Frailty in chronic kidney disease (CKD) is increasingly recognized as a manifestation of accelerated biological aging, characterized by systemic impairments that extend beyond the musculoskeletal domain. A distinctive yet underappreciated feature of CKD-associated frailty is its triple burden—the co-existence of sarcopenia, bone fragility, and cognitive impairment. Rather than isolated phenomena, these deficits share convergent pathophysiological drivers, including uremic toxicity, oxidative stress, hormonal dysregulation, and chronic inflammation. Accumulating evidence highlights the role of organ crosstalk—particularly along the muscle–bone and muscle–brain axes—as a key integrative mechanism linking these outcomes. This review synthesizes current understanding of the epidemiology, diagnostic approaches, and mechanistic underpinnings of this multisystem condition, emphasizing skeletal muscle as a central node in a dynamic physiological network. Recent advances in biomarker development, imaging technologies, and therapeutic strategies point toward a shift from compartmentalized to network-informed care. By framing CKD-related frailty as a disorder of disrupted inter-organ communication resulting in a triple burden of decline, we propose a unified pathophysiological model to guide earlier recognition and personalized, multimodal interventions. Importantly, this perspective also calls for a critical re-evaluation of current treatment targets in CKD management to ensure alignment with the goals of frailty prevention and long-term functional preservation.

Cofilin severs actin filaments and translocates to the nucleus. Though Ser3 dephosphorylation of cofilin is required for its actin-depolymerization activity, the mechanism regulating cofilin’s nuclear translocation remains unclear. In rat basophilic leukemia (RBL-2H3) cells, we previously reported that the transient Ser3 dephosphorylation in cofilin plays a role in actin polymerization/depolymerization after multivalent antigen stimulation. In this study, we revealed that multivalent antigen stimulation rapidly induced the nuclear localization of cofilin within 1 min. Ser3 dephosphorylation and cofilin’s nuclear localization were elicited by ionomycin addition, while pretreatment with BAPTA-AM inhibited the nuclear translocation of cofilin according to multivalent antigen stimulation, suggesting that the increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) is essential for the nuclear translocation of cofilin. Meanwhile, the dephosphorylation at Ser3 and nuclear localization of cofilin occurred in the absence of extracellular Ca²⁺ without multivalent antigen stimulation. Interestingly, the constitutively inactive form of cofilin (Ser3 to glutamic acid) was translocated to the nucleus following multivalent antigen stimulation, but not following extracellular Ca²⁺ depletion. These findings indicate that the increase in [Ca²⁺]_i induced by multivalent antigen triggers the nuclear translocation of cofilin independent of Ser3 dephosphorylation, while extracellular Ca²⁺ depletion-induced nuclear translocation of cofilin depends on Ser3 dephosphorylation. This suggests that distinct pathways regulate the nuclear translocation of cofilin based on Ca²⁺ dependency.

Severe asthma is characterized by both steroid resistance and fibrotic remodeling. We hypothesized that myofibroblasts in fibrotic lung tissue acquire glucocorticoid resistance through the upregulation of the anti-apoptotic factor B-cell lymphoma-extra large (Bcl-xL). This study aimed to determine whether myofibroblasts become steroid-resistant via Bcl-xL expression in vivo and in vitro. A steroid-resistant asthma model was developed by repeatedly challenging sensitized BALB/c mice intratracheally with a high dose of ovalbumin (OVA). Myofibroblasts were identified by flow cytometry as α-smooth muscle actin (α-SMA)⁺ CD31⁻ CD45⁻ CD326⁻ cells. Lung mesenchymal stem cells (MSCs; platelet-derived growth factor receptor α⁺ CD31⁻ CD45⁻ CD326⁻ cells) were isolated and differentiated into myofibroblasts by culturing them with 15% fetal bovine serum (FBS) for 6 d. In asthmatic lungs, α-SMA⁺ myofibroblasts showed increased Bcl-xL expression, which was unaffected by dexamethasone (DEX) treatment. However, co-treatment with the Bcl-xL inhibitor navitoclax significantly restored steroid sensitivity. In vitro, MSCs were susceptible to DEX-induced early apoptosis, whereas differentiated myofibroblasts were resistant to DEX-induced apoptosis and strongly expressed Bcl-xL. In other words, navitoclax treatment overcame steroid resistance in cultured myofibroblasts. These findings indicate that Bcl-xL-expressing myofibroblasts contribute to the development of glucocorticoid resistance in fibrotic lungs in severe asthma. Targeting Bcl-xL may provide a novel therapeutic strategy to restore steroid responsiveness in severe asthma.

