A novel chemically engineered multifunctional statin conjugate as self-assembled nanoparticles inhibiting bile acid transporters.

Statins are widely used to treat hyperlipidemia; however, their mechanism-inhibiting cholesterol production without promoting its utilization-causes problems, such as inducing diabetes. In our research, we develop, for the first time, a chemically engineered statin conjugate that not only inhibits cholesterol production but also enhances its consumption through its multifunctional properties. The novel rosuvastatin (RO) and ursodeoxycholic acid (UDCA) conjugate (ROUA) is designed to bind to and inhibit the core of the apical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the effect of rosuvastatin. Consequently, ROUA not only preserves the cholesterol-lowering function of statins but also prevents the reabsorption of bile acids, thereby increasing cholesterol consumption. Additionally, ROUA's ability to self-assemble into nanoparticles in saline-attributable to its multiple hydroxyl groups and hydrophobic nature-suggests its potential for a prolonged presence in the body. The oral administration of ROUA nanoparticles in animal models using a high-fat or high-fat/high-fructose diet shows remarkable therapeutic efficacy in fatty liver, with low systemic toxicity. This innovative self-assembling multifunctional molecule design approach, which boosts a variety of therapeutic effects while minimizing toxicity, offers a significant contribution to the advancement of drug development.

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Assessing of exercise intensity for a rhythmik exercise program based on cardiopulmonary functions.

This study investigated the determination of exercise intensity for a rhythmik exercise program based on cardiopulmonary functions. Nine female participants in their 20s to 40s performed a rhythmik exercise program for 60 min per session, three sessions weekly, for 8 weeks. All participants underwent a grade exercise test to measure their minute ventilation (VE), oxygen uptake (VO2), maximal volume of minute oxygen consumption (VO2max), heart rate (HR), and oxygen pulse (O2 pulse) at the time of anaerobic threshold (AT) and maximal exercise time (ETmax). To determine the exercise intensity of the rhythmik exercise program, the Polar Heart Monitor was used for quantification, and the Borg Scale was used to measure the rating of perceived exertion (RPE). We did not observe any significant effects on the reaching time of AT, VE, VO2, VO2max, HR, and O2 pulse at either AT or ETmax. However, maximal value of VE (VEmax) was significantly enhanced at ETmax. The exercise intensity of the rhythmik exercise program was found to be low at 62.85% of HRmax with an RPE of 12.22. Our results suggest that the rhythmik exercise program did not directly improve cardiopulmonary functions; however, considering the unstructured nature of the rhythmik exercise program, anticipated positive effects on cardiopulmonary fitness are achievable through changes in the program contents and exercise time according to the goals of the participants.

Neuroprotective effects of hesperetin on H2O2-induced damage in neuroblastoma SH-SY5Y cells.

BACKGROUND/OBJECTIVES: Oxidative stress is a fundamental neurodegenerative disease trigger that damages and decimates nerve cells. Neurodegenerative diseases are chronic central nervous system disorders that progress and result from neuronal degradation and loss. Recent studies have extensively focused on neurodegenerative disease treatment and prevention using dietary compounds. Heseperetin is an aglycone hesperidin form with various physiological activities, such as anti-inflammation, antioxidant, and antitumor. However, few studies have considered hesperetin's neuroprotective effects and mechanisms; thus, our study investigated this in hydrogen peroxide (H2O2)-treated SH-SY5Y cells. MATERIALS/METHODS: SH-SY5Y cells were treated with H2O2 (400 µM) in hesperetin absence or presence (10-40 µM) for 24 h. Three-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays detected cell viability, and 4',6-diamidino-2-phenylindole staining allowed us to observe nuclear morphology changes such as chromatin condensation and apoptotic nuclei. Reactive oxygen species (ROS) detection assays measured intracellular ROS production; Griess reaction assays assessed nitric oxide (NO) production. Western blotting and quantitative polymerase chain reactions quantified corresponding mRNA and proteins. RESULTS: Subsequent experiments utilized various non-toxic hesperetin concentrations, establishing that hesperetin notably decreased intracellular ROS and NO production in H2O2-treated SH-SY5Y cells (P < 0.05). Furthermore, hesperetin inhibited H2O2-induced inflammation-related gene expression, including interluekin-6, tumor necrosis factor-α, and nuclear factor kappa B (NF-κB) p65 activation. In addition, hesperetin inhibited NF-κB translocation into H2O2-treated SH-SY5Y cell nuclei and suppressed mitogen-activated protein kinase protein expression, an essential apoptotic cell death regulator. Various apoptosis hallmarks, including shrinkage and nuclear condensation in H2O2-treated cells, were suppressed dose-dependently. Additionally, hesperetin treatment down-regulated Bax/Bcl-2 expression ratios and activated AMP-activated protein kinase-mammalian target of rapamycin autophagy pathways. CONCLUSION: These results substantiate that hesperetin activates autophagy and inhibits apoptosis and inflammation. Hesperetin is a potentially potent dietary agent that reduces neurodegenerative disease onset, progression, and prevention.

