Therapeutic efficacy of adrenergic agents on systemic and spinal hemodynamics in an acute cervical spinal cord injury rodent model.

BACKGROUND: Cervical spinal cord injury usually results in cardiorespiratory dysfunctions due to interruptions of the bulbospinal pathways innervating the cervical phrenic motoneurons and thoracic sympathetic preganglionic neurons. PURPOSE: The present study aimed to evaluate the therapeutic effects of adrenergic agents on systemic and spinal hemodynamics during acute cervical spinal cord injury. STUDY DESIGN: In vivo animal study. METHODS: The cardiorespiratory function and spinal cord blood flow and oxygenation level were monitored in response to cervical spinal cord contusion and intravenous infusion of three types of adrenergic agents (phenylephrine, dobutamine, and norepinephrine). RESULTS: Cervical spinal cord contusion resulted in immediate reduction of respiratory airflow, arterial blood pressure, and spinal cord blood flow. The arterial blood pressure and spinal cord blood flow remained lower than the pre-injury value in contused animals infused with saline at 60 min post-injury. Infusion of phenylephrine (500, 1000, and 2000 µg/kg) and norepinephrine (125, 250, and 500 µg/kg) significantly increased the arterial blood pressure, while only norepinephrine augmented the spinal cord blood flow. Conversely, dobutamine (1000 and 2000 µg/kg) reduced both arterial blood pressure and spinal cord blood flow. Notably, administration of adrenergic agents tended to increase spinal cord hemorrhage in contused animals. CONCLUSIONS: Infusion of norepinephrine can effectively maintain the blood pressure and improve spinal cord blood flow during acute spinal cord injury. CLINICAL SIGNIFICANCE: Norepinephrine may be a superior medicine for hemodynamic management; however, the potential hemorrhage should be considered when utilizing the vasopressor to regulate systemic and spinal hemodynamics at the acute injured stage.

Compositional effects on structural, electronic, elastic, piezoelectric and dielectric properties of GaInN alloys: a first-principles study.

We conduct a comprehensive theoretical analysis of wurtzite GaxIn1-xN ternary alloys, focusing on their structural, electronic, elastic, piezoelectric, and dielectric properties through rigorous first-principles calculations. Our investigation systematically explores the influence of varying Ga composition (x = 0%, 25%, 50%, 75%, 100%) on the alloy properties. Remarkably, we observe a distinctive non-linear correlation between the band gap and Ga concentration, attributable to unique slopes in the absolute positions of the valence band maximum and conduction band minimum with respect to Ga concentration. Our effective band structure analysis reveals the meticulous preservation of Bloch characters near band extrema, minimizing charge carrier scattering. Furthermore, we scrutinize deviations from linear Vegard-like dependence in elastic, piezoelectric, and dielectric constants. Additionally, our calculations encompass various optical properties, including absorption coefficient, reflectivity, refractive index, energy loss function, and extinction coefficient. We analyze their trends with photon energy, providing valuable insights into the optical behavior of GaxIn1-xN alloys. Our results, in excellent agreement with available experimental data, significantly contribute to a deeper understanding of the alloys' electronic properties. This study offers valuable insights that may illuminate potential applications of GaxIn1-xN alloys in diverse technological fields.

The protective effect and mechanism of piperazine ferulate in rats with 5/6 nephrectomy-caused chronic kidney disease.

Chronic kidney disease (CKD) is a type of chronic disease in which multiple factors are responsible for the structural and functional disorders of the kidney. Piperazine ferulate (PF) has anti-platelet and anti-fibrotic effects, and its mechanism of action remains to be elucidated. This study aimed to investigate the protective effect of PF against CKD in rats and to determine its mechanism of action. Network pharmacology was used to predict potential PF action targets in the treatment of CKD and to further validate them. A rat model of CKD was established; blood was collected, etc., for the assessment of the renal function; renal pathologic damage was examined using hematoxylin and eosin (HE) staining and Masson staining; changes in the levels of TGF-ß1 and α-SMA were determined with ELISA; EPOR, FN, and COL I expression were detected utilizing immunohistochemistry; and HIF-1α, HIF-2α, and EPO protein molecules were analyzed deploying western blotting. PF reduces Scr, BUN, and 24 h UP levels; decreases FN and COL I expression; and attenuates renal injury. Additionally, PF inhibited TGF-ß1 and stimulated the production of HIF-1α and HIF-2α, which downregulated α-SMA and upregulated EPO. PF attenuated the progression of the CKD pathology, and the mechanism of its action is possibly associated with the promotion of HIF-1α/HIF-2α/EPO production and TGF-ß1 reduction.