Lactosome is a biocompatible micelle particle composed of the amphiphilic polymers poly(l-lactic acid)₃₀ (PLLA₃₀) and poly(sarcosine)₇₀ (PSar₇₀) (PLLA₃₀-block-PSar₇₀). Lactosome has tumor accumulation properties via its enhanced permeability and retention effect, making it promising for probe imaging and drug delivery systems in tumor tissues. However, anti-lactosome immunoglobulin M (IgM) is produced after lactosome dosing, causing a marked reduction in the blood circulation and tumor accumulation of lactosome after multiple dosing. This phenomenon is called accelerated blood clearance (ABC). In this study, we aimed to modify lactosome with poly(carboxybetaine)₂₀ (PCB₂₀) to reduce anti-lactosome IgM production and the ABC phenomenon. We designed 10%PCB₂₀-PLLA₃₀-lactosome based on PLLA₃₀-block-PCB₂₀ and 10%PCB₂₀-PSar₇₀-lactosome or 100%PCB₂₀-PSar₇₀-lactosome based on PLLA₃₀-block-PSar₇₀-block-PCB₂₀. Plasma anti-lactosome IgM levels were evaluated using an enzyme-linked immunosorbent assay 7 d after dosing in mice via the tail vein. Compared with lactosome, 10%PCB₂₀-PSar₇₀-lactosome significantly reduced anti-lactosome IgM production, and early blood clearance improved at the second dose. In contrast, 6 h post-dosing, blood clearance accelerated, and tumor accumulation decreased compared with the events under the first dose. The PCB₂₀ modification of PLLA₃₀-block-PSar₇₀ more effectively reduced anti-lactosome IgM production than did the PCB₂₀ modification of PLLA₃₀; the early blood clearance associated with the ABC phenomenon also showed greater improvement in the former. Nevertheless, the promotion of blood clearance and reduction in tumor retention in the later phase could not be suppressed. These findings suggest that evading the ABC phenomenon requires particle design that comprehensively considers factors beyond enhancing the suppression of IgM production.

Antibody–drug conjugates (ADCs) have revolutionized targeted cancer therapy, with human epidermal growth factor receptor 2-targeted ADCs demonstrating notable clinical success. In contrast, the clinical efficacy of epidermal growth factor receptor (EGFR)-targeted ADCs has not yet been clearly demonstrated, owing to several underlying factors. In this study, we focused on one of the key determinants most directly linked to therapeutic efficacy, the intracellular uptake of ADCs, and examined the noncanonical endocytic pathway driven by p38-dependent phosphorylation of EGFR in PC-9 non-small cell lung cancer (NSCLC) cells harboring an EGFR exon 19 deletion. Using tumor necrosis factor-α to activate this pathway, we observed enhanced internalization of cetuximab–monomethyl auristatin E and increased cytotoxicity in vitro. Notably, we also found that cisplatin, the backbone of lung cancer chemotherapy, induces a similar noncanonical endocytic response, further supporting the physiological relevance of this pathway. Collectively, our results highlight noncanonical endocytosis as a tractable mechanism to enhance the intracellular delivery and antitumor activity of EGFR-targeted ADCs. This mechanistic insight provides a foundation for developing improved platforms and combination regimens capable of overcoming resistance in NSCLC.