Seizure outcome in medically treated patients with adult-onset epilepsy and cerebral cavernous malformation.

PURPOSE: We evaluated long-term seizure outcomes of antiseizure medications (ASMs) and risk factors for drug resistance in patients with adult-onset epilepsy associated with cerebral cavernous malformation (CCM). MATERIALS AND METHODS: This retrospective observational study included patients newly diagnosed with adult-onset focal epilepsy associated with CCM. Patients received individualized treatments with ASMs. All patients were followed-up for at least 2 years. The main outcome measure was terminal 2 year seizure freedom (2-YSF). RESULTS: Forty eight subjects (28 men and 20 women) were included. Thirty-one (64.6%) subjects achieved a terminal 2-YSF (range 2.0-17.0 years). After treatment with the first drug regimen, 31 (64.6%) subjects achieved 2-YSF, with 23 remaining seizure-free until final follow-up visit. Of the 23 subjects treated with the second drug regimen and the six treated with the third drug regimen, ten (43.5%) and one (16.7%), respectively, achieved a terminal 2-YSF. Stepwise logistic regression analyses showed that terminal 2-YSF was negatively associated with epileptiform discharge on EEG at the time of diagnosis (odds ratio = 0.214, p = 0.047) and tended to be associated with age ≥ 45 years at seizure onset (odds ratio = 4.260, p = 0.056). CONCLUSION: The present study found that 64.6% of CCM patients with adult-onset epilepsy achieved terminal 2-YSF after ASM initiation. Interictal epileptiform discharge on EEG at the time of diagnosis was associated with poor prognosis. Failure to achieve sustained seizure freedom after two ASMs may indicate the need for surgical treatment.

Neuroprotective Effects of Zerumbone on H2O2-Induced Oxidative Injury in Human Neuroblastoma SH-SY5Y Cells.

Oxidative stress is recognized as one of the main reasons for cellular damage and neurodegenerative diseases. Zerumbone is one of the sesquiterpenoid compounds in the essential oil of Zingiber zerumbet Smith. Zerumbone exhibits various physiological activities, such as anticancer, antioxidant, and antibacterial effects. However, studies on the neuroprotective efficacy of zerumbone and the mechanism behind it are lacking. In this study, we explored the neuroprotective efficacy of zerumbone and its mechanism in hydrogen peroxide-treated human neuroblastoma SH-SY5Y cells. H2O2 treatment (400 µM) for 24 h enhanced the generation of intracellular reactive oxygen species (ROS) compared to untreated cells. By contrast, zerumbone treatment significantly suppressed the production of intracellular ROS. Zerumbone significantly inhibited H2O2-induced nitric oxide production and expression of inflammation-related genes. Moreover, zerumbone decreased H2O2-induced mitogen-activated protein kinase (MAPK) protein expression. Various hallmarks of apoptosis in H2O2-treated cells were suppressed in a dose-dependent manner through downregulation of the Bax/Bcl-2 expression ratio by zerumbone. Since activation of AMP-activated kinase (AMPK) is a promising therapeutic target for neurodegenerative diseases, we also investigated the mammalian target of rapamycin (mTOR) as part of the autophagy mechanism in H2O2-treated SH-SY5Y cells. In this study, zerumbone upregulated the expression of Sirtuin 1 (SIRT1) and p-AMPK (which were downregulated by the H2O2 treatment) and downregulated p-mTOR. Altogether, our results propose that inhibition of apoptosis and inflammation by autophagy activation plays an important neuroprotective role in H2O2-treated SH-SY5Y cells. Zerumbone may thus be a potent dietary agent that reduces the onset and progression, as well as prevents neurodegenerative diseases.