Exploring autistic adults' psychosocial experiences affecting beginnings, continuity and change in camouflaging over time: A qualitative study in Singapore.

LAY ABSTRACT: Over their lifetimes, many autistic people learn to camouflage (hide or mask) their autism-related differences to forge relationships, find work and live independently in largely non-autistic societies. Autistic adults have described camouflaging as a 'lifetime of conditioning . . . to act normal' involving 'years of effort', suggesting that camouflaging develops over an autistic person's lifetime and may start early on, in childhood or adolescence. Yet, we know very little about why and how autistic people start to camouflage, or why and how their camouflaging behaviours continue or change over time. We interviewed 11 Singaporean autistic adults (9 male, 2 female, 22-45 years old) who shared their camouflaging experiences. We found that autistic adults' earliest motivations to camouflage were largely related to the desire to fit in and connect with others. They also camouflaged to avoid difficult social experiences (such as being teased or bullied). Autistic adults shared that their camouflaging behaviours became more complex and that, for some, camouflaging became a part of their self-identity over time. Our findings suggest that society should not pathologise autistic differences, but instead accept and include autistic people, to reduce the pressure on autistic people to hide who they truly are.

Circadian-like patterns in electrochemical skin conductance measured from home-based devices: a retrospective study.

In this study, we investigated the potential of electrochemical skin conductance (ESC) measurements gathered from home-based devices to detect circadian-like patterns. We analyzed data from 43,284 individuals using the Withings Body Comp or Body Scan scales, which provide ESC measurements. Our results highlighted a circadian pattern of ESC values across different age groups and countries. Our findings suggest that home-based ESC measurements could be used to evaluate circadian rhythm disorders associated with neuropathies and contribute to a better understanding of their pathophysiology. However, further controlled studies are needed to confirm these results. This study highlights the potential of digital health devices to generate new scientific and medical knowledge.

Comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury in the rat.

Cervical spinal cord injury interrupts supraspinal pathways innervating thoracic sympathetic preganglionic neurons and results in cardiovascular dysfunction. Both respiratory and locomotor functions were also impaired due to damages of motoneuron pools controlling respiratory and forelimb muscles, respectively. However, no study has investigated autonomic and somatic motor functions in the same animal model. The present study aimed to establish a cervical spinal cord injury model to evaluate cardiorespiratory response and locomotor activity in unanesthetized rats. Cardiovascular response and respiratory behavior following laminectomy or cervical spinal contusion were measured using noninvasive blood pressure analyzer and plethysmography systems, respectively. Locomotor activity was evaluated by an open-field test and a locomotor rating scale. The results demonstrated that mean arterial blood pressure and heart rate were significantly reduced in contused rats compared with uninjured rats at the acute injured stage. Tidal volume was also significantly reduced during the acute and subchronic stages. Moreover, locomotor function was severely impaired, evidenced by decreasing moving ability and locomotor rating scores from the acute to chronic injured stages. Retrograde neurotracer results revealed that cervical spinal cord injury caused a reduction in number of phrenic and triceps motoneurons. Immunofluorescence staining revealed a significant attenuation of serotonergic, noradrenergic, glutamatergic, and GABAergic fibers innervating the thoracic sympathetic preganglionic neurons in chronically contused rats. These results revealed the pathological mechanism underlying the comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury. We proposed that this animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.NEW & NOTEWORTHY The present study establishes a preclinical rodent model to comprehensively investigate physiological functions under unanesthetized condition following cervical spinal cord contusion. The results demonstrated that cervical spinal cord contusion is associated with impairments in cardiovascular, respiratory, and locomotor function. Respiratory and forelimb motoneurons and neurochemical innervations of sympathetic preganglionic neurons were damaged following injury. This animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.

Transcriptomic analysis reveals the regulatory mechanism underlying the indirubin-mediated amelioration of dextran sulfate sodium-induced colitis in mice.