Gene–environment interactions are thought to contribute to neurodevelopmental psychiatric disorders, yet their behavioral and molecular consequences remain incompletely understood. Here, we examined whether partial deficiency of reelin (Reln) increases susceptibility to a mild prenatal immune challenge in mice. Heterozygous Reln mice and wild-type littermates were exposed to low-dose polyinosinic–polycytidylic acid (Poly(I:C); 2 mg/kg, intraperitoneally) at embryonic day 12.5. Adult male offspring were assessed in the open-field, three-chamber social interaction, and marble-burying tests, followed by gene expression analysis in the medial prefrontal cortex (mPFC). In the open-field test, prenatal Poly(I:C) exposure was associated with increased locomotor activity during the late habituation phase, with the clearest increase in the combined-risk group. In the social interaction test, significant social novelty preference was not detected in the combined-risk group, whereas sociability toward an unfamiliar conspecific was preserved across groups. Marble-burying behavior was reduced in heterozygous Reln mice irrespective of immune challenge, suggesting a genotype-related behavioral alteration that was partly distinct from the combined-risk phenotype observed in the other tests. In the mPFC, several γ-aminobutyric acid A (GABA_A) receptor subunit transcripts were altered in a gene- and exposure-specific manner. Gabra2 expression was reduced in the combined-risk group, whereas Reln expression was decreased in heterozygous mice independent of immune challenge. These findings indicate that partial Reln deficiency provides a permissive genetic background in which mild prenatal immune activation subtly alters higher-order behavioral adaptation and prefrontal GABA_A-related gene expression.

Arecoline, a major alkaloid in betel nuts, modulates cognitive function, yet its effects on memory in young, healthy mice remain unclear. We administered arecoline or vehicle to mice and allowed them to perform a novel object recognition task to investigate whether and how acute arecoline administration affected object recognition. Arecoline-treated mice exhibited a significantly higher discrimination index than controls, indicating improved discrimination performance. This enhancement occurred without changes in locomotor activity, anxiety-like behavior, or general exploratory motivation. Time-series analysis further revealed that arecoline treatment led to sustained high discrimination ability during the test session, compared to vehicle treatment. These findings demonstrate that acute arecoline administration enhances object recognition even in a healthy physiological state, possibly by facilitating cholinergic-mediated attention and memory encoding.

Rare sugars have garnered interest for their unique biological properties; however, the effects of allitol on fluid and electrolyte balance remain poorly understood, particularly regarding route-dependent differences between its renal and gastrointestinal actions. In this study, we investigated the effects of the rare sugar allitol on urine formation and whole-body water and electrolyte balance. Intravenous administration of allitol in anesthetized rats induced a marked increase in urine output, accompanied by decreased urinary osmolality and relatively stable sodium and potassium excretion. In contrast, oral administration of allitol softened stools, tended to decrease urine volume in conscious mice, and did not affect total body water or whole-body sodium and potassium content. These findings indicate that orally administered allitol promotes gastrointestinal water retention, thereby limiting renal water excretion without disturbing systemic fluid or electrolyte homeostasis. These results suggest that allitol acts via a novel organ-selective mechanism, highlighting the importance of the administration route in modulating its physiological effects.

Cabozantinib is an oral anticancer agent that causes nausea; however, evidence of these symptoms and their prevention using antiemetics is limited. This study aimed to elucidate the nausea profiles of patients treated with cabozantinib and to evaluate antiemetic therapy. A single-institution, exploratory, retrospective observational study was conducted in 37 patients treated with cabozantinib. The primary outcome was set as nausea during cabozantinib administration. Prescribed antiemetics and opioid analgesics were collected. Changes in the use of these medications after cabozantinib initiation were investigated in patients who experienced nausea. Nausea occurred in 12 patients (32.0%), and the median time to onset was 22 d. No association was found between the number of antiemetics and the rate of nausea. Univariate logistic regression analysis suggested that age (odds ratio [OR] = 0.900, 95% confidence interval [CI]: 0.867–0.993; p = 0.0279), daily dose of cabozantinib (OR = 4.32, 95% CI: 1.35–17.6; p = 0.0117), concomitant use of opioid analgesics (OR = 72.0, 95% CI: 9.31–1.61 × 10³; p < 0.001), hypoalbuminemia (OR = 12.0, 95% CI: 1.51–254; p = 0.0176), and a history of chemotherapy-induced nausea and vomiting (OR = 5.20, 95% CI: 1.03–31.4; p = 0.0459) were potentially associated with nausea. Antiemetic management after the onset of symptoms mainly consisted of the addition or change of dopamine D₂ receptor antagonists, which resulted in symptom improvement in six patients, whereas symptoms persisted or worsened in six patients. Careful monitoring may be required during the first month in patients harboring risk factors.

The pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of drug-metabolizing enzymes in response to various chemicals. Ligand binding to PXR induces a conformational alteration of the C-terminal coactivator–binding motif activation function 2 (AF2), leading to the recruitment of coactivators. The contribution of each coactivator to PXR-mediated transcription may vary depending on the ligand. Therefore, identifying ligand-dependent differences in coactivator recruitment is important for understanding the biological functions of PXR. In this study, we investigated the ligand-dependent recruitment of coactivators using a PXR mutant containing a three-alanine insertion immediately upstream of AF2 (PXR-3A). Mammalian two-hybrid assays showed that PXR-3A recruited coactivators in a ligand-dependent manner. Treatment with the PXR ligand SR12813 induced the interaction of PXR-3A with coactivator peptides. Using reporter assays with the PXR-binding motifs from CYP3A4, CYP2C19, and CYP2C9 promoters, we evaluated the influences of coactivator overexpression on ligand-dependent reporter activity. In assays with the CYP3A4 promoter, rifampicin, rifaximin, or SR12813 induced reporter activity, and overexpression of peroxisome proliferator–activated receptor γ coactivator-1α (PGC1α) or nuclear receptor coactivator 1 (NCoA1) enhanced rifaximin- and SR12813-dependent transactivation. In assays using the CYP2C19 promoter, rifampicin and rifaximin induced reporter activity, whereas SR12813 did not. PGC1α enhanced rifaximin- or SR12813-induced transcription, whereas NCoA1, NCoA2, and activating signal cointegrator-2 (ASC2) did not exhibit clear ligand-dependent effects. NCoA3 knockdown in HepaRG cells attenuated SR12813-dependent induction of CYP2C19. Taken together, using the PXR-3A mutant, we demonstrated ligand-dependent recruitment of coactivators by PXR.

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Tetrabenazine (TBZ), a vesicular monoamine transporter 2 inhibitor, is commonly used to manage chorea; however, it may exhibit fluctuating plasma levels and elicit frequent adverse events. In this study, we aimed to clarify the effects of TBZ deuteration on its safety profile. We compared the safety profiles of TBZ and deutetrabenazine (DTBZ) in real-world clinical practice using disproportionality analysis and the large-scale pharmacovigilance database, VigiBase—the WHO’s global database of adverse drug reactions. Adverse event signals were assessed using the information component (IC). Seriousness was classified according to clinical outcome, and time to onset (TTO) was analyzed for selected events. TBZ showed signals for disorientation, dystonia, and sleep disorders (IC₀₂₅ > 0), whereas DTBZ did not. Serious adverse events were reported in 54.7% of TBZ cases and 37.9% of DTBZ cases. The TTO of sleep disorder was also evaluated; however, the number of cases with available TTO information was limited. DTBZ showed fewer adverse event signals and a lower proportion of serious adverse events than TBZ. These findings suggest potential differences in the safety profiles of the two drugs, which may influence tolerability in the treatment of HD.

Targeted α-radionuclide therapy (TAT) is a promising cancer therapy using α-emitters. However, therapeutic efficacy varies due to differences in the pharmacokinetics of TAT agents among patients. Vorinostat, a histone deacetylase inhibitor, is known to upregulate drug transporter expression, enhance the cellular uptake of β-emitting radiopharmaceuticals, and increase their antitumor efficacy. However, effective strategies or agents to enhance the tumor accumulation of TAT agents remain poorly understood. In this study, we focused on meta-[²¹¹At]At-astatobenzylguanidine ([²¹¹At]MABG) and investigated the potential utility of combining [²¹¹At]MABG with vorinostat. We evaluated protein expression of the norepinephrine transporter (NET), which is critical for the uptake of [²¹¹At]MABG, by immunoblotting in rat pheochromocytoma PC-12 cells and mouse embryonic fibroblast NIH/3T3 cells following vorinostat treatment. The synthesis of [²¹¹At]MABG was performed as previously described, and its cellular uptake was compared between vorinostat-treated and untreated cells. The cytotoxic effect was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) staining. NET expression in PC-12 cells increased from 24 h after vorinostat treatment, reaching approximately 2.8-fold at 48 h compared to control. No change in NET expression was observed in NIH/3T3 cells after vorinostat treatment. The cellular uptake of [²¹¹At]MABG in PC-12 cells increased by approximately 1.4-fold at 24 h post-vorinostat treatment. Moreover, colony growth of PC-12 cells after 24 h exposure to [²¹¹At]MABG was significantly reduced when combined with vorinostat. In conclusion, vorinostat increased NET expression and enhanced accumulation of [²¹¹At]MABG in pheochromocytoma. In addition, the combination of vorinostat and [²¹¹At]MABG significantly enhanced cytotoxicity. These results suggest that vorinostat is potentially beneficial in optimizing [²¹¹At]MABG therapy.