Sodium butyrate inhibits high glucose-induced inflammation by controlling the acetylation of NF-κB p65 in human monocytes.

BACKGROUND/OBJECTIVES: Hyperglycemia is a major cause of diabetes and diabetes-related diseases. Sodium butyrate (NaB) is a short-chain fatty acid derivative that produces dietary fiber by anaerobic bacterial fermentation in the large intestine and occurs in foods, such as Parmesan cheese and butter. Butyrate has been shown to prevent obesity, improve insulin sensitivity, and ameliorate dyslipidemia in diet-induced obese mice. Therefore, this study examined the effects and mechanism of NaB on the secretion of inflammatory cytokines induced by high glucose (HG) in THP-1 cells. MATERIALS/METHODS: THP-1 cells were used as an in vitro model for HG-induced inflammation. The cells were cultured under normal glycemic or hyperglycemic conditions with or without NaB (0-25 µM). Western blotting and quantitative polymerase chain reaction were used to evaluate the protein and mRNA levels of nuclear factor-κB (NF-κB), interleukin-6, tumor necrosis factor-α, acetylated p65, acetyl CREB-binding protein/p300 (CBP/p300), and p300 using THP-1 cells. Histone acetyltransferase (HAT), histone deacetylase (HDAC), and pro-inflammatory cytokine secretion activity were analyzed using an enzyme-linked immunosorbent assay. RESULTS: HG significantly upregulated histone acetylation, acetylation levels of p300, NF-κB activation, and inflammatory cytokine release in THP-1 cells. Conversely, the NaB treatment reduced cytokine release and NF-κB activation in HG-treated cells. It also significantly reduced p65 acetylation, CBP/p300 HAT activity, and CBP/p300 gene expression. In addition, NaB decreased the interaction of p300 in acetylated NF-κB and TNF-α. CONCLUSIONS: These results suggest that NaB suppresses HG-induced inflammatory cytokine production through HAT/HDAC regulation in monocytes. NaB has the potential for preventing and treating diabetes and its related complications.

Effects of Continuous Positive Airway Pressure on Sleep State Misperception in Patients With Obstructive Sleep Apnea.

BACKGROUND: Little is known regarding the effects of continuous positive airway pressure (CPAP) on sleep misperception in obstructive sleep apnea (OSA). METHODS: Sleep state perception was measured by subtracting the objective total sleep time from the subjective sleep duration. Sleep underestimation and overestimation were defined as ± 60 minutes sleep perception. Insomnia and depressive symptoms were assessed using questionnaires. Finally, nonparametric statistical analyses were performed. RESULTS: Of the 339 patients with OSA included in the study, 90 (26.5%) and 45 (13.3%) showed sleep underestimation and overestimation, respectively. Overall, a significant underestimation of sleep was noted during CPAP titration comparing to a diagnostic PSG (P < 0.001). OSA patients with insomnia or depressive symptoms did not show any changes in sleep perception between diagnostic and CPAP titration studies, whereas those without insomnia or depressed mood showed significantly underestimated sleep duration during CPAP titration. Patients with OSA and either underestimated or overestimated misperception showed perceptual improvements during CPAP titration regardless of the presence of insomnia or depressive symptoms. However, of 204 patients with normal sleep perception, 138 (67.6%) and 10 (4.9%) had underestimation and overestimation of sleep during CPAP titration. CONCLUSION: CPAP titration may improve sleep perception with moderate to severe OSA who have sleep misperception. However, CPAP titration may result in sleep misperception especially underestimation of sleep in those who have normal sleep perception.

