 1.06–1.21, p < 0.001). Within-patient analysis demonstrated a 57.9% cost increase in the month of diagnosis (from ¥371360 to ¥586405), with costs remaining 21.7% elevated post-diagnosis. Cost composition shifted from procedures (1.3 vs. 5.4%) toward home care (8.6 vs. 5.7%) in cachexia patients. Median survival following cachexia diagnosis was only 1.0 month, with 71% of patients dying within 3 months. Anamorelin use increased from 2.4 to 29.8% post-diagnosis, although 70.2% of patients did not receive this therapy. Cachexia diagnosis in lung cancer patients is associated with substantial cost increases in Japan. The extremely short survival after diagnosis and the shift toward supportive care highlight the need for earlier recognition and intervention. These findings provide essential data for the economic evaluation of cachexia therapies.

The acetic acid-induced writhing test is a standard model for visceral pain and analgesic screening. While writhing behavior may have been implicitly assumed to be associated with gastrointestinal motor activity, whether gastrointestinal motility directly triggers writhing behavior has remained untested. We simultaneously recorded antral and duodenal motility using strain gauge transducers in freely moving rats during acetic acid-induced writhing events. Our analysis, employing a hidden Markov model, found no evidence that antral or duodenal motility exhibited time-locked changes relative to writhing events. Furthermore, writhing behavior persisted even when gastrointestinal motility was pharmacologically suppressed with scopolamine butylbromide, providing direct evidence that writhing occurs independently of gut motor activity. Thus, acetic acid-induced writhing is temporally dissociated from gastrointestinal contraction, indicating that writhing reflects visceral nociceptive signaling distinct from gut motility.