Background/Objectives: The relationship between metabolic syndrome (MetS) and mental health disorders has gained increasing attention, yet evidence from large population-based studies remains limited. This study aimed to examine the association between MetS and psychiatric morbidity in a nationwide Taiwanese adult cohort using a cross-sectional design. Methods: Between 2008 and 2019, a total of 121,575 adults aged 30-70 years were recruited from 29 community health screening stations across Taiwan. Demographic characteristics, lifestyle factors, medical history, and physical measurements were collected. Participants were classified as having MetS or not according to standard criteria. Psychiatric morbidity was defined as depressive and/or anxiety burden identified by validated screening instruments (Patient Health Questionnaire-2 score ≥3 or Generalized Anxiety Disorder-2 score ≥3) or self-reported physician-diagnosed depression. Multivariable logistic regression analyses were performed to evaluate the association between MetS and psychiatric morbidity after adjustment for potential confounders. Results: Psychiatric morbidity was identified in 1366 of 27,349 participants with MetS (5.0%) and in 4047 of 94,226 participants without MetS (4.3%). The prevalence of psychiatric morbidity was higher among participants with MetS than those without MetS (5.0% vs. 4.3%). After multivariable adjustment, MetS was significantly associated with increased odds of psychiatric morbidity (adjusted odds ratio [aOR] 1.235; 95% confidence interval [CI] 1.152-1.325). Among individual MetS components, hypertension, increased waist circumference, and hypertriglyceridemia were independently associated with higher odds of psychiatric morbidity. Conclusions: MetS was associated with a modest increase in psychiatric morbidity in this large Taiwanese community cohort. Because of the cross-sectional design, causal inference is limited. Future longitudinal studies are needed to clarify the direction of association and underlying mechanisms linking metabolic and mental health conditions.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger N-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.

Mitochondrial dysfunction and energy imbalance caused by chemotherapy are key contributors to skeletal muscle atrophy, which severely impacts the quality of life in cancer patients. Paclitaxel, a commonly used chemotherapeutic agent, is known to promote muscle wasting and cellular senescence, largely by impairing mitochondrial function. In this study, we investigated the protective role of loganin, a naturally occurring iridoid glycoside, in preventing paclitaxel-induced damage to skeletal muscle cells. Using C2C12 cells, we assessed whether loganin could counteract the harmful effects of paclitaxel. Our results demonstrated that loganin significantly improved cell viability and protected mitochondrial function, as reflected by better preservation of mitochondrial DNA content, membrane potential, and ATP production, while further enhancing mitochondrial biogenesis through upregulation of PGC-1α, TFAM, and NRF1. In parallel, loganin activated metabolic regulators SIRT1 and AMPK, while restoring PDK4 expression, suggesting improved energy regulation. Additionally, glycogen levels and myotube morphology were maintained, alongside sustained myosin heavy chain expression. Loganin effectively reduced both cellular and mitochondrial reactive oxygen species and increased antioxidant defenses, including superoxide dismutase activity and glutathione levels. Notably, it also suppressed paclitaxel-induced senescence and inflammation, as shown by decreased p21 expression, reduced NFκB phosphorylation, and lower levels of Cdkn1a and Il6 as well as reduced SA-β-gal staining. Overall, our findings demonstrate that loganin offers comprehensive protection against paclitaxel-induced skeletal muscle injury by preserving mitochondrial function, supporting metabolic homeostasis, reducing oxidative stress, and limiting senescence. These results highlight the potential of loganin as a preventive adjunctive agent to mitigate chemotherapy-related muscle toxicity.