Neuroprotective effects of hesperetin on H 2 O 2 -induced damage in neuroblastoma SH-SY5Y cells

BACKGROUND/OBJECTIVES@#Oxidative stress is a fundamental neurodegenerative disease trigger that damages and decimates nerve cells. Neurodegenerative diseases are chronic central nervous system disorders that progress and result from neuronal degradation and loss. Recent studies have extensively focused on neurodegenerative disease treatment and prevention using dietary compounds. Heseperetin is an aglycone hesperidin form with various physiological activities, such as anti-inflammation, antioxidant, and antitumor. However, few studies have considered hesperetin’s neuroprotective effects and mechanisms; thus, our study investigated this in hydrogen peroxide ( H 2 O 2 )-treated SH-SY5Y cells.MATERIALS/METHODS: SH-SY5Y cells were treated with H 2 O 2 (400 µM) in hesperetin absence or presence (10–40 µM) for 24 h. Three-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays detected cell viability, and 4′,6-diamidino-2-phenylindole staining allowed us to observe nuclear morphology changes such as chromatin condensation and apoptotic nuclei. Reactive oxygen species (ROS) detection assays measured intracellular ROS production; Griess reaction assays assessed nitric oxide (NO) production. Western blotting and quantitative polymerase chain reactions quantified corresponding mRNA and proteins. @*RESULTS@#Subsequent experiments utilized various non-toxic hesperetin concentrations, establishing that hesperetin notably decreased intracellular ROS and NO production in H 2 O 2 -treated SH-SY5Y cells (P < 0.05). Furthermore, hesperetin inhibited H 2 O 2 -induced inflammation-related gene expression, including interluekin-6, tumor necrosis factor-α, and nuclear factor kappa B (NF-κB) p65 activation. In addition, hesperetin inhibited NFκB translocation into H 2 O 2 -treated SH-SY5Y cell nuclei and suppressed mitogen-activated protein kinase protein expression, an essential apoptotic cell death regulator. Various apoptosis hallmarks, including shrinkage and nuclear condensation in H 2 O 2 -treated cells, were suppressed dose-dependently. Additionally, hesperetin treatment down-regulated Bax/ Bcl-2 expression ratios and activated AMP-activated protein kinase-mammalian target of rapamycin autophagy pathways. @*CONCLUSION@#These results substantiate that hesperetin activates autophagy and inhibits apoptosis and inflammation. Hesperetin is a potentially potent dietary agent that reduces neurodegenerative disease onset, progression, and prevention

Sodium butyrate inhibits high glucose-induced inflammation bycontrolling the acetylation of NF-κB p65 in human monocytes

BACKGROUND/OBJECTIVES@#Hyperglycemia is a major cause of diabetes and diabetesrelated diseases. Sodium butyrate (NaB) is a short-chain fatty acid derivative that produces dietary fiber by anaerobic bacterial fermentation in the large intestine and occurs in foods, such as Parmesan cheese and butter. Butyrate has been shown to prevent obesity, improve insulin sensitivity, and ameliorate dyslipidemia in diet-induced obese mice. Therefore, this study examined the effects and mechanism of NaB on the secretion of inflammatory cytokines induced by high glucose (HG) in THP-1 cells.MATERIALS/METHODS: THP-1 cells were used as an in vitro model for HG-induced inflammation. The cells were cultured under normal glycemic or hyperglycemic conditions with or without NaB (0–25 μM). Western blotting and quantitative polymerase chain reaction were used to evaluate the protein and mRNA levels of nuclear factor-κB (NF-κB), interleukin-6, tumor necrosis factor-α, acetylated p65, acetyl CREB-binding protein/p300 (CBP/p300), and p300 using THP-1 cells. Histone acetyltransferase (HAT), histone deacetylase (HDAC), and pro-inflammatory cytokine secretion activity were analyzed using an enzyme-linked immunosorbent assay. @*RESULTS@#HG significantly upregulated histone acetylation, acetylation levels of p300, NF-κB activation, and inflammatory cytokine release in THP-1 cells. Conversely, the NaB treatment reduced cytokine release and NF-κB activation in HG-treated cells. It also significantly reduced p65 acetylation, CBP/p300 HAT activity, and CBP/p300 gene expression. In addition, NaB decreased the interaction of p300 in acetylated NF-κB and TNF-α. @*CONCLUSIONS@#These results suggest that NaB suppresses HG-induced inflammatory cytokine production through HAT/HDAC regulation in monocytes. NaB has the potential for preventing and treating diabetes and its related complications.