CONTEXT: Aryl hydrocarbon receptor (AhR) agonists are potential therapeutic agents for ulcerative colitis (UC). Indirubin (IDR), which is a natural AhR ligand approved for leukemia treatment, ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. However, the therapeutic mechanisms of IDR are unknown, limiting its application. OBJECTIVE: This study explores the therapeutic mechanisms of IDR in DSS-induced colitis using transcriptomic analysis. MATERIALS AND METHODS: Male BALB/c mice were categorized to six groups: normal, DSS model (2% DSS), IDR treatment (10, 20 and 40 mg/kg), and sulfasalazine (520 mg/kg) groups. The drugs were intragastrically administered for 7 consecutive days. The disease activity index (DAI) was recorded. After euthanasia, the colon length was measured, and histopathological examination, immunohistochemistry staining using F4/80, and colonic transcriptomic analysis were conducted. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting (WB) were conducted to verify our findings. RESULTS: Compared with DSS, IDR treatment decreased the DAI score by 64.9% and increased colon length by 26.2%. Moreover, it alleviated mucosal injury and reduced macrophage infiltration. Transcriptomic analysis identified several downregulated genes (Igkvs and Nlrp3), as well as Nlrp3/Il1ß and hemoglobin gene networks, after IDR treatment. The abundances of NF-κB p65, NLRP3, IL-1ß, and HBA decreased by 69.1, 59.4, 81.1, and 83.0% respectively, after IDR treatment. DISCUSSION AND CONCLUSION: Apart from the well-documented NF-κB signalling pathway, IL-17A, and NLRP3-IL-1ß, the suppression of haemoglobin-induced lipid peroxidation could be a previously unknown mechanism of IDR. Our study can help improve its application for UC treatment.

Echocardiographic evaluation of the effect of dapagliflozin on epicardial adipose tissue and left ventricular systolic function in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Epicardial adipose tissue (EAT) is associated with cardiovascular disease, and sodium-glucose cotransporter-2 inhibitors (SGLT-2I) have been reported to reduce the occurrence of cardiovascular events. This study was designed to investigate the effect of an SGLT-2 inhibitor (dapagliflozin) on EAT and left ventricular (LV) systolic function in type 2 diabetes mellitus (T2DM) patients during a 6-month follow-up. METHODS: Twenty-seven T2DM patients who received dapagliflozin for the first time were enrolled in this study to measure EAT thickness and evaluate LV function before and after 6 months of SGLT-2 administration. The thickness of EAT was measured as the echo-free space between the free wall of the right ventricle and the visceral layer of the pericardium at end-systole by echocardiography. LV systolic function was evaluated by LV global longitudinal strain (LV GLS) obtained through two-dimensional speckle tracking echocardiography (2D-STE) technology. RESULTS: After a 6-month follow-up, twenty-five patients completed this study. The values of EAT thickness, HbA1c, body weight, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly reduced, while the LV GLS value was significantly increased. Moreover, the increase in LV GLS was independently associated with the reduction in EAT thickness, HbA1c, weight, and SBP (all p < 0.05). CONCLUSIONS: Dapagliflozin can reduce EAT thickness and improve LV systolic function in T2DM patients. 2D-STE can be used for the early evaluation of the beneficial effect of dapagliflozin on LV systolic function. The improvement in LV systolic function is independently associated with a reduction in EAT thickness.

Pitfalls of hip hop pedagogy: Re-examining and questioning the definition.

Recently, hip-hop pedagogy or Hip-Hop Based Education (HHBE) have become buzz words in the academic and public debate around hip-hop. However, we found that most definitions of hip-hop pedagogy are missing the concept of pedagogy itself. One consequence of failing to adequately explain the concept of pedagogy is that it may lead future hip-hop researchers, students, and teachers inadvertently to disseminate misinformation or foster unclear thinking by using "hip-hop pedagogy" in inaccurate or vague ways. For these reasons, it is important to have a shared understanding of hip-hop pedagogy. In this article, we present three updated, expanded definitions of hip-hop pedagogy with the potential for widespread acceptance. These definitions aim to convey in the simplest terms what hip-hop pedagogy is for the purpose of informing educators and preparing them to use data.

20(S)-protopanaxatriol inhibited D-galactose-induced brain aging in mice via promoting mitochondrial autophagy flow.

Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C. A. Meyer exerted obvious memory-enhancing and antiaging effects, and the simpler the structure of ginsenosides, the better the biological activity. In this work, we aimed to explore the therapeutic effect and underlying molecular mechanism of 20(S)-protopanaxatriol (PPT), the aglycone of panaxatriol-type ginsenosides, by establishing D-galactose (D-gal)-induced subacute brain aging model in mice. The results showed that PPT treatment (10 and 20 mg/kg) for 4 weeks could significantly restore the D-gal (800 mg/kg for 8 weeks)-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Meanwhile, PPT also significantly reduced the histopathological changes caused by D-gal exposure. Moreover, PPT could increase TFEB/LAMP2 protein expression to promote mitochondrial autophagic flow. Importantly, the results from molecular docking showed that PPT had good binding ability with LAMP2 and TFEB, suggesting that TFEB/LAMP2 might play an important role in PPT to alleviate D-gal-caused brain aging.

Platycodin D stimulates AMPK activity to inhibit the neurodegeneration caused by reactive oxygen species-induced inflammation and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) was considered to be a neurodegenerative disease that caused cognitive impairment. Reactive Oxidative stress (ROS) was considered to be one of a major cause of the onset and progression of AD. Platycodin D (PD), a representative saponin from Platycodon grandiflorum, has conspicuous antioxidant activity. However, whether PD could protect nerve cell against oxidative injury remains unknown. AIM OF STUDY: This study investigated the regulatory effects of PD on neurodegeneration caused by ROS. To determine whether PD could play its own antioxidant role in neuronal protection. MATERIALS AND METHODS: First, PD(2.5, 5 mg/kg) ameliorated the memory impairment induced by AlCl3 (100 mg/kg) combined with D-galactose (D-Gal) (200 mg/kg) in mice, using the radial arm maze (RAM) test, and neuronal apoptosis in the hippocampus was evaluated by hematoxylin and eosin staining (HE). Next, the effects of PD (0.5, 1, and 2 µM) on okadaic-acid (OA) (40 nM) -induced apoptosis and inflammation of HT22 cells were investigated. Mitochondrial ROS production was measured by fluorescence staining. The potential signaling pathways were identified through Gene Ontology enrichment analysis. The role of PD in regulating AMP-activated protein kinase (AMPK) was assessed using siRNA silencing of genes and an ROS inhibitor. RESULTS: In vivo, PD improved memory in mice, and recovered the morphological changes of brain tissue and nissl bodies. In vitro experiment, PD increased cell viability (p < 0.01; p < 0.05;p < 0.001), decreased apoptosis (p < 0.01), reduced excessive ROS and MDA, rised SOD and CAT content(p < 0.01; p < 0.05). Morover, it can block the inflammatory response caused by ROS. Be important, PD strengthen antioxidant ability by elevating AMPK activation both in vivo and in vitro. Furthermore, molecular docking suggested a good likelihood of PD-AMPK binding. CONCLUSION: AMPK activity is vital for the neuroprotective effect of PD, suggesting that PD may be a potential pharmaceutical agent to treat ROS-induced neurodegeneration.

Exploring the mechanism of active components from ginseng to manage diabetes mellitus based on network pharmacology and molecular docking.

A large body of literature has shown that ginseng had a role in diabetes mellitus management. Ginsenosides are the main active components of ginseng. But what ginsenosides can manage in diabetic are not systematic. The targets of these ginsenosides are still incomplete. Our aim was to identify which ginsenosides can manage diabetes mellitus through network pharmacology and molecular docking. To identify the targets of these ginsenosides. In this work, we retrieved and screened ginsenosides and corresponding diabetes mellitus targets across multiple databases. PPI networks of the genes were constructed using STRING, and the core targets were screened out through topological analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed by using the R language. Finally, molecular docking was performed after bioinformatics analysis for verification. Our research results showed that 28 ginsenosides in ginseng might be against diabetes mellitus by modulating related proteins such as VEGFA, Caspase 3, and TNF-α. Among the 28 ginsenosides, 20(R)-Protopanaxatriol, 20(R)-Protopanaxadiol, and Ginsenoside Rg1 might play a significant role. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis showed that the management of diabetes mellitus by ginsenosides may be related to the positive regulation of reactive oxygen metabolic processes, associated with the insulin signaling pathway, TNF signaling pathway, and AMPK signaling pathway. Molecular docking results and molecular dynamics simulation showed that most ginsenosides could stably bind to the core target, mainly hydrogen bonding and hydrophobic bond. This study suggests the management of ginseng on diabetes mellitus. We believe that our results can contribute to the systematic study of the mechanism of ginsenosides for the management of diabetes mellitus. At the same time, it can provide a theoretical basis for subsequent studies on the management of ginsenosides in diabetes mellitus.

