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Protein synthesis regulation is critical for skeletal muscle hypertrophy, yet other established cellular processes are necessary for growth-related cellular remodeling. Autophagy has a well-acknowledged role in muscle quality control, but evidence for its role in myofiber hypertrophy remains equivocal. Both mammalian target of rapamycin complex I (mTORC1) and bone morphogenetic protein (BMP)-Smad1/5 (Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively) signaling are reported regulators of myofiber hypertrophy; however, gaps remain in our understanding of how this regulation is integrated with growth processes and autophagy regulation. Therefore, we investigated the mTORC1 and Smad1/5 regulation of protein synthesis and autophagy flux during serum-stimulated myotube growth. Chronic serum stimulation experiments were performed on day 5 differentiated C2C12 myotubes incubated in differentiation medium [2% horse serum (HS)] or growth medium [5% fetal bovine serum (FBS)] for 48 h. Rapamycin or LDN193189 was dosed for 48 h to inhibit mTORC1 and BMP-Smad1/5 signaling, respectively. Acute serum stimulation was examined in day 7 differentiated myotubes. Protein synthesis was measured by puromycin incorporation. Bafilomycin A1 and immunoblotting for LC3B were used to assess autophagy flux. Chronic serum stimulation increased myotube diameter 22%, total protein 21%, total RNA 100%, and Smad1/5 phosphorylation 404% and suppressed autophagy flux. Rapamycin, but not LDN193189, blocked serum-induced myotube hypertrophy and the increase in total RNA. Acute serum stimulation increased protein synthesis 111%, Smad1/5 phosphorylation 559%, and rpS6 phosphorylation 117% and suppressed autophagy flux. Rapamycin increased autophagy flux during acute serum stimulation. These results provide evidence for mTORC1, but not BMP-Smad1/5, signaling being required for serum-induced myotube hypertrophy and autophagy flux by measuring LC3BII/I expression. Further investigation is warranted to examine the role of autophagy flux in myotube hypertrophy. NEW & NOTEWORTHY: The present study demonstrates that myotube hypertrophy caused by chronic serum stimulation requires mammalian target of rapamycin complex 1 (mTORC1) signaling but not bone morphogenetic protein (BMP)-Smad1/5 signaling. The suppression of autophagy flux was associated with serum-induced myotube hypertrophy and mTORC1 regulation of autophagy flux by measuring LC3BII/I expression. Rapamycin is widely investigated for beneficial effects in aging skeletal muscle and sarcopenia; our results provide evidence that rapamycin can regulate autophagy-related signaling during myotube growth, which could benefit skeletal muscle functional and metabolic health. [ABSTRACT FROM AUTHOR]

Objective. To predict the major comorbidities of type 2 diabetes based on the distribution characteristics of syndromes, and to explore the relationship between TCM syndromes and comorbidities of type 2 diabetes. Methods. Based on the electronic medical record data of 3413 outpatient visits from 995 type 2 diabetes patients with comorbidities, descriptive statistical methods were used to analyze the basic characteristics of the population, the distribution characteristics of comorbidities, and TCM syndromes. A neural network model for the prediction of type 2 diabetic comorbidities based on TCM syndromes was constructed. Results. Patients with TCM syndrome of blood amassment in the lower jiao were diagnosed with renal insufficiency with 95% test sensitivity. The patients with spleen deficiency combined with ascending counterflow of stomach qi and cold-damp patterns were diagnosed with gastrointestinal lesions with 92% sensitivity. The patients with TCM syndrome group of spleen heat and exuberance of heart fire were diagnosed as type 2 diabetes complicated with hypertension with a sensitivity of 91%. In addition, the prediction accuracy of combined neuropathy, heart disease, liver disease, and lipid metabolism disorder reached 70∼90% in TCM syndrome groups. Conclusion. The fully connected neural network model study showed that syndrome characteristics are highly correlated with type 2 diabetes comorbidities. Syndrome location is commonly in the heart, spleen, stomach, lower jiao, meridians, etc., while syndrome pattern manifests in states of deficiency, heat, phlegm, and blood stasis. The different combinations of disease location and disease pattern reflect the syndrome characteristics of different comorbidities forming the characteristic syndrome group of each comorbidity. Major comorbidities could be predicted with a high degree of accuracy through TCM syndromes. Findings from this study may have further implementations to assist with the diagnosis, treatment, and prevention of diabetic comorbidities at an early stage. [ABSTRACT FROM AUTHOR]