Introduction: Depression and anxiety are major global public health concerns associated with various negative outcomes. Secondhand smoke (SHS) exposure has been proposed as a potential risk factor. We aimed to investigate whether SHS exposure is associated with psychiatric morbidity in a large population-based cohort study. Methods: Data were derived from the Taiwan Biobank between December 2008 and December 2019, including over 120,000 noncancer participants aged 30–70 years. The cross-sectional analysis involved 88,510 never-smokers, while a longitudinal cohort of 19,575 participants with follow-up validated findings. SHS exposure was assessed through self-reported questionnaires, categorizing participants into exposure and nonexposure groups. Psychiatric morbidity was defined by either a self-reported history of diagnosed depression, a Patient Health Questionnaire 2-item (PHQ-2) score ≥3, or a Generalized Anxiety Disorder 2-item (GAD-2) score ≥3. Logistic regression adjusted for demographics and health factors analyzed the associations. Results: In the cross-sectional analysis, 8% reported SHS exposure, which was significantly associated with a higher prevalence of psychiatric morbidity (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.12–1.42). Longitudinal analysis (mean follow-up: 47 months) supported these findings, with SHS exposure linked to an elevated risk of psychiatric morbidity (OR = 1.37, 95% CI = 1.07–1.74). Notably, SHS exposure ≥1 h/week nearly doubled the risk (OR = 1.97, 95% CI = 1.46–2.67). Conclusion: SHS exposure significantly increases the risk of psychiatric morbidity. Public health efforts are essential to reduce SHS exposure and address its mental health impacts.

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.

BACKGROUND:Methylglyoxal (MGO) is a potent precursor of glycative stress that leads to oxidative stress and muscle atrophy in diabetes. Spatheliachromen (FPATM-20), derived from Ficus pumila var. awkeotsang, exhibited potential antioxidant activity. PURPOSE:This study aimed to evaluate the potential impact and underlying mechanisms of FPATM-20 on MGO-induced myotube atrophy and mitochondrial dysfunction in mouse skeletal C2C12 myotubes. METHODS:Atrophic and antioxidant factors were evaluated using immunofluorescence, enzyme-linked immunosorbent assay, and western blotting. Mitochondrial function was assessed using the ATP assay and Seahorse Cell Mito Stress Test. The glycogen content was determined using periodic acid-Schiff staining. Molecular docking was performed to determine the interaction between FPATM-20 and Keap1. RESULTS:In myotubes treated with MGO, FPATM-20 activated the Nrf2 pathway, reduced ROS levels, enhanced antioxidant defense, and increased glycogen content. FPATM-20 improved myotube viability and size, upregulated myosin heavy chain (MyHC) expression, modulated ubiquitin-proteasome molecules (nuclear FoxO3a, atrogin-1, MuRF-1, and p62/SQSTM1), and inhibited apoptosis (Bax/Bcl-2 ratio and cleaved caspase 3). Moreover, FPATM-20 restored mitochondrial function, including mitochondrial membrane potential, mitochondrial oxygen consumption rate, and mitochondrial biogenesis pathway (nuclear PGC-1α/TFAM/FNDC5). The inhibition of Nrf2 with ML385 reversed the effects of FPATM-20 on MGO. Furthermore, molecular docking confirmed the binding of FPATM-20 to Keap1, a suppressor of Nrf2, showing the crucial role of Nrf2 in protective effects. CONCLUSIONS:FPATM-20 protects myotubes from MGO toxicity by activating the Nrf2 antioxidant defense, reducing protein degradation and apoptosis, and enhancing mitochondrial function. Thus, FPATM-20 may be a novel agent for preventing skeletal muscle atrophy.

