Membrane-bound guanylyl cyclase (GC-G), a noncanonical receptor, has been implicated in intestinal epithelial homeostasis. This study investigated the role of GC-G in intestinal ischemia-reperfusion (IIR) injury and its involvement in nitric oxide (NO)–related responses using male wild-type (WT) and GC-G knockout (KO) mice. Mice underwent superior mesenteric artery occlusion followed by 3- or 24-hour reperfusion and were intraperitoneally administered arginine (NO donor), aminoguanidine (selective iNOS inhibitor), or L-NAME (non-selective NOS inhibitor). In WT mice, IIR reduced jejunal mass, increased IL-6 and TUNEL-staining at 3 h, and suppressed nitrate/nitrite (NOx) and Ki-67 at 24 h. Arginine reduced caspase-3 activity at 3 h and enhanced Ki-67 and DNA content at 24 h. Aminoguanidine suppressed early apoptosis and improved later proliferation. L-NAME reduced early injury but enhanced later proliferation without restoring DNA content. GC-G deficiency was associated with attenuated early apoptotic responses but impaired mucosal regeneration following IIR. In KO mice, arginine failed to enhance proliferation and was associated with elevated apoptosis and cytokines, while NOS inhibitors reduced systemic NOx and IL-6 without improving epithelial proliferation or altering caspase-3 activity or bulk cGMP levels. Notably, intestinal NOx levels remained elevated in KO mice. Together, these findings suggest that GC-G contributes to the coordination of NO-related epithelial responses and influences intestinal sensitivity to NO-associated interventions during IIR, without detectable changes in total tissue cGMP levels.

BACKGROUND/OBJECTIVES:Carbohydrate-enriched diets and sedentary behavior contribute to diabetes risk. However, their impacts on glucose metabolism in abdominal (ASAT) and gluteal subcutaneous adipose tissues (GSAT), especially considering sex differences, remain unexplored. SUBJECTS/METHODS:Twenty (median age 29.2 years, median BMI 23.1 kg/m2) healthy participants (10 females) underwent mixed-feeding trials lasting 320 min, with carbohydrate-enriched meals following either prolonged sitting (SIT) or interrupted prolonged sitting (ACTIVE) in a randomized crossover design. Continuous glucose monitoring (CGM) was inserted simultaneously at abdominal and gluteal fat depots. Body composition was quantified by dual-energy x-ray absorptiometry. Oral glucose tolerance test was performed for measuring insulin sensitivity and resistance. In vitro experiments using paired human abdominal and gluteal preadipocyte cell lines were conducted to investigate molecular mechanisms. RESULTS:In the SIT trial, GSAT CGM showed a slower increase in interstitial glucose during lunch compared to ASAT CGM, particularly in females. In the ACTIVE trial, intermittent brisk walking led to numerically lower interstitial glucose levels in both ASAT and GSAT CGM, with the most significant impact observed in female ASAT CGM. While males with higher hepatic insulin resistance or android fat displayed a notable correlation with decreased interstitial glucose levels in the ACTIVE trial. Our in vitro experiments further revealed steady glucose uptake (GLUT1 expression) and de novo lipogenesis (ChREBP protein) were specifically enhanced in gluteal adipocytes during post-feeding 3-6 h. CONCLUSIONS:Breaking up prolonged sitting improves postprandial glucose control. Whereas gluteal fat depot may play roles to stabilize carbohydrate-enriched diets-induced hyperglycemia.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by mitochondrial dysfunction and oxidative stress. Although levodopa remains the gold standard for managing PD motor symptoms, it lacks neuroprotective and disease-modifying effects, highlighting the need for new neuroprotective therapies. Mitophagy, the selective mitochondrial degradation by autophagy, is critical for neuronal health. Oleanolic acid, a natural hepatoprotective compound, shows uncertain efficacy in PD treatment. This study investigated the neuroprotective effects and underlying mechanisms of oleanolic acid using the 1-methyl-4-phenylpyridinium (MPP⁺)-induced cellular model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In vitro, oleanolic acid demonstrated dopaminergic neuroprotection by reducing mitochondrial dysfunction and reactive oxygen species accumulation in PD cells. It upregulated the mitophagic protein DJ-1, enhancing the sequestration of damaged mitochondria into autophagosomes by mitophagy. DJ-1 knockdown attenuated oleanolic acid's neuroprotection, confirming DJ-1's role in oleanolic acid's action. In vivo, pre-treatment with oleanolic acid in MPTP-induced PD mice prevented PD-like motor symptoms, reduced neuronal death in the substantia nigra, and mitigated striatal neurodegeneration. Post-treatment with oleanolic acid not only reduced these effects but also increased Bcl-2 and DJ-1 levels in the substantia nigra and striatum. In vitro, oleanolic acid activated JNK for Sp1 upregulation and nuclear translocation, which induced DJ-1 expression. Computational modeling predicted that oleanolic acid likely interacts with JNK, suggesting this binding might be necessary for JNK-Sp1-DJ-1 axis activation for mitophagy-driven neuroprotection. These results highlight oleanolic acid's potential as a therapeutic agent in PD prevention and treatment via the JNK-Sp1-DJ-1 pathway. Further studies are required to validate its efficacy.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are widely used to manage type 2 diabetes mellitus (T2DM) to ameliorate hyperglycemia, albuminuria, and obesity, with established cardiorenal benefits. However, predictive biomarkers for therapeutic responses remain limited. In this study, seventy patients initiating SGLT2i therapy were evaluated clinically and through plasma proteomics and transcriptomics. Treatment significantly improved HbA1c (71.2%), albuminuria (47.5%), and weight (58.6%), with benefits in insulin resistance, β-cell function, blood pressure, uric acid, and body composition. Proteomic analysis identified IL-18R1 reduction linked to improved glycemic control, albuminuria, fat mass, and liver function. Transcriptomic profiling revealed genetic alterations in blood mononuclear cells, reinforcing anti-inflammatory changes. Receiver operating characteristic analysis indicated high baseline IL-18/IL-18R1 predicted overall response (area under the curve: 0.75, p = 0.005; cutoffs: IL-18 = 244.29 pg/mL, IL-18R1 = 325.97 pg/mL). IL-18/IL-18R1 signaling emerges as a promising biomarker for predicting therapeutic responses, guiding clinical decisions regarding SGLT2i use in T2DM management.

