Statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, are widely prescribed lipid-lowering agents. Nevertheless, their use is occasionally associated with muscle toxicity, including rhabdomyolysis. Exercise reportedly exacerbates statin-induced muscle injury; however, the underlying mechanisms remain poorly understood. Here, we investigated the role of protein kinase C (PKC) signaling in the development of statin-induced cytotoxicity using a rhabdomyosarcoma-derived cell line (RD cells), with particular emphasis placed on the regulation of monocarboxylate transporter 4 (MCT4), a lactate transporter implicated in intracellular acidification and cytotoxic responses. Treatment with simvastatin, atorvastatin, and fluvastatin reduced RD cell viability in a concentration-dependent manner. Co-treatment with bisindolylmaleimide I (BIM), an inhibitor of PKCα, β, γ, δ, and ε, attenuated statin-induced cytotoxicity and tended to suppress simvastatin-induced MCT4 upregulation. Furthermore, co-treatment with Gö6976, a selective inhibitor of PKCα and β, did not mitigate the simvastatin-induced reduction in cell viability. Small interfering RNA-mediated knockdown of PKCδ significantly rescued simvastatin-induced cytotoxicity. Tamoxifen, a clinically available drug with PKC inhibitory activity, including against the δ isoform, attenuated simvastatin-induced cell injury, paralleling the effects of BIM. Collectively, our findings demonstrate that PKCδ contributes to statin-induced cytotoxicity in rhabdomyosarcoma cells, at least in part by regulating MCT4 expression.
Delirium is an acute neurocognitive impairment triggered by physiological stressors such as medical illness, surgery, or medication use. Although often transient, it is associated with adverse clinical outcomes. Current management primarily relies on nonpharmacological or symptomatic approaches; however, their effectiveness remains limited. Therefore, strategies that target the underlying pathophysiological mechanisms of delirium are of considerable clinical interest. Neuroinflammation has been proposed as a key mechanism in the development of delirium, with inflammatory cytokines produced during systemic inflammation impairing neuronal function. Vitamin D3 (VD3) exerts neuroprotective effects by suppressing the production of inflammatory cytokines. In this study, we hypothesized that VD3 reduces the risk of delirium. To test this hypothesis, a mouse model of postoperative delirium was established using anesthesia and surgery (AS). Cognitive function was assessed using behavioral tests, including the novel object recognition test. Mice subjected to AS exhibited impaired cognitive function, whereas VD3 administration attenuated this impairment. Serum interleukin-6 levels were elevated in the AS group but were reduced following VD3 treatment, consistent with the behavioral findings. These findings suggest that VD3 attenuates cognitive impairment in this postoperative delirium-like mouse model and is associated with reduced serum IL-6 levels. Further studies are required to clarify the underlying mechanisms and the relationship between peripheral and central inflammatory responses.
γ-Linolenic acid (GLA) is an n-6 polyunsaturated fatty acid (PUFA) with reported vasoprotective effects. GLA has been shown to inhibit contractions in pig coronary arteries via competitive antagonism at prostanoid TP receptors. α-Linolenic acid (ALA), an n-3 PUFA and a structural isomer of GLA, has been shown to inhibit contractions in pig basilar arteries (PBAs) via prostanoid TP receptor antagonism and activation of K+ channels. However, the actions of GLA in cerebral arteries remain unclear. In this study, we examined the effects of GLA on contractile responses in PBAs. GLA (10-5-10-4 M) concentration-dependently inhibited contractions induced by the TP receptor agonist U46619 (3 × 10-8 M) and prostaglandin F2α (PGF2α; 3 × 10-6 M). GLA (3 × 10-6-3 × 10-5 M) shifted the concentration-response curve for U46619 to the right. Schild analysis yielded a slope of 1.33 (95% confidence interval: 0.70-1.96), which was not significantly different from unity, but GLA also reduced the maximal response to U46619. The apparent pA2 value was 5.43. GLA (10-4 M) also inhibited PGF2α-induced contractions in the presence of the TP receptor antagonist SQ 29,548 (10-6 M); this inhibitory effect was attenuated by Ba2+ (10-3 M) but not by other tested K+ channel inhibitors. GLA also inhibited endothelin-1 (10-8-3 × 10-8 M)-induced contractions, and this effect was attenuated by Ba2+. These findings indicate that GLA, like ALA, suppresses contractile responses in PBAs through dual mechanisms involving TP receptor antagonism and activation of Ba2+-sensitive K+ channels.