Background and aim:Skeletal muscle is the largest organ of the human body. It affects body metabolism and cooperates with other organs to maintain various physiological functions. Gan-Mai-Da-Zao-Tang (, gān mài dà zǎo tāng, GMDZ) is a traditional Chinese medicine consisting of licorice, wheat, and jujube. GMDZ is commonly used to treat anxiety and depression. Increasing evidence shows a correlation exists between sarcopenia and depression. Muscle wasting, particularly in older individuals, increases the risk of depressive symptoms. The study aims to explore the effects of GMDZ water extract (WE) on age-induced muscle wasting and mitochondrial dysfunction in 25-week-old and 82-week-old mice. Experimental procedure:Exercise capacity was assessed through locomotor activity, rotarod performance, and grid-hanging tests. Grip strength was measured to assess muscle strength, while histological analysis and immunofluorescence staining were used to evaluate muscle mass and myofiber cross-sectional area. Protein expression, mRNA, and ATP levels were determined using western blots, real-time PCR, and ATP bioluminescence assays. Results and conclusion:GMDZ-WE significantly improved motor performance, grip strength, muscle mass, and myofiber cross-sectional area in aging mice. These enhancements were associated with increased MyHC expression and the IGF-1R/Akt protein synthesis pathway in skeletal muscle. In addition, GMDZ-WE decreased age-related protein degradation and inflammatory signaling, enhanced mitochondrial biogenesis signaling, increased GSH levels, SOD activity, and reduced lipid oxidation in the skeletal muscle of aging mice. In conclusion, GMDZ-WE reduces age-related skeletal muscle wasting, motor impairment, oxidative stress, inflammation, and mitochondrial dysfunction, demonstrating anti-aging potential on skeletal muscles.

Guilu Erxian Jiao (GEJ) is a commonly used nutritional supplement due to its rich content of amino acids. It is also a traditional herbal medicine for improving degenerative joint. This study aimed to investigate the effect and mechanism of GEJ water extract (GEJ-WE) on skeletal muscle in C2C12 myotubes and C57BL/6J mice. Analysis of GEJ-WE were performed by high-performance liquid chromatography fingerprinting with chemical standards. Protein expression, mRNA level, glycogen content, mitochondria activity and ATP level were evaluated by western blots, real-time PCR, PAS staining, MTT and ATP bioluminescence assay, respectively. Skeletal muscle strength was evaluated by grip strength. Skeletal muscle volume, mass and fiber types were evaluated by micro computed tomography, histological analysis and immunofluorescence staining, respectively. Motor function was evaluated by rotarod performance and locomotor activity. In C2C12 myotubes, GEJ-WE significantly enhanced myogenic differentiation and myotube growth, protein synthesis signaling IGF-1/IGF-1R/IRS-1/Akt, Glut4 translocation, glycogen content, mitochondrial biogenesis signaling PGC-1α/NRF1/TFAM, mitochondrial activity and ATP production. However, IGF-1R antagonist AG1024 and PI3K inhibitor wortmannin reduced GEJ-WE-induced protein expression of MyHC, p-Akt, p-mTOR and p-GSK-3β, Glut4 translocation and glycogen content. In C57BL/6J mice, GEJ-WE not only upregulated protein synthesis and mitochondrial biogenesis signaling, but it also increased muscle volume, relative muscle weight, cross-sectional area of myofibers, glycogen content and transition of fast-to-slow type fibers of skeletal muscles. Moreover, GEJ-WE enhanced grip strength and motor activity of mice. In conclusion, the upregulation of protein synthesis, myogenic differentiation, glucose homeostasis, mitochondrial biogenesis and slow-twitch fibers contributes to the mechanisms of GEJ-WE on the enhancement of skeletal muscle mass and motor function.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect, with no approved therapy for prevention or treatment. Here, we aimed to establish a high-content image platform based on the neurite outgrowth of dorsal root ganglia (DRG)-derived neuron cells for the discovery of neuroprotective agents against paclitaxel-induced CIPN. ND7/23 cells, an immortalized hybrid DRG cell line, were maturely differentiated by induction with nerve growth factor and upregulation of intracellular cAMP levels. High-content image analyses of the neurofilament-stained neurite network showed that paclitaxel disrupted the neurite outgrowth of well-differentiated ND7/23 DRG neuron cells, recapitulating characteristic effects of paclitaxel on primary cultured DRG neurons. This process coincided with the upregulated activity of store-operated Ca2+ entry, similar to those found in rodent models of paclitaxel-induced CIPN. The previously identified neuroprotective agents, minoxidil and 8-Br-cyclic adenosine monophosphate ribose (8-Br-cADPR), attenuated the reduction in total neurite outgrowth in paclitaxel-damaged ND7/23 cells. Additionally, the total neurite outgrowth of welldifferentiated ND7/23 cells was concentration-dependently reduced by the neurotoxic chemotherapeutic agents, oxaliplatin and bortezomib, but not the less neurotoxic 5-fluorouracil. We demonstrated that highcontent analyses of neurite morphology in well-differentiated DRG neuron-derived cells provide an effective, reproducible, and high-throughput strategy for developing therapeutics against CIPN.