In this study, a Taguchi-based optimization method is proposed to search the coil parameters used for low-power wireless charging that will maximize the transmission efficiency. The coils were then implemented to charge a battery with a nominal voltage of 3.7 V and a rated capacity of 760 mAh, and it was found that the coil transmission efficiency increased by 3.7% compared to adopting the coil parameters obtained by using a genetic algorithm. Moreover, a 5-watt wireless charging system integrated with the Taguchi-based coils was built to charge a battery with a nominal voltage of 3.7 V and a rated capacity of 2200 mAh. The results showed that the coil transmission efficiency was higher than that of a commercial charger, but the dimension of the coil was larger than that of the commercial charger. Nevertheless, the air gap between transmitter and receiver coils was larger than that in the charger, and the charge time required for a 2200 mAh battery to reach a full charge was shorter than that required for the commercial charger. Although outcomes are still far from being satisfactory in the transmission efficiency, the proposed approach can greatly reduce computation cost in designing coils used for wireless charging.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Asiatic acid (AA) is a natural triterpene, which is recognized as effect of antioxidant and antitumor. Sorafenib (Sor), an orally target drug, has been applicate for the HCC therapy. However, the synergistic effect of AA and Sor on human HCC is still unclear. Here, we explore the effect of combined treatment with AA and Sor in the HCC cell line SK-HEP-1 and HepG2. Compared with treating alone, our results demonstrated that AA combined with Sor synergistically inhibited proliferative rates in MTT assay and colony formation assay. We also found that AA combined with Sor in HCC cells strongly caused cell cycle arrest in G0/G1 phase and affected the protein level of cyclin D1 and SKP2. Furthermore, combination treatment strongly enhanced ferroptosis through cellular accumulation of iron ions, lipid peroxidation, and ferroptosis-related proteins (GPX4 and FTH1) in HCC cells. In addition, the combined treatment resulted in higher phosphorylation of JNK1/2 in the promotion of ferroptosis than drug treatment alone. These results indicate that AA combined with Sor synergistically improved ferroptosis in HCC cells through the regulation of JNK1/2 signaling. Taken together, the combinatorial strategy may serve as the potential treatment in HCC.