Objective. The purpose of this study is to analyze and summarize the syndrome distribution, syndrome evolution, and Chinese herb medicine characteristics of T2D in heat stage. Method. In this study, 228 heat-stage T2D patients were divided into three groups based on the course of disease. Group 1 (the course of disease ≤5 years) included 118 patients. Group 2 (5< the course of disease ≤10 years) had 73 patients. Group 3 (the course of disease >10 years) consisted of 37 patients. The main methods used in our study were complex network community partitioning algorithms and Sankey diagram visualization, based on the clinical electronic medical record data we collected. Result. In the three groups, the nodes with the highest node degree are all "heat syndrome." Edge weight between "heat" and "dampness," "qi stagnation," "phlegm," "liver," and "stomach" is the largest. During the whole course of treatment, 60.17%, 63.01%, and 62.16% of the patients' syndromes in groups 1, 2, and 3, respectively, were ascribed to the heat stage all the time. The patients' syndromes in groups 1 and 2 easily transformed to the syndrome of deficiency of both qi and yin of the spleen and stomach. In group 3, 27% of the patients' syndromes were easily transformed into kidney yin deficiency and qi deficiency and blood stasis syndrome. The largest Chinese herb communities of the patients whose syndromes did not change after treatment in the three groups were all heat-clearing drugs. The proportion of blood-activating drugs in patients with syndrome changes increased significantly after treatment. Conclusion. (1) The basic syndrome of T2D patients in the heat stage is liver-stomach heat syndrome. (2) T2D patients in the heat stage tend to deteriorate towards the direction of qi and yin deficiency syndrome. However, the longer the course of the disease is, the more likely it is to deteriorate to the direction of kidney yin deficiency syndrome and blood stasis syndrome. (3) Drugs that can help T2D patients in the heat stage to maintain their condition stably are heat-clearing drugs represented by Coptis chinensis, which usually need to be combined with warming interior drugs such as Zingiberis Rhizoma and Pinelliae Rhizoma. [ABSTRACT FROM AUTHOR]

A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G-protein–coupled receptor GPRC6A to directly regulate glucose and fat metabolism in liver, muscle, and fat, and to stimulate the release of metabolism-regulating hormones, including insulin, fibroblast growth factor 21, glucagon-like peptide 1, testosterone, and interleukin 6. Ocn/GPRC6A activation has also been implicated in cancer progression. GPRC6A is activated by cations, amino acids, and testosterone. The multiligand specificity, the regulation of energy metabolism in diverse tissues, and the coordinated release of metabolically active hormones make the GPRC6A endocrine networks unique. Recently, the significance of Ocn/GPRCA has been questioned. There is a lack of metabolic abnormalities in newly created genetically engineered Ocn - and Gprc6a -deficient mouse models. There are also paradoxical observations that GPRC6A may function as a tumor suppressor. In addition, discordant published studies have cast doubt on the function of the most prevalent uniquely human GPRC6A-KGKY polymorphism. Explanations for these divergent findings are elusive. We provide evidence that the metabolic susceptibility of genetically engineered Ocn - and Gprc6a -deficient mice is influenced by environmental challenges and genetic differences in mouse strains. In addition, the GPRC6A-KGKY polymorphism appears to be a gain-of-function variant. Finally, alternatively spliced isoforms of GPRC6A may alter ligand specificity and signaling that modulate oncogenic effects. Thus, genetic, post-translational and environmental factors likely account for the variable results regarding the functions of GPRC6A in animal models. Pending additional information, GPRC6A should remain a potential therapeutic target for regulating energy and fat metabolism, hormone production, and cancer progression. [ABSTRACT FROM AUTHOR]

New insights into G protein coupled receptor regulation of glucose metabolism by β-cells, skeletal muscle and liver hepatocytes identify GPRC6A as a potential therapeutic target for treating type 2 diabetes mellitus (T2D). Activating GPRC6A with a small molecule drug represents a potential paradigm-shifting opportunity to make significant strides in regulating glucose homeostasis by simultaneously correcting multiple metabolic derangements that underlie T2D, including abnormalities in β-cell proliferation and insulin secretion and peripheral insulin resistance. Using a computational, structure-based high-throughput screening approach, we identified novel tri-phenyl compounds predicted to bind to the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A. Experimental testing found that these compounds dose-dependently stimulated GPRC6A signaling in a heterologous cell expression system. Additional chemical modifications and functional analysis identified one tri-phenyl lead compound, DJ-V-159 that demonstrated the greatest potency in stimulating insulin secretion in β-cells and lowering serum glucose in wild-type mice. Collectively, these studies show that GPRC6A is a “druggable” target for developing chemical probes to treat T2DM. [ABSTRACT FROM AUTHOR]