Lappaol F regulates the cell cycle by activating CDKN1C/p57 in human colorectal cancer cells.

CONTEXT: Lappaol F (LAF), a natural lignan from Arctium lappa Linné (Asteraceae), inhibits tumor cell growth in vitro and in vivo. The underlying mechanism involves the suppression of the Yes-associated protein. However, the specific role of LAF in cell cycle regulation remains unknown. OBJECTIVE: This study determined the molecular mechanism by which LAF regulates cell cycle progression. MATERIALS AND METHODS: Various colon cancer cell lines (SW480, HCT15, and HCT116) were treated with LAF (25, 50, and 75 µmol/L) for 48 h. The effects of LAF on cell proliferation and cell cycle were determined using sulforhodamine B and flow cytometry assays. Differentially expressed proteins (DEPs) were identified using quantitative proteomics. Bioinformatic analysis of DEPs was conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Expression levels of DEPs in the cell cycle pathway were analyzed using RT-qPCR and western blotting. RESULTS: LAF suppressed the proliferation of SW480, HCT15, and HCT116 cells (IC50 47.1, 51.4, and 32.8 µmol/L, respectively) and induced cell cycle arrest at the S phase. A total of 6331 proteins were identified and quantified, of which 127 were differentially expressed between the LAF-treated and untreated groups. GO and KEGG enrichment analyses revealed that DEPs mainly participated in the cell cycle. CDKN1C/p57 showed the most significant differential expression, with the highest fold-change (3.155-fold). Knockdown of CDKN1C/p57 attenuated the S phase cell cycle arrest and proliferation inhibition induced by LAF. CONCLUSION: LAF exerts antitumor effects via S phase arrest by activating CDKN1C/p57 in colorectal cancer cells.

Echocardiographic Association of Epicardial Adipose Tissue with Ascending Aorta Elasticity in Patients with Type 2 Diabetes Mellitus.

Epicardial adipose tissue (EAT) is an emerging cardiovascular risk factor located between the myocardium and visceral pericardium. In order to investigate the association between EAT and ascending aorta elasticity in patients with type 2 diabetes mellitus (T2DM), we prospectively enrolled a total of 135 T2DM patients and 63 age- and gender-matched non-T2DM controls in this study. They all underwent transthoracic echocardiography to measure EAT thickness and ascending aorta inner diameters which were used to calculate ascending aorta elastic parameters: compliance (C), distensibility (D), strain (S), stiffness index (SI), and Peterson's elastic modulus (EM). We found that the values of C, D, and S were significantly lower, while SI, EM, and EAT thickness were significantly higher in T2DM patients compared with non-T2DM controls. Compared with T2DM patients with EAT < 5 mm group, C, D, and S were significantly reduced, SI and EM were significantly increased in T2DM patients with EAT ≥ 5 mm group (all P < .05). Bivariate correlation and multivariate linear regression analysis revealed that EAT was independently associated with ascending aorta elasticity. Our findings suggest that thickened EAT in patients with T2DM is associated with ascending aorta elasticity, independent of blood glucose.

Effect of 3D-printed nano-β-tricalcium phosphate in repairing seawater-soaked tibial defects in rabbits / 中华创伤杂志