Effects of Continuous Positive Airway Pressure on Sleep State Misperception in Patients With Obstructive Sleep Apnea

Background@#Little is known regarding the effects of continuous positive airway pressure (CPAP) on sleep misperception in obstructive sleep apnea (OSA). @*Methods@#Sleep state perception was measured by subtracting the objective total sleep time from the subjective sleep duration. Sleep underestimation and overestimation were defined as ± 60 minutes sleep perception. Insomnia and depressive symptoms were assessed using questionnaires. Finally, nonparametric statistical analyses were performed. @*Results@#Of the 339 patients with OSA included in the study, 90 (26.5%) and 45 (13.3%) showed sleep underestimation and overestimation, respectively. Overall, a significant underestimation of sleep was noted during CPAP titration comparing to a diagnostic PSG (P < 0.001). OSA patients with insomnia or depressive symptoms did not show any changes in sleep perception between diagnostic and CPAP titration studies, whereas those without insomnia or depressed mood showed significantly underestimated sleep duration during CPAP titration. Patients with OSA and either underestimated or overestimated misperception showed perceptual improvements during CPAP titration regardless of the presence of insomnia or depressive symptoms. However, of 204 patients with normal sleep perception, 138 (67.6%) and 10 (4.9%) had underestimation and overestimation of sleep during CPAP titration. @*Conclusion@#CPAP titration may improve sleep perception with moderate to severe OSA who have sleep misperception. However, CPAP titration may result in sleep misperception especially underestimation of sleep in those who have normal sleep perception.

Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer.

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.

Comparisons of impulsivity among patients with different subtypes of epilepsy.

PURPOSE: This study assessed whether patients with epilepsy have a higher level of impulsivity than healthy controls, and compared impulsivity among patients with different subtypes of epilepsy. METHODS: The multicenter study included 108 subjects with epilepsy and 56 healthy volunteers. Subjects were evaluated by the Barratt Impulsiveness Scale-11 (BIS-11) and Patient Health Questionnaire-9, with BIS-11 scores analyzed as both dichotomized and continuous variables. High impulsivity was defined as a total BIS-11 score ≥ 67. RESULTS: Of the 108 subjects with epilepsy, 36 had idiopathic generalized epilepsy (IGE), 47 had temporal lobe epilepsy (TLE), and 25 had frontal lobe epilepsy (FLE). A significantly higher percentage of subjects with epilepsy (22.2%) than controls (1.8%) had BIS-11 scores ≥ 67 (p = 0.001), although mean BIS-11 scores were similar in subjects with epilepsy (59.5 ± 10.0) and controls (58.8 ± 4.6). Higher percentages of subjects with IGE and FLE had BIS-11 scores ≥ 67 than subjects with TLE and controls. Mean total BIS-11 scores did not differ between controls and subjects with IGE and FLE, but were lower in subjects with TLE than in controls. Differences in impulsivity among controls and subjects with epilepsy subtypes varied depending on BIS-11 subscale. CONCLUSIONS: Patients with epilepsy, particularly IGE and FLE, were more likely to have high impulsivity scores, defined by a certain cutoff on the BIS-11, than controls and subjects with TLE. However, mean impulsivity scores did not differ among controls and subjects with IGE and FLE. Dichotomizing BIS-11 scores may be necessary to avoid false negative results in subjects with epilepsy.

Sex Differences in Excessive Daytime Sleepiness Among Patients With Obstructive Sleep Apnea.

BACKGROUND AND PURPOSE: To identify sex differences in daytime sleepiness associated with apnea severity and periodic limb movements during sleep (PLMS) in subjects with obstructive sleep apnea (OSA). METHODS: This study used the Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI), and Sleep Hygiene Index (SHI) in logistic regression analyses with interaction terms. Severe OSA, excessive daytime sleepiness (EDS), and PLMS were defined as an apnea-hypopnea index of ≥30, an ESS score of ≥11, and a periodic limb movements index of >15, respectively. RESULTS: The 1,624 subjects with OSA (males, 79.1%) comprised 45.3%, 38.2%, and 16.4% with severe OSA, EDS, and PLMS, respectively. Multiple logistic regression without interaction terms showed that sex, severe OSA, and PLMS were not significantly associated with EDS. However, significant interactions were noted between sex and severe OSA and PLMS in EDS in both crude and adjusted models (all p values<0.05). In the adjusted model, severe OSA was associated with EDS in males (p=0.009) but not in females. PLMS were more likely to be associated with EDS in females (p=0.013), whereas PLMS were less likely to be associated with EDS in males (p=0.041). The models were adjusted by the BDI score, SHI, and presence of medical comorbidities. CONCLUSIONS: There are significant sex differences in subjective daytime sleepiness in subjects with severe OSA and PLMS. Severe OSA and PLMS may influence daytime sleepiness more in males and females, respectively.