INTRODUCTION:Levonorgestrel (LNG) tablets are used for emergency contraception and must be taken within 72 h after unprotected intercourse. In Japan, access had historically been restricted, although it has improved with the introduction of over-the-counter LNG tablets. However, barriers such as cost and convenience might still lead some individuals to obtain LNG through personal importation websites. We assessed the accessibility, regulatory compliance, and pharmaceutical quality-specifically, content assay and content uniformity-of LNG products obtained through these unregulated online pathways. METHODS:We identified nine personal importation websites through a Google search and purchased one LNG product from each site, assessing characteristics such as price, delivery time, packaging method, and insert availability. We evaluated pharmaceutical quality through quantitative analysis and content uniformity testing. RESULTS:Imported LNG tablets were cheaper than those available through official channels (mean: ¥1835/dose in 2022). However, the mean delivery time through personal importation was 19 d, making these products unsuitable for urgent use. Moreover, we observed missing instructions and foreign-language labeling. Quality testing revealed that five of the nine products were out of specification for the United States Pharmacopeia assay, and eight of the nine failed to meet the Japanese Pharmacopoeia XVIII content uniformity criteria. DISCUSSION:Although recent regulatory changes have allowed LNG tablet purchases from pharmacies without a prescription, structural and regulatory barriers to timely access remain-specifically, prohibitive costs compared to other nations and limited pharmacy access. These barriers potentially lead individuals to rely on personal importation, posing public health concerns. Ensuring equitable and prompt access to emergency contraception through appropriate regulatory frameworks and information is essential.
Ependymal cells are specialized multiciliated epithelial cells that line the brain ventricles. Their coordinated ciliary beating contributes to cerebrospinal fluid circulation and neural homeostasis. Hydrocephalus, a severe neurological condition affecting ∼1-3 per 1000 births worldwide, can arise from defects in ciliary motility, ependymal cell differentiation, planar cell polarity (PCP), and cytoskeletal organization. Mutations in genes that regulate these processes have been identified in patients with congenital hydrocephalus and related ciliopathies, establishing the clinical relevance of these pathways. This review summarizes the recent advances in the molecular mechanisms underlying ependymal cell biology. We describe the structural and functional organization of the ependymal cilia and discuss how ciliary defects range from severe developmental disruptions causing neonatal hydrocephalus to subtle maintenance defects underlying late-onset forms of the disease. We then examine the hierarchical transcriptional programs controlling ependymal differentiation, from master regulators such as GemC1 and Multicilin to downstream effectors, including FoxJ1 and Regulatory Factor X proteins. The core PCP pathway, comprising Vangl, Celsr, Frizzled, and Dishevelled proteins, coordinates tissue-wide ciliary orientation. Recent cryo-electron microscopy studies have provided structural insights into core components. Finally, we discuss the role of cytoskeletal networks in ependymal maintenance. Actin networks support structural integrity through mechanosensitive feedback loops and transduce mechanical forces into transcriptional activation of multiciliogenesis. In parallel, microtubule-based systems coordinate the planar polarized ciliary orientation via the Daple-dynein axis. Taken together, these molecular insights advance our understanding of the pathogenesis of hydrocephalus and may inform future diagnostic and therapeutic strategies.