Inflammation is a major cause of skeletal muscle atrophy in various diseases. 2-Hydroxy-4′-methoxychalcone (AN07) is a chalcone-based peroxisome-proliferator-activated receptor gamma (PPARγ) agonist with various effects, such as antiatherosclerosis, anti-inflammation, antioxidative stress, and neuroprotection. In this study, we examined the effects of AN07 on protein homeostasis pathway and mitochondrial function in inflammation-associated myotube atrophy induced by lipopolysaccharides (LPS). We found that AN07 significantly attenuated NF-κB activation, inflammatory factors (TNF-α, IL-1β, COX-2, and PGE2), Nox4 expression, and reactive oxygen species levels in LPS-treated C2C12 myotubes. Moreover, AN07 increased SOD2 expression and improved mitochondrial function, including mitochondrial membrane potential and mitochondrial oxygen consumption rate. We also demonstrated that AN07 attenuated LPS-induced reduction of myotube diameter, MyHC expression, and IGF-1/IGF-1R/p-Akt-mediated protein synthesis signaling. Additionally, AN07 downregulated LPS-induced autophagy–lysosomal protein degradation molecules (LC3-II/LC3-I and degraded p62) and ubiquitin–proteasome protein degradation molecules (n-FoxO1a/MuRF1/atrogin-1). However, the regulatory effects of AN07 on protein synthesis and degradation signaling were inhibited by the IGF-1R inhibitor AG1024 and the PI3K inhibitor wortmannin. In addition, the PPARγ antagonist GW9662 attenuated the effects of AN07 against LPS-induced inflammation, oxidation, and protein catabolism. In conclusion, our findings suggest that AN07 possesses protective effects on inflammation-induced myotube atrophy and mitochondrial dysfunction.

Hyperbaric oxygen therapy (HBOT) has been suggested as a potential adjunctive therapy for Parkinson’s disease (PD). PD is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The aim of this study was to investigate the protective mechanisms of HBOT on neurons and motor function in a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and 1-methyl-4-phenylpyridinium (MPP+)-mediated neurotoxicity in SH-SY5Y cells on the potential protective capability. In vivo: male C57BL/6 mice were randomly divided into three groups: control, MPTP group and MPTP+HBOT group. The MPTP-treated mice were intraperitoneally received MPTP (20 mg/kg) four times at 2 h intervals within a day. The day after MPTP treatment, MPTP+HBOT mice were exposed to hyperbaric oxygen at 2.5 atmosphere absolute (ATA) with 100% oxygen for 1 h once daily for 7 consecutive days. In vitro: retinoic acid (RA)-differentiated SH-SY5Y cells were treated with MPP+ for 1 h followed by hyperbaric oxygen at 2.5 ATA with 100% oxygen for 1 h. The results showed that MPTP induced a significant loss in tyrosine hydroxylase (TH)-positive neurons in the SNpc of mice. HBOT treatment significantly increased the number of TH-positive neurons, with enhanced neurotrophic factor BDNF, decreased apoptotic signaling and attenuated inflammatory mediators in the midbrain of MPTP-treated mice. In addition, MPTP treatment decreased the locomotor activity and grip strength of mice, and these effects were shown to improve after HBOT treatment. Furthermore, MPTP decreased mitochondrial biogenesis signaling (SIRT-1, PGC-1α and TFAM), as well as mitochondrial marker VDAC expression, while HBOT treatment was shown to upregulate protein expression. In cell experiments, MPP+ reduced neurite length, while HBOT treatment attenuated neurite retraction. Conclusions: the effects of HBOT in MPTP-treated mice might come from promoting mitochondrial biogenesis, decreasing apoptotic signaling and attenuating inflammatory mediators in the midbrain, suggesting its potential benefits in PD treatment.