Objective:To explore the repairing effects of 3D-printed nano-β-tricalcium phosphate (β-TCP) scaffolds loaded with vancomycin and bone morphogenetic protein-2 (BMP-2) for seawater -soaked tibial bone defects in rabbits. Methods:A total of 27 male New Zealand White rabbits were assigned to the normal group using a random number table method, with each group consisting of 9 rabbits. The rabbit tibial bone defect model was created using the osteotomy surgical method. Eight hours after operation, the wounds in the control group and seawater group were immersed in seawater for 2 hours, and those in the normal group were not immersed. After an observation period of 5-7 days, no significant redness or purulent discharge was observed in the wound appearance, then debridement was performed followed by corresponding implantations: the control group with gelatin sponges loaded with vancomycin and BMP-2, and the other two groups with 3D-printed nano-β-TCP scaffolds loaded with vancomycin and BMP-2. After filling the bone defects with the respective materials, all groups underwent layer-by-layer suturing of the wound, followed by disinfection with iodine and injection of gentamicin to prevent infection. The affected limbs were then immobilized using a plaster cast. The affected limbs were imaged using anteroposterior X-ray at 4, 8 and 16 weeks after operation, and the repair effects were evaluated using the Lane-Sandhu X-ray scoring system. At 16 weeks after operation, the bone defect tissues were collected for HE staining to observe bone tissue growth.Results:At 4 weeks after operation, the Lane-Sandhu X-ray score in the control group was significantly lower than that in the normal group [(2.8±1.1)points vs. (1.1±0.9)points] ( P<0.05), and that in the seawater group [(2.2±1.0)points] was not significantly different from those in the other two groups (all P>0.05). At 8 weeks after operation, the seawater group [(6.1±0.9)points] and the control group [(2.8±1.0)points] exhibited lower Lane-Sandhu X-ray score compared to the normal group [(8.2±1.0)points] (all P<0.05), and the seawater group showed a higher score compared to the control group ( P<0.05). At 16 weeks after operation, the control group [(3.8±1.0)points] exhibited a lower Lane-Sandhu X-ray score compared to the normal group [(10.0±1.3)points] and the seawater group [(9.3±1.2)points] (all P<0.05), while no significant difference was noted between the latter two ( P>0.05). At 16 weeks after operation, histological observations revealed varying degrees of bone tissue formation in three groups, with the normal group showing the best bone defect repair effect, followed by the seawater group. Conclusion:The 3D-printed nano-β-TCP scaffolds loaded with vancomycin and BMP-2 are effective for the treatment of seawater -soaked bone defects, which can promote bone tissue repair.

The new mechanism of cognitive decline induced by hypertension: High homocysteine-mediated aberrant DNA methylation.

The prevalence and severity of hypertension-induced cognitive impairment increase with the prolonging of hypertension. The mechanisms of cognitive impairment induced by hypertension primarily include cerebral blood flow perfusion imbalance, white and gray matter injury with blood-brain barrier disruption, neuroinflammation and amyloid-beta deposition, genetic polymorphisms and variants, and instability of blood pressure. High homocysteine (HHcy) is an independent risk factor for hypertension that also increases the risk of developing early cognitive impairment. Homocysteine (Hcy) levels increase in patients with cognitive impairment induced by hypertension. This review summarizes a new mechanism whereby HHcy-mediated aberrant DNA methylation and exacerbate hypertension. It involves changes in Hcy-dependent DNA methylation products, such as methionine adenosyltransferase, DNA methyltransferases, S-adenosylmethionine, S-adenosylhomocysteine, and methylenetetrahydrofolate reductase (MTHFR). The mechanism also involves DNA methylation changes in the genes of hypertension patients, such as brain-derived neurotrophic factor, apolipoprotein E4, and estrogen receptor alpha, which contribute to learning, memory, and attention deficits. Studies have shown that methionine (Met) induces hypertension in mice. Moreover, DNA hypermethylation leads to cognitive behavioral changes alongside oligodendroglial and/or myelin deficits in Met-induced mice. Taken together, these studies demonstrate that DNA methylation regulates cognitive dysfunction in patients with hypertension. A better understanding of the function and mechanism underlying the effect of Hcy-dependent DNA methylation on hypertension-induced cognitive impairment will be valuable for early diagnosis, interventions, and prevention of further cognitive defects induced by hypertension.

Arginyl-fructosyl-glucose, a major Maillard reaction product of red ginseng mitigates cisplatin-evoked intestinal toxicity in vivo and in vitro.

Cisplatin-evoked profound gastrointestinal symptomatology is one of the most common side effects of chemotherapy drugs, further causing gastrointestinal cell damage, diarrhea and vomiting. Panax ginseng C. A. Meyer, a widely used medicinal and edible plant in China, shows many pharmacological activities. Nevertheless, the role of non-saponin is less known and has great potential in the treatment of severe toxic side effects related to the cisplatin treatment. The present work evaluates the efficiency of a major Maillard reaction product (MRP) of red ginseng, arginyl-fructosyl-glucose (AFG), against cisplatin-evoked intestinal toxicity in vivo and vitro, and the underlying possible mechanisms are also explored. The cisplatin-treated mice (a dose of 20 mg kg-1 for one time) showed serious intestinal mucosa damage accompanied by increased indicators of diamine oxidase (DAO) and decreased expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin. Moreover, cisplatin exposure increased intestinal cell apoptosis with decreased expression of Bcl-2 and increased expression of Bax and cleaved-caspase 3/9 as well as NF-κB related proteins. Interestingly, the supplements of AFG at doses of 40 and 80 mg kg-1 day-1 for 10 days significantly ameliorated these changes. It was also demonstrated in cultured IEC-6 cells that AFG enhanced the expression levels of apoptotic proteins during cisplatin exposure and reduced the sensitivity of IEC-6 cells to cisplatin by inhibiting the activation of GSK3ß and up-regulating the protein expression of ß-catenin. In conclusion, AFG exerted protective effects against cisplatin-induced intestinal toxicity, at least partially by the inhibition of NF-κB-mediated apoptosis, via regulating Wnt/ß-catenin signaling pathway.