Nuclear bodies are membrane-less compartments formed via liquid-liquid phase separation (LLPS) and serve as "dynamic information-processing hubs" for key molecular processes, including transcription and RNA metabolism. In the nervous system, these functional condensates provide a physical substrate for the formation of diverse splicing isoforms, which are essential for maintaining the complexity of the human brain. Recent findings suggest that the collapse of this "nuclear infrastructure" is the underlying cause of several psychiatric disorders. This collapse is due to an aberrant phase transition, where the nuclear environment shifts from a reversible, dynamic state to an irreversible, rigid state-a disruption of the homeostatic mechanism known as "Interstasis." This review discusses how this physical transition leads to systemic splicing failure and explores next-generation therapeutic strategies, such as antisense oligonucleotides (ASOs) and small-molecule modifiers, to restore nuclear integrity. This review is structured as follows to systematically explore the nexus between subnuclear architecture and neuropsychiatric pathogenesis. Section 1 establishes the biophysical foundations of nuclear bodies, highlighting LLPS and homeostatic mechanisms like interstasis. Section 2 addresses the advanced diversity and spatiotemporal regulation of alternative splicing in the nervous system, with a particular focus on the neuron-specific long non-coding RNA Gomafu. Section 3 comprehensively dissects the molecular mechanisms of nuclear infrastructure collapse-encompassing aberrant phase transitions, microexon/novel exon dysregulation, and 3D genome and transport deficits-in neurodevelopmental disorders and schizophrenia. Finally, Section 4 outlines next-generation drug discovery strategies, focusing on therapeutic modalities such as ASOs and small molecules capable of modulating network-level analog states.
The mechanistic role of microglial activation in Alzheimer's disease pathology is typically investigated using mouse models with aggressive amyloid accumulation, leaving the dynamics of microglial responses under the relatively slow deposition of amyloid-β (Aβ) characteristic of the early stages of the disease poorly understood. In this study, we examined microglial gene expression in the brains of AppNL-F knock-in mice, which gradually develop Aβ pathology in an aging-dependent manner without amyloid-β precursor protein overexpression. Quantitative PCR (qPCR) analysis revealed that microglial gene expression presents a stepwise activation pattern: early-induced genes increased at 12 months, whereas late-induced genes emerged at 18 months. Notably, neither group showed further induction at 24 months despite continued Aβ accumulation, indicating that microglial activation does not scale proportionally with the amyloid burden. Several canonical components of the disease-associated microglia program were not induced in AppNL-F mice, whereas a set of previously unrecognized microglial genes (Ly86, Snx20, and Pram1) was upregulated. The induction of these novel genes was preserved in the brains of Trem2 R47H knock-in mice, corroborating that the R47H variant exhibits only mild, if any, phenotype. Immunoblotting of selected proteins confirmed these qPCR-based findings. Together, these results reveal a stepwise mode of microglial gene activation under slow amyloid progression and identify novel genes that may be relevant to the early stages of Alzheimer's disease.
Drug-food interactions are highly diverse, sometimes leading to clinically significant outcomes. A classic example is the contraindicated coadministration of grapefruit juice with specific medications due to the inhibition of intestinal drug-metabolizing enzymes. This review delineates the diverse mechanisms by which fruit-derived small- and macromolecules modulate intestinal transporters. First, the key determinants of intestinal drug absorption and how dietary factors influence these processes are briefly described. Polyphenols in apple, grapefruit, and orange juices competitively inhibit intestinal uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1), thereby reducing the systemic exposure of its substrate drugs. Notably, apple polyphenols trigger the internalization of OATP2B1 from the plasma membrane via protein kinase C activation, a phenomenon experimentally characterized as a "pre-incubation effect." A pre-incubation effect is also induced by apple-derived extracellular vesicles (APEVs); microRNAs contained within APEVs bind to the SLCO2B1-3'UTR, leading to the down-regulation of OATP2B1 expression. Furthermore, both apple polyphenols and APEV-contained microRNAs suppress the expression of the apical sodium-dependent bile acid transporter (ASBT). Mechanistically, these apple-derived microRNAs down-regulate retinoic acid receptor alpha, a transcription factor for ASBT expression. The physiological and pharmacological relevance of these APEV effects has been demonstrated. Regarding OATP2B1, suppressing the intestinal accumulation of SN-38 significantly mitigates SN-38-induced gastrointestinal toxicity. Meanwhile, the reduction in ASBT activity aligns with the well-documented health benefits of apple consumption on functional constipation. In conclusion, fruit-derived small and macromolecules regulate intestinal uptake transporters through multifaceted mechanisms. Elucidating these pathways is essential not only for preventing adverse interactions but also for understanding and leveraging the health-promoting benefits of functional foods.