Objectives The relationship between metabolic syndrome (MetS) components and leukocyte telomere length (LTL) attrition in major depressive disorder (MDD) remains unclear. Methods We recruited 70 MDD patients (mean age: 44.6 years, 60.0% female) and 51 age- and sex-matched controls (mean age: 41.2 years, 68.6% female) to examine the associations of MetS components and LTL. Five MetS components-waist circumference, systolic/diastolic blood pressure, serum levels of fasting glucose, high-density lipoprotein cholesterol (HDL-C), and triglycerides-were assessed. LTL was measured through quantitative polymerase chain reaction. Results MDD had higher prevalence of MetS (34.3 vs. 17.6%, p=.042), low HDL-C (25.7 vs. 7.8%, p=.009) and shorter LTL (-0.038 +/- 0.169 vs. 0.033 +/- 0.213, p=.042). Regression analysis revealed that MDD (p=.046) and age (p=.003) associated with LTL, while a significant interaction effect of group (MDD vs. controls) x HDL-C (p=.037) was observed. Post-hoc analysis showed MDD with low HDL-C had greater LTL attrition than controls without low HDL-C (p=.020). In MDD, HDL-C dysregulation negatively correlated with LTL (p=.010); but no significance after Bonferroni correction. Conclusions HDL-C may be involved in accelerated ageing process regarding metabolic disturbance in MDD only. The relationship merits prospective investigations with larger sample size for clarification.

Kynurenic acid (KYNA, 4-oxoquinoline-2-carboxylic acid), an intermediate of the tryptophan metabolism, has been recognized to exert different neuroactive actions; however, the need of how it or its aminoalkylated amide derivative N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide (KYNA-A4) exerts any effects on ion currents in excitable cells remains largely unmet. In this study, the investigations of how KYNA and other structurally similar KYNA derivatives have any adjustments on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were performed by patch-clamp technique. KYNA or KYNA-A4 increased the amplitude of M-type K+ current (IK(M)) and concomitantly enhanced the activation time course of the current. The EC50 value required for KYNA- or KYNA-A4 -stimulated IK(M) was yielded to be 18.1 or 6.4 μM, respectively. The presence of KYNA or KYNA-A4 shifted the relationship of normalized IK(M)-conductance versus membrane potential to more depolarized potential with no change in the gating charge of the current. The voltage-dependent hysteretic area of IK(M) elicited by long-lasting triangular ramp pulse was observed in GH3 cells and that was increased during exposure to KYNA or KYNA-A4. In cell-attached current recordings, addition of KYNA raised the open probability of M-type K+ channels, along with increased mean open time of the channel. Cell exposure to KYNA or KYNA-A4 mildly inhibited delayed-rectifying K+ current; however, neither erg-mediated K+ current, hyperpolarization-activated cation current, nor voltage-gated Na+ current in GH3 cells was changed by KYNA or KYNA-A4. Under whole-cell, current-clamp recordings, exposure to KYNA or KYNA-A4 diminished the frequency of spontaneous action potentials; moreover, their reduction in firing frequency was attenuated by linopirdine, yet not by iberiotoxin or apamin. In hippocampal mHippoE-14 neurons, the addition of KYNA also increased the IK(M) amplitude effectively. Taken together, the actions presented herein would be one of the noticeable mechanisms through which they modulate functional activities of excitable cells occurring in vivo.