Caspase-3 mediated switch therapy of self-triggered and long-acting prodrugs for metastatic TNBC.

Triple-negative breast cancer (TNBC) is characterized by its highly heterogeneous microenvironment and propensity for aggressive behavior, both of which represent, along with poor prognosis and high incidence of relapse, the main challenges of curing the disease. Although recent progress in targeted chemotherapy combinations has shown promising outcomes, conventional targeted chemotherapeutic approaches have relied on exploiting the expression of certain molecules or proteins overexpressed on cancer cells as drug targets, which have demonstrated limited clinical benefit against metastatic cancers. Here, we describe a tumoral caspase-3 mediated peptide-doxorubicin conjugates (PDC) switch therapy that adopts two different caspase-3 cleavable PDCs, RGDEVD-DOX (TPD1) and EMC-KGDEVD-DOX (MPD1), for targeting metastatic triple-negative breast cancer (mTNBC). First, using TPD1, an integrin αVß3 based targeted strategy was utilized to target tumor cells or tumor vasculature associated with the highly malignant progression of mTNBC. TPD1 triggered the tumor cell-specific initial apoptosis and the induction of caspase-3 expression in the target tumor site. Then MPD1 was administered sequentially, which is an albumin-binding prodrug, and activated by induced caspase-3 in order to maintain the tumoral caspase-3 level and release the cytotoxic payload. The PDC switch therapy markedly accumulated doxorubicin in the tumor site and augmented tumor-specific in situ amplification of apoptosis. Importantly, the PDC switch therapy exerted a bystander killing effect on the neighboring cancer cells thus demonstrating potent therapeutic efficacy against both local and metastatic cancers. Given the limited therapeutic outcomes with conventional targeted therapies, our strategy of regulating the expression of caspase-3 level as a drug target could provide as a more durable and effective alternative in the treatment of highly heterogeneous mTNBC.

Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer.

Despite recent breakthroughs in the development of direct KRAS inhibitors and modulators, no drugs targeting pan-KRAS mutant cancers are clinically available. Here, we report a novel strategy to treat pan-KRAS cancers using a caspase-3 cleavable peptide-drug conjugate that exploits enhanced albumin metabolism in KRAS altered cancers to deliver a cytotoxic agent that can induce a widespread bystander killing effect in tumor cells. Increased albumin metabolism in KRAS mutant cancer cells induced apoptosis via the intracellular uptake of albumin-bound MPD1. This allowed caspase-3 upregulation activated MPD1 to release the payload and exert the non-selective killing of neighboring cancer cells. MPD1 exhibited potent and durable antitumor efficacy in mouse xenograft models with different KRAS genotypes. An augmentation of anti-cancer efficacy was achieved by the bystander killing effect derived from the caspase-3 mediated activation of MPD1. In summary, albumin metabolism-induced apoptosis, together with the bystander killing effect of MPD1 boosted by caspase-3 mediated activation, intensified the efficacy of MPD1 in KRAS mutant cancers. These findings suggest that this novel peptide-drug conjugate could be a promising breakthrough for the treatment in the targeting of pan-KRAS mutant cancers.

Aggression is more strongly associated with suicidality, independent of depression, than emotional instability and impulsivity in people with epilepsy.