Sickness behavior is defined by a coordinated set of behavioral changes that emerge during infection and other inflammatory states. A major challenge for assessment, however, is the broad suppression of behavioral output, which hampers the dissociation of specific affective states from generalized motor inhibition. In this study, we applied facial expression analysis to characterize the sickness state in lipopolysaccharide (LPS)-injected male mice, leveraging the well-established capacity of rodents to express affective states through facial action units. LPS induced changes in both movement-related and grimace-like facial features. Inter-feature correlation analysis revealed that grimace-like features, including orbital tightening and nose bulging, showed LPS-specific temporal correlations in a subset of time bins. Furthermore, grimace-like readouts showed greater inter-individual variability than movement-related measures. Together, these findings support the viability of facial expression analysis as a noninvasive readout for behavioral states in inflammatory models that induce hypoactivity.

Sterile preparations require a sterility test, commonly performed by membrane filtration (MF) or direct inoculation (DI) as specified in pharmacopeias. MF is the preferred method for filterable aqueous preparations because of its high sensitivity, and DI is often used to test devices due to the difficulty in eluting microorganisms from the surfaces. A recent amendment to International Organization for Standardization 11737-2 now permits MF for liquid products of medical devices. Injections of hyaluronic acid (HA) are listed as drugs in the Japanese Pharmacopoeia (JP), but are classified as liquid products of medical devices in Europe and the U.S.A. The JP mandates DI for HA-based injections. HA-based injections for osteoarthritis were recently considered for reclassification as drugs in the United States because of their anti-inflammatory, analgesic, and chondroprotective effects. This study examined the suitability of MF and DI for sterility testing of an HA-based injection product. In DI, the maximum allowable volume of HA-based injection was set at 0.25 mg/mL of HA in the culture medium. All tested bacterial and fungal growths in media supplemented with 0.25 mg/mL of HA were observed within 3 d (bacteria) and 5 d (fungi). In MF, the injection was diluted with 0.1% peptone–0.1% polysorbate 80 solution. The solution was filtered, and the membrane was washed twice. All tested bacterial and fungal growths were observed in the culture medium. For the sterility test of the HA-based injection product, no growth was observed after 14 d of incubation in both methods. In conclusion, both DI and MF are suitable for sterility testing of HA-based injections.

Pinolenic acid (PA), an 18 : 3 n-6 polyunsaturated fatty acid abundant in pine nut oil, is a structural isomer of γ-linolenic acid (GLA) and α-linolenic acid (ALA). Notably, GLA and ALA have been reported to inhibit prostanoid TP receptor–mediated vascular contraction. Whether PA similarly modulates TP receptor–dependent responses, however, remains unknown. In the present study, we investigated the effects of PA on TP receptor–mediated contraction in porcine coronary arteries (PCAs), TP receptor–evoked intracellular Ca²⁺ responses in human TP receptor–expressing cells, and its potential binding mode using molecular docking. In endothelium-denuded PCAs, PA (3–30 μM) concentration-dependently inhibited contractions induced by the TP receptor agonist U46619 and prostaglandin F_2α (PGF_2α), whereas it had little effect on contractions evoked by depolarization (high-KCl) or by other vasoactive agonists. PA caused a parallel rightward shift of the U46619 concentration–response curve, and Schild analysis yielded a slope not significantly different from unity; the corresponding pA₂ value was 4.91. In human TP receptor–expressing 293T cells, PA significantly attenuated U46619-induced intracellular Ca²⁺ elevation, whereas it did not affect PGF_2α-induced Ca²⁺ responses in prostanoid FP receptor–expressing cells. Docking simulations based on the human TP receptor crystal structure (Protein Data Bank ID: 8XJO) suggested that PA may occupy the orthosteric binding pocket, with its carboxylate group positioned near His89. Collectively, these findings suggest that PA inhibits TP receptor–mediated contraction and exhibits pharmacological properties consistent with competitive antagonism, supporting the concept that C18:3 fatty acids may modulate TP receptor signaling.