OBJECTIVE:Microglia in the central nervous system regulate neuroinflammation that leads to a wide range of neuropathological alterations. The present study investigated the anti-neuroinflammatory properties of nobiletin (Nob) derivative, 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone (5-Ac-Nob), in lipopolysaccharide (LPS)-activated BV2 microglia. MATERIALS AND METHODS:By using the MTT assay, Griess method, flow cytometry, and enzyme-linked immunosorbent assay (ELISA), we determined the cell viability, the levels of nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory factors (interleukin 1 beta; IL-1β, interleukin 6; IL-6, tumor necrosis factor alpha; TNF-α and prostaglandin E2; PGE2) in LPS-stimulated BV2 microglia. Toll-like receptor 4 (TLR4)-mediated myeloid differentiation primary response gene 88 (MyD88)/nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) signaling pathway and signal transducer and activator of transcription 3 (STAT3) were measured by western blotting. Analysis of NO generation and mRNA of pro-inflammatory cytokines was confirmed in the zebrafish model. RESULTS:5-Ac-Nob reduced cell death, the levels of NO, ROS, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and pro-inflammatory factors in LPS-activated BV-2 microglial cells. TLR4-mediated MyD88/NF-κB and MAPK pathway (p38, ERK and JNK) after exposure to 5-Ac-Nob was also suppressed. Moreover, 5-Ac-Nob inhibited phosphorylated STAT3 proteins expression in LPS-induced BV-2 microglial cells. Furthermore, we confirmed that 5-Ac-Nob decreased LPS-induced NO generation and mRNA of pro-inflammatory cytokines in the zebrafish model. CONCLUSIONS:Our findings suggest that 5-Ac-Nob represses neuroinflammatory responses by inhibiting TLR4-mediated signaling pathway and STAT3. As a result of these findings, 5-Ac-Nob has potential as an anti-inflammatory agent against microglia-mediated neuroinflammatory disorders.

This study implements a possible use of the state of charge (SOC) instead of the charge voltage limit (Vlimit) to control the charging process for a four-stage constant current charging strategy. To determine the charging current in each stage, an iterative optimization procedure based on Taguchi method is employed to find near-optimal values. To control the change of the charging stage and terminate the charging process, the Coulomb counting method combined with battery's open circuit voltage estimation is adopted for SOC estimation. Tests of Sanyo 840 mA h, 3.6 V lithium-ion (Li-ion) batteries have been conducted with a Keithley 2230-30-1 triple power supply and a Prodigit 3332 F dual electronic load. The implemented charger has an input voltage of 12 V, output currents of 1.176 A, 0.840 A, 0.588 A, and 0.336 A, as well as an output voltage ranged from 0.168 V to 0.588 V. By performing the experiments, the proposed charging strategy has shorter charging time than the equivalent constant current constant voltage (CCCV) and the Vlimit-based charging methods. However, it yields a slightly lower charging efficiency than the equivalent CCCV and pulse current charging methods.

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in reduced dopamine levels in the striatum and eventual onset of motor symptoms. Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a monoterpene in aromatic plants exhibiting antioxidant, antidepressant, and anti-anxiety properties. The objective of this study is to evaluate the neuroprotective impacts of linalool on dopaminergic SH-SY5Y cells, primary mesencephalic and cortical neurons treated with 1-methyl-4-phenylpyridinium ion (MPP+), as well as in PD-like mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell viability, α-tubulin staining, western blotting, immunohistochemistry and behavioral experiments were performed. In MPP+-treated SH-SY5Y cells, linalool increased cell viability, reduced neurite retraction, enhanced antioxidant defense by downregulation of apoptosis signaling (B-cell lymphoma 2 (Bcl-2), cleaved caspase-3 and poly ADP-ribose polymerase (PARP)) and phagocyte NADPH oxidase (gp91phox), as well as upregulation of neurotrophic signaling (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) and nuclear factor-erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In MPP+-treated primary mesencephalic neurons, linalool enhanced the expressions of tyrosine hydroxylase (TH), Sirtuin 1 (SirT1), and parkin. In MPP+-treated primary cortical neurons, linalool upregulated protein expression of SirT1, γ-Aminobutyric acid type A-α1 (GABAA-α1), and γ-Aminobutyric acid type B (GABAB). In PD-like mice, linalool attenuated the loss of dopamine neurons in SNpc. Linalool improved the motor and nonmotor behavioral deficits and muscle strength of PD-like mice. These findings suggest that linalool potentially protects dopaminergic neurons and improves the impairment symptoms of PD.

Thyroid cancer (TC) stands out as the most prevalent endocrine malignancy globally, with a steadily increasing incidence. Its clinical manifestations include enlarged thyroid nodules, dysphagia, enophthalmos, and various other symptoms. While standard treatments such as thyroidectomy and radioiodine therapy effectively manage most cases of differentiated thyroid cancers (DTC), some recurrent cases of DTC or those involving poorly differentiated thyroid cancers (PDTC) require specialized interventions. However, existing drugs primarily address symptom management without offering a curative solution. Therefore, the development of a new therapeutic agent for these challenging cases is of utmost importance. Flavopereirine, derived from Geissospermum vellosii, has demonstrated promise as a potential anti-cancer agent across various human cancers. However, its specific anti-cancer effects on human thyroid cancer (TC) have remained unclear. Therefore, this study aims to investigate the anti-cancer activity of flavopereirine in human TC. The research findings revealed that flavopereirine effectively hinders the growth of human TC cells, induces cell cycle arrest, promotes apoptosis, and modulates autophagy. Moreover, the study delved into the underlying mechanisms by which flavopereirine influenced signaling pathways. To validate these anti-cancer effects, an in vivo zebrafish model was utilized, confirming the efficacy of flavopereirine against human TC cells. In summary, this study establishes that flavopereirine exhibits notable anti-human TC activities, positioning it as a promising therapeutic candidate for the treatment of human thyroid cancer.