PURPOSE: We evaluated the relative contributions of emotional instability, impulsivity, and aggression to the presence of suicide risk in people with epilepsy after adjusting for depressive symptoms. METHODS: This was a cross-sectional study that used the short form of the Affective Lability Scale (ALS-18), the Barratt Impulsiveness Scale Version 11 (BIS-11), the Brief Aggression Questionnaire (BAQ), and the Patient Health Questionnaire-9 (PHQ-9). Suicidality was assessed using the Mini International Neuropsychiatric Interview (MINI), and the presence of suicide risk was defined as a MINI suicidality score ≥1. Stepwise logistic regression and mediation analyses using a two-stage regression method were performed. RESULTS: Of the 171 subjects (63.2% men) included, suicide risk was present in 38 subjects (22.2%). The stepwise logistic regression analysis identified four variables that were independently associated with suicide risk: higher PHQ-9 score, higher BAQ score, longer duration of epilepsy, and unemployment. The univariate analysis showed that ALS-18 and BIS-11 scores were significantly associated with suicide risk; however, they were backward eliminated from the logistic model according to the criterion of p > 0.1. The mediating effects of ALS-18 and BIS-11 scores on suicide risk via PHQ-9 scores (but not BAQ scores) were significant, with the proportion mediated 61.5% and 54.0% of the total effect, respectively. CONCLUSIONS: Alongside depressive symptoms, aggression may be a more useful concept than emotional instability and impulsivity for identifying suicidal risk in people with epilepsy.

Zerumbone suppresses high glucose and LPS-induced inflammation in THP-1-derived macrophages by inhibiting the NF-κB/TLR signaling pathway.

Diabetes mellitus is characterized by hyperglycemia. Low-grade bacterial infection with hyperglycemia in patients with diabetes is associated with atherosclerosis development. Therefore, this study hypothesized that macrophages lead to more severe diabetic complications under combined conditions of high glucose and lipopolysaccharide (LPS)-induced inflammation than under normoglycemic conditions. Zerumbone is the main component of Zingiber zerumbet Smith essential oil, a type of wild ginger. It possesses various biomedical activities, including antibacterial, antioxidant, anti-inflammatory, and anticancer activities; however, the precise mechanism of its anti-inflammatory and epigenetic effects is not fully understood. In this study, the effects of zerumbone on the secretion of proinflammatory cytokines and its underlying regulatory mechanism were investigated in THP-1-derived macrophages exposed to high glucose and LPS. THP-1-derived macrophages were cultured under normoglycemic (5.5 mmol/L glucose) or hyperglycemic (25 mmol/L glucose) conditions in the absence or presence of zerumbone (5-50 µM) for 48 hours and then treated with 100 ng/mL LPS for 6 hours. Zerumbone (25 and 50 µM) suppressed the production of tumor necrosis factor-α and interleukin-6 and the activation of cyclooxygenase-2, nuclear factor-κB, histone deacetylases 3 proteins, and Toll-like receptor messenger RNA (mRNA) and increased the transcription of the sirtuin 1 (SIRT1), SIRT3, and SIRT6 mRNAs. Taken together, our results suggest that zerumbone may exert beneficial effects on diabetes and its complications.

Factors associated with sleep state misperception in patients with obstructive sleep apnea.

PURPOSE: Little is known regarding the prevalence of sleep state misperception and the factors related to this in patients with obstructive sleep apnea (OSA). METHODS: This retrospective study included patients with OSA defined by an apnea-hypopnea index (AHI) of ≥ 5 and used the Insomnia Severity Index (ISI), the Epworth sleepiness scale, the Patient Health Questionnaire-9, and the Generalized Anxiety Disorder-7. Underestimation and overestimation of sleep state perception were defined as < 80% and > 120%, respectively, of the ratio between subjective and objective total sleep time. An ISI score > 14 indicated clinically significant insomnia and an AHI ≥ 30 indicated severe OSA. A multinomial logistic regression was conducted with the category of sleep state perception as an outcome variable. RESULTS: Of the 707 patients with OSA, underestimation and overestimation of sleep state perception were noted in 22.5% and 10.6% of subjects, respectively. The median absolute differences (and percentages of the ratio) between subjective and objective total sleep time were 116 min (66.9%) and 87 min (127.3%) in the underestimated and overestimated perception groups, respectively. In the adjusted model, the underestimated group was more likely to have an ISI score > 14 (OR = 1.812, P = .006). The overestimated group was more likely to be older (OR = 1.025, P = .025) and has severe OSA (OR = 1.729, P = .035). CONCLUSIONS: There are two patterns of sleep state misperception in patients with OSA: underestimation associated with comorbid insomnia symptoms and overestimation associated with severe OSA. These findings enhance understanding of the pathophysiology of sleep state misperception in patients with OSA.