Rheumatoid arthritis is characterized by chronic synovial inflammation and recurrent flares, which are thought to involve joint-specific inflammatory memory. Synovial fibroblasts (SFs) contribute to this process through altered responses to repeated inflammatory stimulation. However, pharmacological targeting of these state-dependent responses remains limited, partly due to the lack of screening systems that distinguish responses under initial and repeated stimulation conditions. Here, we established a quantitative in vitro system using primary murine SFs. Repeated tumor necrosis factor-α stimulation enhanced interleukin-6 (IL-6) production, recapitulating key features previously reported in human SFs. This system enabled direct comparison of drug effects under single and repeated stimulation conditions, revealing distinct response patterns and identifying compounds that selectively modulate the enhanced response induced by repeated stimulation. Notably, a complement receptor antagonist attenuated the additional increase in IL-6 production observed after repeated stimulation, accompanied by the attenuation of glycolysis-related gene expression, while showing no significant effect under single stimulation conditions. These findings highlight the importance of state-dependent pharmacological evaluation and demonstrate the utility of this experimental framework for analyzing differential responses associated with repeated inflammatory stimulation.

Peonidin is a compound derived from cyanidin, belonging to the anthocyanin group, which imparts a purplish-red color to flowers and fruits. It exhibits antioxidant, anti-inflammatory, and antiproliferative properties. This study investigated the anticancer properties of peonidin in human colon cancer cell lines. Normal and colon cancer cells were exposed to different doses of peonidin for different durations. Cell-based assays and Western blotting were performed to investigate the mechanisms driving peonidin activity. Peonidin exhibited cytotoxic effects on colon cancer cells in a dose- and time-dependent manner while sparing normal colon epithelial cells. Furthermore, peonidin triggered autophagy, as evidenced by the increase in autophagosomes in colon cancer cells. Western blot analysis revealed that peonidin elevated the levels of autophagy-related 4B, microtubule-associated protein 1 light chain 3-I/II, and sequestosome-1 (SQSTM/p62). Conversely, peonidin reduced cell invasion and the expression of matrix metalloproteinase-9, Snail, Slug, and vimentin. From a mechanistic standpoint, Western blotting indicated that peonidin might inhibit the extracellular signal-regulated kinase/nuclear factor-κB/cyclooxygenase-2 pathways, leading to autophagy induction and inhibition of cell invasion in colon cancer cells. These results provide preliminary evidence supporting the use of peonidin as a new potent candidate for colorectal cancer chemotherapy.

In 2024, we reported a brain-penetrant formulation of the vasoactive intestinal peptide receptor 2 (VIPR2) antagonist peptide KS-133 that mitigated cognitive dysfunction in the VIPR2 hyperactivation mouse model of schizophrenia. In this formulation, KS-133 was encapsulated in the hydrophobic core of nanoparticles (NPs) coated with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine–KS-487 (DPPE–KS-487), a conjugate of the cyclic peptide KS-487 and DPPE produced by a click reaction that binds low-density lipoprotein-related protein 1, enabling blood–brain barrier penetration upon subcutaneous injection. However, the click reaction generated multiple positional isomers and manufacturing required repetitive cycles of ultrasonication at high and low temperatures, posing challenges for industrial scalability. In the current study, we coated KS-133-containing NPs with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine–KS-487 (DSPE–KS-487), a novel conjugate of KS-487 with DSPE produced through a non-click method, thus eliminating positional isomers, and also established a simplified manufacturing process allowing a unidirectional transition from ultrasonication at high to low temperatures. This formulation remained physically and chemically stable for at least 12 months under refrigeration, with no changes in particle size, zeta potential, KS-133 content, or KS-487 presentation level. The formulation also exhibited brain penetration and therapeutic efficacy against VIPR2 agonist-induced novel object recognition impairment in mice comparable to those of DPPE–KS-487 NPs. Furthermore, no systemic side effects of hematologic, brain, heart, liver, and lung toxicity were detected following daily injections to mice for two weeks at five times the effective dose. This new KS-133 formulation incorporating DSPE–KS-487 as a brain-penetrant shuttle is a promising drug candidate for the treatment of cognitive dysfunction in schizophrenia.