Induction motors (IMs) have been commonly applied to industrial fields since the past decades; thus, developing advanced fault diagnosis methods becomes vital for IM applications. This study proposed an online fault diagnosis system for IMs based on the Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) algorithms to reduce the additional repair costs and prevent unexpected downtime. It focused on detecting healthy three-phase IMs and five common fault conditions of the IMs, involving broken rotor bars, rotor unbalance, and composite faults with short-circuited stator windings that combined two or three types of the faults, for practical purposes. The experimental results show that the model performance improved by 15% over the default model when train-test split ratios, feature selection, and hyperparameter optimization, notably in XGBoost, are considered. The proposed XGBoost model enables a high accuracy of 96.06% for RF to perform a motor fault diagnosis under six different motor conditions. Furthermore, the execution time required by the proposed fault diagnosis system is 57% less than the time required by existing motor fault diagnosis methods. These results successfully demonstrate the effectiveness of the methods proposed in this study for online motor diagnosis.

Hepatocellular carcinoma (HCC), the primary form of liver cancer, is the third leading cause of cancer-related death globally. Hernandonine is a natural alkaloid derived from Hernandia nymphaeifolia that has been shown to exert various biological functions. In a previous study, hernandonine was shown to suppress the proliferation of several solid tumor cell lines without affecting normal human cell lines. However, little is known about the effect of hernandonine on HCC. Therefore, this study aimed to investigate the effect and mechanism of hernandonine on HCC in relation to autophagy. We found that hernandonine inhibited HCC cell growth in vitro and in vivo. In addition, hernandonine elicited autophagic cell death and DNA damage in HCC cells. RNA-seq analysis revealed that hernandonine upregulated p53 and Hippo signaling pathway-related genes in HCC cells. Small RNA interference of p53 resulted in hernandonine-induced autophagic cell death attenuation. However, inhibition of YAP sensitized HCC cells to hernandonine by increasing the autophagy induction. This is the first study to illustrate the complex involvement of p53 and YAP in the hernandonine-induced autophagic cell death in human HCC cells. Our findings provide novel evidence for the potential of hernandonine as a therapeutic agent for HCC treatment.

BackgroundStudies have confirmed that osteoporosis has been considered as one of the complications of diabetes, and the health hazards to patients are more obvious. This study is mainly based on the Taiwan National Health Insurance Database (TNHID). Through the analysis of TNHID, it is shown that the combined treatment of traditional Chinese medicine (TCM) medicine in patients of diabetes with osteoporosis (T2DOP) with lower related risks.MethodsAccording to the study design, 3131 patients selected from TNHID who received TCM treatment were matched by 1-fold propensity score according to gender, age, and inclusion date as the control group. Cox proportional hazards analyzes were performed to compare fracture surgery, hospitalization, and all-cause mortality during a mean follow-up from 2000 to 2015.ResultsA total of 1055/1469/715 subjects (16.85%/23.46%/11.42%) had fracture surgery/inpatient/all-cause mortality of which 433/624/318 (13.83%/19.93%/10.16%) were in the TCM group) and 622/845/397 (19.87%/26.99%/12.68%) in the control group. Cox proportional hazards regression analysis showed that subjects in the TCM group had lower rates of fracture surgery, inpatient and all-cause mortality (adjusted HR = 0.467; 95% CI = 0.225-0.680, P<0.001; adjusted HR = 0.556; 95% CI = 0.330-0.751, P<0.001; adjusted HR = 0.704; 95% CI = 0.476-0.923, P = 0.012). Kaplan-Meier analysis showed that the cumulative risk of fracture surgery, inpatient and all-cause mortality was significantly different between the case and control groups (all log-rank p<0.001).ConclusionThis study provides longitudinal evidence through a cohort study of the value of integrated TCM for T2DOP. More research is needed to fully understand the clinical significance of these results.