Focal impaired consciousness seizures (FICS) are among the most common seizure types in epilepsy and are a major cause of reduced QOL, occurring predominantly in temporal lobe epilepsy. Although seizure activity often remains confined to a focal temporal lobe network, patients develop widespread impairment of consciousness, indicating dysfunction of distributed brain systems rather than local seizure activity alone. Over the past two decades, converging evidence from human electrophysiological recordings, neuroimaging, and experimental animal models has substantially advanced our understanding of the neural mechanisms underlying this phenomenon. This review summarizes current knowledge of the clinical features and pathophysiology of FICS in temporal lobe epilepsy. We discuss evidence supporting the network inhibition hypothesis, in which seizure activity propagates from the hippocampus to subcortical relay structures that suppress the ascending arousal system, leading to impaired consciousness. We further examine emerging evidence implicating thalamocortical oscillations as a potential mechanism of cortical disconnection and review findings on the bilateral network engagement observed during FICS. By reviewing the substantial progress in defining the circuitry underlying impaired consciousness, we highlight the key questions that remain to be addressed in future research.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by severe pulmonary dysfunction, with persistently high global incidence and mortality. Although glucocorticoids, the standard pharmacotherapy for ALI/ARDS, have been reported to reduce short-term mortality and improve outcomes, their clinical benefit is limited by dose- and duration-dependent adverse effects, thereby driving the exploration of complementary or alternative approaches. Natural saponins, a structurally diverse group of glycosides widely distributed in medicinal plants, have gained considerable interest owing to their multitarget anti-inflammatory, antioxidant, and antiapoptotic activities demonstrated in various in vitro and in vivo ALI models. Here, we systematically review the protective mechanisms of natural saponins from the perspectives of cellular regulation and signaling pathways, highlighting their modulatory effects on macrophages, neutrophils, and other effector cells, as well as their actions through key pathways related to inflammation, oxidative stress, and apoptosis. We further discuss current strategies to overcome the major translational barriers of saponins, particularly structural modifications and formulation approaches aimed at improving oral bioavailability and reducing hemolytic activity. This review consolidates the pharmacological basis for saponin-based ALI therapy and provides a forward-looking perspective on addressing their limitations to facilitate clinical translation.
Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the progressive degeneration of photoreceptor cells, representing a leading cause of blindness. A substantial proportion of patients with RP report photopsia-the perception of spontaneous flashes of light in the visual field. Photopsia can act as visual "noise" and may interfere with visual processing, even compromising restored visual signals following emerging therapeutic interventions. In retinal degeneration (rd) animal models, retinal ganglion cells (RGCs) exhibit pathological periodic spontaneous firing, or oscillations, which have been implicated as a retinal circuit substrate for photopsia. In this review, we summarize current findings on pathological retinal oscillations in rd models and incorporate recent evidence from congenital stationary night blindness (CSNB) models. Together, these studies suggest that RGC oscillations are not simply a consequence of photoreceptor degeneration, but instead arise from a pathological state of the ON bipolar cell-AII amacrine cell network associated with TRPM1-dependent signaling. We propose that altered input balance within this network, including reduced rod bipolar cell-to-AII amacrine cell signaling and altered ON cone bipolar cell activity, may represent a shared mechanism underlying pathological oscillations across distinct retinal diseases.