A new 3D supramolecular framework, [Ag6(2-PyBIM)6(ClO4)6(CH3OH)2(H2O)11] (1) (2-PyBIM = bis[(2-pyridinyl)-imidazol-1-yl]methane), has been prepared and structurally characterized. Compound1exhibits a 2D cationic network as a wave-like brick wall with a multi-coordinated Ag mode (di-, tri-, and tetranitrogen coordinated Ag centers) and multinary Ag cluster centers (Ag, Ag2, and Ag3) with the ligand-unsupported Ag—Ag interaction, encapsulated in an unprecedented 2D perchlorate-methanol-water layer of [(ClO4)6(CH3OH)4(H2O)11]6–anions. Additionally, the thermal stabilities and photoluminescence spectra of the complex1are also discussed. [ABSTRACT FROM AUTHOR]

Objective To explore the effect of electroacupuncture at conception vessel and governor vessel on correlative signals of inflammatory response stress-injury-repair in cerebral ischemia reperfusion rats. Methods A total of 216 rats were included in the experiment, of which 192 rats were randomly divided into four groups, including sham operation group (group A), model group (group B), governor vessel group (group C), and conception vessel and governor vessel group (group D), 48 rats in each group. The rats in each group were further divided into six sub-groups, including 12 h group, 24 h group, 48 h group, 72 h group, 96 h group and 144 h group. MCAO operation course was simulated in group A, and the common carotid artery, internal carotid artery and external carotid artery on the right side were exposed, without insertion of suture or treatment. After completion of modeling in group B, treatment was not conducted. After completion of modeling in group C, “Shuigōu ( GV 26)”, “Baihuì ( GV 20)” and “Dàzhuī ( GV 14)” of governor vessel were selected, and electroacupuncture device was connected with “GV 14” and “GV 20”. After completion of modeling in group D, “GV 26”, “GV 20” and “GV 14” of governor vessel, and “Qìhai ( CV 6)”, “Guānyuán ( CV 4)” and “Chéngjiāng ( CV 24)” of conception vessel were selected; electroacupuncture device was connected with “GV 14” and “GV 20”, “CV 4” and “CV 6”. Neurological severity score was conducted. Enzyme linked immunosorbent assay (ELISA) was applied to determine the concentration of peripheral serum adrenocorticotropic hormone (ACTH) of rats, and immunohistochemical method was adopted to detect the expression levels of tumor necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1) in brain tissue of rats. The other 24 rats were also randomly divided into four groups mentioned above, 6 rats in each group, to detect cerebral ischemie volume. Results Compared with group B, the ischemia volume in brain tissue at 144 h after cerebral ischemia reperfusion decreased significantly in group C and group D ( P <0.05), and the ischemia volume in group D was less than that in group C ( P <0.05). The neurological impairment scores of group C and group D at all time points were lower than those of group B, and the differences were statistically significant (all P <0.05). The scores of group D at all time points were lower than those of group C, and the differences since 24 h were statistically significant (all P <0.05). Compared with group B, the excessive expression of ACTH was suppressed dynamically and generally in group C and group D ( P <0.05); the expression level of TNF-α was down-regulated and TGF-β1 was up-regulated as well in group C and group D ( P <0.05). The effect in group D was superior to that in group C. Conclusion Electroacupuncture at conception vessel and governor vessel can protect brain through the intervention of the expression of correlative signals of inflammatory response stress-injury-repair of cerebral ischemia reperfusion. [ABSTRACT FROM AUTHOR]