Background and PurposeIncreasing evidence suggests systemic inflammation‐caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti‐inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation‐induced skeletal muscle atrophy.Experimental ApproachThe effects of triptolide on skeletal muscle atrophy were investigated in LPS‐treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro‐CT and grip strength, respectively. Locomotor activity was measured using the open field test.KEY RESULTSTriptolide (10–100 fM) up‐regulated protein synthesis signals (IGF‐1/p‐IGF‐1R/IRS‐1/p‐Akt/p‐mTOR) and down‐regulated protein degradation signal atrogin‐1 in C2C12 myotubes. In LPS (100 ng·ml−1)‐treated C2C12 myotubes, triptolide up‐regulated MyHC, IGF‐1, p‐IGF‐1R, IRS‐1 and p‐Akt. Triptolide also down‐regulated ubiquitin‐proteasome molecules (n‐FoxO3a/atrogin‐1/MuRF1), proteasome activity, autophagy‐lysosomal molecules (LC3‐II/LC3‐I and Bnip3) and inflammatory mediators (NF‐κB, Cox‐2, NLRP3, IL‐1β and TNF‐α). However, AG1024, an IGF‐1R inhibitor, suppressed triptolide‐mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS‐treated C2C12 myotubes. In LPS (1 mg·kg−1, i.p.)‐challenged mice, triptolide (5 and 20 μg·kg−1·day−1, i.p.) decreased plasma TNF‐α levels and it increased skeletal muscle volume, cross‐sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion.Conclusions and ImplicationsThese findings reveal that triptolide prevented LPS‐induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.

The relationship between preexisting major psychiatric disorders and outcomes of spine surgery for degenerative thoracic/lumbar disease remains unclear. A 5% subset of inpatients was randomly selected from the Taiwan National Health Insurance Research Database. A total of 10,109 inpatients aged 18 years or over with degenerative thoracic/lumbar disease and underwent spine surgery met inclusion criteria. Major psychiatric disorders diagnosed by psychiatrists preceding index surgery, including anxiety disorder, depression disorder, bipolar disorder, schizophrenia and dementia, were identified. The prevalence of psychiatric disorders, and their differential risks on in-hospital and post-discharge outcomes were examined. 10.4% had major psychiatric disorders, of which depression (6.6%) and anxiety (4.9%) were most common. Logistic regression revealed increased risks of ventilator use in depression (OR = 1.62, 95% CI = 1.04–2.54, p < 0.05), extended hospitalization length in bipolar (OR = 1.77, 95% CI = 1.08–2.89, p < 0.05), and higher rehabilitation utilization in depression (OR = 1.25, 95% CI = 1.06–1.47, p < 0.01) and bipolar (OR = 1.69, 95% CI = 1.04–2.76, p < 0.05). Those patients with anxiety had a decreased risk of longer hospitalization duration (OR = 0.77, 95% CI = 0.60–0.98, p < 0.05), while those with dementia and schizophrenia had no change in risks. Preoperative recognition of major psychiatric disorders for risk and treatment assessment is suggested as people with preexisting depression or bipolar disorder have worse outcomes after spine surgery.

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (Ih) and membrane electroporation-induced current (IMEP). OXAL increased the amplitude or activation rate constant of Ih in a concentration-dependent manner with effective EC50 or KD values of 3.2 or 6.4 μM, respectively, in pituitary GH3 cells. The stimulation by this agent of Ih could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 μM) resulted in an approximately 11 mV rightward shift in Ih activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of IMEP elicited by large hyperpolarization in GH3 cells with an EC50 value of 1.3 μM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of IMEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (IMEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated Ih remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase IMEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of Ih and IMEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur.

UCL-2077 (triphenylmethylaminomethyl)pyridine) was previously reported to suppress slow afterhyperpolarization in neurons. However, the information with respect to the effects of UCL-2077 on ionic currents is quite scarce. The addition of UCL-2077 decreased the amplitude of erg-mediated K+ current (IK(erg)) together with an increased deactivation rate of the current in pituitary GH3 cells. The IC50 and KD values of UCL-2077-induced inhibition of IK(erg) were 4.7 and 5.1 μM, respectively. UCL-2077 (10 μM) distinctly shifted the midpoint in the activation curve of IK(erg) to less hyperpolarizing potentials by 17 mV. Its presence decreased the degree of voltage hysteresis for IK(erg) elicitation by long-lasting triangular ramp pulse. It also diminished the probability of the opening of intermediate-conductance Ca2+-activated K+ channels. In cell-attached current recordings, UCL-2077 raised the frequency of action currents. When KCNH2 mRNA was knocked down, a UCL-2077-mediated increase in AC firing was attenuated. Collectively, the actions elaborated herein conceivably contribute to the perturbating effects of this compound on electrical behaviors of excitable cells.