Neuronal Intranuclear Inclusion Disease (NIID) is caused by GGC repeat expansions in the 5' untranslated region of the notch 2 N-terminal like C (NOTCH2NLC) gene. An upstream open reading frame within the mutant transcript produces the NOTCH2NLC upstream open reading frame-derived polyglycine protein (uN2CpolyG) containing expanded polyglycine (polyG), which forms intranuclear inclusions. Although uN2CpolyG is thought to play a critical role in disease pathogenesis, the mechanisms underlying its toxicity and inclusion formation remain incompletely understood. In this study, we first expressed a pure GGC repeat encoding polyG in Neuro2a cells and identified aggregate-associated proteins by mass spectrometry. We then confirmed the formation of intracellular aggregates using both transient expression and drug-inducible expression systems for uN2CpolyG. Among the proteins identified by mass spectrometry, Calpain small subunit 1 (Capns1), the regulatory subunit of calpain, was found to be sequestered into uN2CpolyG aggregates. Notably, the N-terminus of Capns1 contains a glycine-rich sequence, which mediated its co-aggregation with uN2CpolyG. Furthermore, knockdown of Capns1 appeared to reduce the accumulation of uN2CpolyG aggregates. Collectively, these findings identify Capns1 as a potential modifier of NIID pathology.
Diabetic retinopathy, a major cause of visual impairment, involves multiple pathological processes, including disruption of water homeostasis regulated by Müller glial cells. Aquaporin-4 (AQP4) is a water channel that mediates passive water transport driven by an osmotic gradient, whereas Na+/K+-ATPase (NKA) maintains the ionic balance underlying this process. We previously demonstrated that ouabain, an NKA inhibitor, preferentially induces neuronal cell loss in the inner retina. This study aimed to elucidate the role of AQP4 in ouabain-induced inner retinal injury using male Sprague-Dawley rats and rat retinal Müller cells (rMC-1). Immunohistochemical analysis revealed that AQP4 was localized to the endfeet of Müller cells along the deep retinal capillaries and was expressed throughout the cell body in rMC-1 cells. To assess the role of AQP4 in ouabain-induced retinal injury, we examined the effects of TGN020, an AQP4 inhibitor, using both in vitro and in vivo models. Ouabain induced acute cell swelling in rMC-1 cells, and this effect was significantly attenuated by TGN020 treatment. In vivo, rats were intravitreally injected with ouabain alone or in combination with TGN020, and retinal histological changes were evaluated 7 d after injection. Ouabain induced cell loss in both the ganglion cell layer (GCL) and inner nuclear layer (INL). Co-administration of TGN020 reduced cell loss in the INL, but not in the GCL. These findings suggest that the disruption of AQP4-mediated water transport in Müller cells may contribute to INL neurodegeneration associated with NKA dysfunction in rats.
The transcription factor c-Myc is frequently upregulated in human cancers through multiple mechanisms, including chromosomal translocation and gene amplification. Since the human TRIB1 gene is located on chromosome 8q24 in close proximity to the MYC oncogene, the MYC and TRIB1 genes may be co-amplified in a large percentage of human cancers. We herein demonstrate molecular crosstalk between TRB1 and c-Myc. Bioinformatic analyses reveal a positive correlation between MYC and TRIB1 expression across multiple cancer types. In prostate cancer cells, the knockdown of c-Myc reduces TRB1 expression. Mechanistically, c-Myc directly binds to the proximal promoter region of the TRIB1 gene and activates its transcription. Conversely, the depletion of TRB1 decreases c-Myc levels and affects the expression of c-Myc target genes. These results indicate that TRB1 contributes to the oncogenic functions of c-Myc and suggest the potential of the TRB1-c-Myc axis as a therapeutic target for cancer treatment.