IntroductionIntestinal ischemia and reperfusion (IIR) injury is closely associated with oxidative stress. Evidence shows that oral supplementation with glutamine and citrulline alleviates IIR-induced jejunal damage. We investigated the effects of a combination of glutamine, citrulline, and antioxidant vitamins on IIR-induced jejunal damage, oxidative stress, and inflammation.MethodMale Wistar rats that underwent 60 min of superior mesenteric artery occlusion were orally administered glutamine plus citrulline (GC), vitamin C plus E (CE), or a combination of GC and CE 15 min before and 3, 9, and 21 h after reperfusion. Healthy rats without IIR were used as controls.ResultsAfter reperfusion for 24 h, rats with IIR showed lower levels of red blood cells, hemoglobin, serum glucose, and jejunal DNA and increased white blood cell counts compared to controls (1-way ANOVA with the least significant difference, P < 0.05). The IIR-induced decrease in serum albumin and increase in plasma interleukin-6 and jejunal thiobarbituric acid-reactive substances (TBARS) were significantly reversed by GC and/or CE. The results of the 2-way ANOVA indicated that GC was the main factor that increased jejunal villus height and muscularis DNA, and CE was the main factor that increased jejunal muscularis protein and decreased jejunal proinflammatory cytokine levels and myeloperoxidase activity. In addition, GC and CE are the main factors that decrease plasma proinflammatory cytokine levels and the jejunal apoptotic index.ConclusionOral post-treatment supplementation with glutamine and citrulline, combined with vitamins C and E, may alleviate IIR-induced oxidative stress, inflammation, and jejunal damage.

Background Oral squamous cell carcinoma (OSCC) is a frequently occurring type of head and neck cancer with a high mortality and morbidity rate. Rhopaloic acid A (RA), a terpenoid derived from sponges, has demonstrated a promising anti-tumor activity, but its effectiveness for treating OSCC remains unknown. Purpose The aim of this study was to investigate whether RA inhibits the growth of OSCC. Methods Cell viability was evaluated using CCK-8 assays in OSCC cells (Ca9-22, HSC-3 and SAS) and in normal cells (HGF-1) treated with RA. DAPI staining, AO staining, JC-1 staining and immunofluorescence were used to determine apoptosis, mitochondrial membrane potential and autophagy in RA-treated OSCC cells. Protein expression levels were determined by western blotting. Furthermore, the anti-tumor effect of RA was confirmed in vivo using a zebrafish oral cancer xenotransplantation model. Results OSCC cells had a significantly reduced viability after RA treatment, but normal cells were not affected. Treatment with RA caused chromatin condensation in OSCC cells, which increased their expression of autophagy- and apoptosis-related proteins. Furthermore, RA caused mitochondrial damage and increased autophagosome formation. Mitophagy was also induced by RA through the JNK/BNIP3/Nix/LC3B pathway. The JNK inhibitor SP600125 prevented both RA-mediated cell death and mitophagy of OSCC cells. A zebrafish xenograft model demonstrated that RA inhibits OSCC growth. Conclusion In conclusion, RA showed a potent anticancer activity in in vitro and in in vivo oral cancer models by promoting mitochondrial damage-induced apoptosis and mitophagy, which suggests that RA may be useful as a novel and effective treatment for OSCC.

Marine antimicrobial peptides have been demonstrated in numerous studies to possess anti-cancer properties. This research investigation aimed to explore the fundamental molecular mechanisms underlying the antitumor activity of Tilapia piscidin 4 (TP4), an antimicrobial peptide, in human bladder cancer. TP4 exhibited a remarkable inhibitory effect on the proliferation of bladder cancer cells through cell cycle arrest at the G2/M phase. Additionally, TP4 upregulated the expression of cleaved caspase-3, caspase-9, and PARP, leading to the activation of apoptotic pathways in bladder cancer cells. TP4 exhibit a marked rise in mitochondria reactive oxygen species, leading to the subsequent loss of potential for the mitochondrial membrane. Furthermore, the inhibition of mitochondrial oxidative phosphorylation resulted in a decrease in downstream ATP production. Meanwhile, TP4-treated bladder cancer cells showed an increase in Bax and ERK but a decrease in SIRT1, PGC-1 alpha, and Bcl2. ERK activation, SIRT1/PGC-1 alpha-axis, and TP4-induced apoptosis were all significantly reversed by the ERK inhibitor SCH772984. Finally, the inhibitory effect of TP4 on tumor growth has been confirmed in a zebrafish bladder cancer xenotransplantation model. These findings suggest that TP4 may be a potential agents for human bladder cancer through apoptosis induction, ERK activation, and the promotion of SIRT1-mediated signaling pathways.