Chalcones belong to a class of biologically active polyphenolic natural products. As a result of their simple chemical nature, they are easily synthesized and show a variety of promising biological activities. 2-Hydroxy-4′-methoxychalcone (AN07) is a synthetic chalcone derivate with potential anti-atherosclerosis effects. In this study, we demonstrated the novel antioxidant, anti-inflammatory, and neuroprotective effects of AN07. In RAW 264.7 macrophages, AN07 attenuated lipopolysaccharide (LPS)-induced elevations in reactive oxygen species (ROS) level and oxidative stress via down-regulating gp91phox expression and stimulating the antioxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, which were accompanied by increased glutathione (GSH) levels. Additionally, AN07 attenuated LPS-induced inflammatory factors, including NO, inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and phosphorylated inhibitor of nuclear factor kappa B-alpha (p-IκBα) in RAW 264.7 macrophages. However, the effects of AN07 on promoting nuclear Nrf2 levels and decreasing COX-2 expressions were significantly abrogated by the peroxisome proliferator-activated receptor-γ (PPARγ) antagonist GW9662. In human dopaminergic SH-SY5Y cells treated with or without methylglyoxal (MG), a toxic endogenous by-product of glycolysis, AN07 up-regulated neurotrophic signals including insulin-like growth factor 1 receptor (IGF-1R), p-Akt, p-GSK3β, glucagon-like peptide 1 receptor (GLP-1R), and brain-derived neurotrophic factor (BDNF). AN07 attenuated MG-induced apoptosis by up-regulating the B-cell lymphoma 2 (Bcl-2) protein and down-regulating the cytosolic expression of cytochrome c. AN07 also attenuated MG-induced neurite damage via down-regulating the Rho-associated protein kinase 2 (ROCK2)/phosphorylated LIM kinase 1 (p-LIMK1) pathway. Moreover, AN07 ameliorated the MG-induced down-regulation of neuroprotective Parkinsonism-associated proteins parkin, pink1, and DJ-1. These findings suggest that AN07 possesses the potentials to be an anti-inflammatory, antioxidant, and neuroprotective agent

Background: Honokiol (HNK), a dimer of allylphenol obtained from the bark of Magnolia officinalis was demonstrated to exert an array of biological actions in different excitable cell types. However, whether or how this compound can lead to any perturbations on surface–membrane ionic currents remains largely unknown. Methods: We used the patch clamp method and found that addition of HNK effectively depressed the density of macroscopic hyperpolarization-activated cation currents (Ih) in pituitary GH3 cells in a concentration-, time- and voltage-dependent manner. By the use of a two-step voltage protocol, the presence of HNK (10 μM) shifted the steady-state activation curve of Ih density along the voltage axis to a more negative potential by approximately 11 mV, together with no noteworthy modification in the gating charge of the current. Results: The voltage-dependent hysteresis of Ih density elicited by long-lasting triangular ramp pulse was attenuated by the presence of HNK. The HNK addition also diminished the magnitude of deactivating Ih density elicited by ramp-up depolarization with varying durations. The effective half-maximal concentration (IC50) value needed to inhibit the density of Ih or delayed rectifier K+ current identified in GH3 cells was estimated to be 2.1 or 6.8 μM, respectively. In cell-attached current recordings, HNK decreased the frequency of spontaneous action currents. In Rolf B1.T olfactory sensory neurons, HNK was also observed to decrease Ih density in a concentration-dependent manner. Conclusions: The present study highlights the evidence revealing that HNK has the propensity to perturb these ionic currents and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is proposed to be a potential target for the in vivo actions of HNK and its structurally similar compounds.