Clazosentan is used to prevent cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), but it is often associated with fluid retention-related adverse events. This retrospective study investigated the relationship between the pretreatment Albumin-Bilirubin (ALBI) score and clazosentan-associated fluid retention in patients with SAH. Patients who newly initiated clazosentan treatment at Saga University Hospital between April 2022 and March 2026 were enrolled. Clinical characteristics and laboratory data were retrospectively obtained from electronic medical records. Patients were divided into fluid retention and non-fluid retention groups, and factors associated with fluid retention were analyzed. A total of 61 patients were included, with clazosentan-associated fluid retention observed in 32 patients (52.5%). The ALBI score was significantly higher (i.e., less negative) in the fluid retention group than in the non-fluid retention group (median: -2.62 vs. -2.94, p = 0.007). Multivariate logistic regression analysis revealed that an elevated ALBI score was independently associated with fluid retention (odds ratio per 0.1-point increase: 1.17; 95% confidence interval: 1.01-1.37; p = 0.03). Additionally, patients requiring loop diuretics for fluid management had significantly higher ALBI scores than those not requiring them (median: -2.61 vs. -2.91; p = 0.006). These findings suggest that an elevated pretreatment ALBI score may be linked to an increased risk of clazosentan-associated fluid retention. Further validation in patients with varying degrees of hepatic function is warranted to establish its clinical utility.
Pharmacotherapy persistence in adults with attention-deficit/hyperactivity disorder (ADHD) remains concerning; however, evidence describing early treatment changes and discontinuation is limited. This study aimed to describe initial ADHD pharmacotherapy patterns and quantify claims-based initial regimen instability in Japanese adults. Using a Japanese claims database, we assembled a cohort of adults who initiated ADHD medication with methylphenidate, atomoxetine, guanfacine, or polytherapy (combination therapy) at initiation. Initial regimen instability was defined as the first observed regimen modification, including switching, add-on/polytherapy, de-escalation or combination-pattern change among initial polytherapy users, or a temporary drug-free interruption followed by restart after 31-179 d. A sustained medication-free period of ≥180 d without restart was treated as a competing event. We estimated cumulative incidence functions for initial regimen instability, treating the sustained medication-free period as a competing event. Fine-Gray models adjusted for age, sex, and major psychiatric comorbidities were used to compare initial regimens with methylphenidate as a reference. Landmark analysis was used to assess robustness. Among 14814 initiators, 3085, 8517, 3076, and 136 started methylphenidate, atomoxetine, guanfacine, and initial polytherapy, respectively. In the adjusted Fine-Gray model, the subdistribution hazard ratio for initial regimen instability was 0.74 for atomoxetine and 0.72 for guanfacine, whereas it was higher (2.65) for initial polytherapy in the main analysis. However, this estimate was sensitive to the operational definition of regimen instability. Landmark analysis yielded consistent differences between regimens. Initial ADHD pharmacotherapy showed heterogeneity in Japanese adults and included initial polytherapy, with initial regimen instability differing substantially depending on the starting regimen.
Although immune checkpoint inhibition has proven highly effective in patients with metastatic or advanced squamous cell carcinomas, such as oral cancer, the role of innate immune responses in regulating oral cancer progression remains poorly understood. In this study, we examined the impact of innate immune responses in an orthotopic oral squamous cell carcinoma model (NR-S1-Luc cells) using bioluminescence imaging. In severe combined immunodeficiency mice lacking adaptive immune cells, CD11b+ Ly6Ghi Ly6Chi (Ly-6G+) myeloid cells accumulated more prominently than CD11b+ Ly6Gint Ly6Chi (Ly-6C+) cells within NR-S1-Luc tumors. Although Ly-6G+ myeloid cells were predominant in orthotopic NR-S1 tumors, in vivo depletion of Ly-6G+ cells did not alter tumor growth. Treatment with a Toll-like receptor 3 (TLR3) agonist (poly I:C) significantly inhibited tumor growth, accompanied by enhanced inflammation and upregulation of Ly-6C expression on Ly-6G+ myeloid cells. Moreover, depletion of Ly-6G+ cells partially impaired this TLR3-mediated effect. Transcriptomic analysis of Ly-6G+ myeloid cells from NR-S1-Luc tumor-bearing mice revealed that poly I:C treatment induced functional reprogramming of these cells, accompanied by broad alterations in immune-related and metabolic pathways within the orthotopic oral tumor microenvironment. Collectively, these findings suggest that tumor-infiltrating Ly-6G+ myeloid cells are functionally plastic and can be reprogrammed by TLR3 stimulation, thereby contributing to the regulation of tumor progression.