Epicardial adipose tissue and right ventricular function in type 2 diabetes mellitus using two-dimensional speckle tracking echocardiography.

BACKGROUND: Epicardial adipose tissue is an emerging cardiovascular risk factor. The aim of this study was to evaluate right ventricular function and investigate its association with EAT in T2DM patients. METHODS: 154 T2DM patients were divided into two groups according to EAT thickness: T2DM with EAT <5 mm and T2DM with EAT ≥5 mm. Seventy non-T2DM patients were enrolled as control group. RV function was evaluated using both conventional echocardiography as well as two-dimensional speckle tracking echocardiography. EAT thickness was measured as the echo-free space between the free wall of the right ventricle and the visceral layer of pericardium at end-systole. RESULTS: Compared to control group, EAT thickness was significantly higher and RV systolic function and early diastolic function are all impaired in all T2DM patients. In T2DM with EAT ≥5 mm group, RV systolic function and early diastolic function suffered more severe impairment when compared with T2DM with EAT <5 mm group. Multivariate linear regression analysis revealed that EAT was associated with RV systolic and early diastolic dysfunction independent of traditional cardiovascular risk factors. CONCLUSIONS: Our research suggest that in T2DM patients RV systolic function and early diastolic function are all impaired which are associated with the thickened EAT.

An ester derivative of tenacigenin B from Marsdenia tenacissima (Roxb.) Wight et Arn reversed paclitaxel-induced MDR in vitro and in vivo by inhibiting both P-gp and MRP2.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima is a medicinal plant, used as a raw material for cancer treatment in China. In our previous studies, 11α-O-2-methylbutanoyl-12ß-O-tigloyl-tenacigenin B (MT2), the main steroid aglycone isolated from M. tenacissima, was found to significantly enhance the antitumor activity of paclitaxel (PTX) in vivo. However, it is unclear whether MT2 reverses multidrug resistance (MDR) in tumors. AIM OF THE STUDY: To determine the role and mechanism of MT2 in reversing tumor MDR. MATERIALS AND METHODS: MDR cell line HeLa/Tax was established from the human cervical carcinoma cell line HeLa by long-term exposure to subtoxic concentrations of PTX and was used to evaluate the ability of MT2 to restore chemosensitivity of cells both in vitro and in a nude mouse model. The expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) was determined using western blotting and immunohistochemistry. The substrate transport function was assessed using an MDR function assay kit. The binding modes of MT2 and P-gp were determined using the conformation-sensitive anti-P-gp antibodies. The permeability and transport properties of MT2 were analyzed in Caco-2 cell monolayers. RESULTS: Compared to parental cells, HeLa/Tax cells overexpress P-gp and MRP2 and are approximately 100-360 fold more resistant to the anticancer drugs PTX, docetaxel, and vinblastine. MT2 at 5 or 10 µmol/L significantly increased the sensitivity of HeLa/Tax to these three anticancer drugs (18-56-fold decrease in IC50 value) and suppressed the expression of P-gp and MRP2. Knockdown of P-gp with small interfering RNA partially reversed MT2-induced sensitivity to PTX in HeLa/Tax cells. Moreover, MT2 directly inhibited P-gp-mediated substrate transport while interacting with membrane P-gp in non-substrate ways. MT2 was highly permeable and could not be transported in the Caco-2 cell monolayers. In nude mice bearing HeLa/Tax xenografts, the combination treatment with MT2 and PTX exerted a synergistic inhibitory effect on the growth of tumors and the expression of P-gp and MRP2 without increasing toxicity. CONCLUSION: MT2 is a potential agent for reversing MDR. It impedes membrane drug efflux pumps by suppressing P-gp and MRP2 expression, and directly inhibiting the transport function of P-gp.