The Hou-Yan-Qing oral liquid (HYQ) is a popular traditional Chinese medicine for the treatment of pharyngitis. However, due to its complex composition, little attention has been directed toward the analysis of its mechanism and active components. An ammonia-induced acute pharyngitis rat model was established, with HYQ's effects and mechanism assessed via histopathology, enzyme-linked immunosorbent assay, and Western blot. Furthermore, the active components of HYQ were analyzed using HPLC and ultra performance LC (UPLC)-QTOF-MS in conjunction with an in vitro lipopolysaccharide-induced RAW264.7 cell model. Treatment with HYQ significantly reduced the levels of cytokines such as pro-inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor α [TNF-α]) and inflammatory mediators (Prostaglandin E2 [PGE2]), inhibited the expression of cyclooxygenase-2 (COX-2), 5-LOX, p-IKKβ, p-nuclear factor-kappaB (NF-κB) and p-inhibitor of kappaBα (p-IκBα) proteins, and promoted the expression of nuclear factor-E2-related factor 2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase 1 proteins. Chemical profiling of ten batch HYQ specimens via HPLC and UPLC-QTOF-MS established characteristic fingerprints and identified 24 shared components. Using spectrum-effect relationship modeling, which employed gray relational analysis to correlate chromatographic peaks with bioactivity indices, we found that components such as 25S-Inokosterone and β-ecdysterone may be the key active components of HYQ's anti-inflammatory effect. Subsequent validation confirmed that β-ecdysterone (1-100 μM) exhibited no cytotoxicity in RAW264.7 cells. Furthermore, treatment with β-ecdysterone significantly reduced levels of pro-inflammatory cytokines (IL-6, TNF-α) and inflammatory mediators (PGE2), and inhibited the expression of COX-2, 5-LOX, p-IKKβ, p-NF-κB, and p-IκBα proteins.
Rat adipose tissues were shown to exhibit a high level of autotaxin having lysophospholipase D activity. Previously, we reported that an elevated level of lysophosphatidic acid (LPA) in rat plasma was due to a decreased lysophosphatidylcholine concentration, increased plasma lysophospholipase D activity, and decreased lipid phosphate phosphatase activity toward LPA in adrenalectomized (ADL) rats. We hypothesized that the profiles of LPA, its precursor lysophospholipids (LPLs), and parent phospholipids (PLs) also may be altered in adipose tissues of ADL rats. To examine this possibility, we determined the tissue levels of molecular species of PLs and LPLs, including LPA, by LC-tandem MS. The levels of six LPLs in rat brown adipose tissue (BAT) were increased in ADL rats. In rat epididymal white adipose tissue (EpiWAT), the levels of LPLs except for LPA were increased. In rat inguinal WAT, the level of phosphatidylglycerol was increased. These results suggest that tissue levels of LPLs were upregulated by adrenal hormones in BAT and EpiWAT by different mechanisms.
Pharmacy education in Indonesia is expected to prepare pharmacists for a wide range of roles in a health system where medicines are central to prevention and treatment. Yet workforce studies describing capability gaps, uneven distribution, and variation in service delivery across sectors and regions suggest that ensuring new graduates are ready for practice remains a persistent challenge. This evidence-informed narrative review describes the pharmacist education pipeline in Indonesia and maps how competency expectations are specified, taught and assessed across the main stages of education and early professional transition. It synthesizes national levers that shape curriculum expectations and external assurance, including the Ministry of Health professional standard and national competency standard, nationally agreed learning outcomes, external accreditation instruments, and the national pharmacist competency examination. The review outlines the undergraduate pharmacy program followed by the professional program, including supervised work-based learning, and highlights implementation considerations reported in the literature. Key challenges include heterogeneity in institutional and placement capacity, difficulty translating broad competency domains into observable performance during experiential learning, and ongoing debate about the benefits and limitations of national assessment. This review integrates policy and standards documents with empirical studies while noting limitations in the availability of national outcome data, sparse multi-site reporting on experiential learning implementation, and limited longitudinal evidence linking education processes to early-career practice and service outcomes.