A second-order weakly nonlinear analysis has been made of the temporal instability for the linear sinuous mode of two-dimensional planar viscoelastic liquid sheets moving in an inviscid gas. The convected Jeffreys models including the corotational Jeffreys model, Oldroyd A model, and the Oldroyd B model are considered as the rheology model of the viscoelastic fluid of the sheet. The solution for the second-order gas-to-liquid interface displacement has been derived, and the temporal evolution leading to the breakup has been shown. The second-order interface displacement of the linear sinuous mode is varicose, which causes the sheet to fragment into ligaments. First-order constitutive relations of the three rheology models become identical after linearization, so the linear instability results are also the same. For the second-order weakly nonlinear instability, the second-order constitutive relation varies among the corotational Jeffreys model, Oldroyd A model, and the Oldroyd B model, but although they have different disturbance pressures, their disturbance velocities and interface displacements are the same, and therefore, the sheets of the corotational Jeffreys fluid, Oldroyd A fluid, and the Oldroyd B fluid have the same instability behavior characterized by the wave profile and breakup time. The reason for the identical instability behavior is that the effect of different codeformations of the corotational frame, covariant frame, and the contravariant frame is counteracted by the corresponding change in the second-order disturbance pressure, leaving no influence on the second-order velocity. At wavenumbers with maximum instabilities, an increase in the elasticity, or a reduction of the deformation retardation time, leads to a larger linear temporal growth rate, greater second-order disturbance amplitude, and shorter breakup time, thereby enhancing instability. The mechanism of linear instability has been examined using an energy approach, which shows that the main cause of instability is the aerodynamic force. [ABSTRACT FROM AUTHOR]

A weakly nonlinear spatial instability of a two-dimensional planar viscous sheet for sinuous disturbances in a co-flowing inviscid gas stream is investigated theoretically, with an emphasis on the effect of the surrounding gas velocity. The solutions of the second-order interface disturbances are derived and the wave deformation has been computed. The results indicate that the second-order surface disturbance of the fundamental sinuous mode is varicose, which causes the thinning and the subsequent breakup of the liquid sheet. The nonlinear behaviors of the planar sheet are quite sensitive to variations in gas-to-liquid velocity ratio. The deviation of the velocity ratio from the value of unity leads to a larger growth rate, a larger second-order initial amplitude, and a shorter breakup length, and therefore enhances the instability. The growth rates predicted by the present nonlinear analysis according to the shortest breakup length are generally smaller than the linear predictions and can better conform to the experimental measures of Barreras et al. ["Linear instability analysis of the viscous longitudinal perturbation on an air-blasted liquid sheets," Atomization Sprays 11, 139 (2001)]. Furthermore, the wave deformations of the most unstable disturbances are presented. The nonlinear instability of the planar sheet for a fixed velocity difference is performed. An equal increase of the gas and liquid velocity reduces the spatial growth rate and increases the breakup length, but generally has no influences on the second-order initial amplitude and the wavelength of the disturbance. [ABSTRACT FROM AUTHOR]

This paper presents theoretically the spatial-temporal instability behavior of an electrified viscoelastic liquid jet. Dimensionless parameters have been tested for their influence on the transition of absolute and convective instability for the electrified visco-elastic liquid jet. The results show that larger electrical Euler and Weber numbers can change the flow to convectively unstable. The increase of Reynolds number can decrease the absolute growth rate. Variations of time constant and density ratio rarely change the spatial-temporal instability behavior of the jet. The disturbance wavelength changes very little with these parameters when the flow is absolutely unstable. [ABSTRACT FROM AUTHOR]

In the present research, the high pressure homogenization (HPH) technology was applied to prepare ursodeoxycholic acid (UDCA) nanosuspension. The aim of developing this new UDCA formulation was to enhance its bioavailability. The physicochemical characterization of UDCA nanosuspension was performed through particle size and Zeta potential measurements, differential scaning calorimetry (DSC) analysis, x-ray diffraction (XRD) measurements, and drug solubility and dissolution determinations. The mean particle size of UDCA nanosuspension was 297.5 nm with a polydispersity index of 0.162. Its particle size and Zeta potential did not show essential changes before and after water removal. The DSC curve of bulk UDCA showed a sharp endothermic peak at 207.82°C indicating the melting point. The XRD profile of dried powder of UDCA nanosuspension showed 2 intense peaks at 11.92° and 21.56°, respectively, indicating difference from the crystal characteristics of bulk UDCA. Its highest solubility and dissolution rate were 278.6 µg/mL and 98.77%, respectively. The feasibility of preparing nanosuspension by HPH technology was testified through successful preparation of UDCA nanosuspension. [ABSTRACT FROM AUTHOR]

Two coordination polymers [Cu(BIM)(suc)]n (1) and [Cd(BIM)(ox)(H2O)]n (2) (where BIM = bis(imidazol-1-yl)methane, suc = succinic dianion, and ox = oxalic dianion) have been solvothermally synthesized and characterized by single-crystal X-ray diffraction. Complex 1 crystallizes in the monoclinic space group C2/c with a = 12.2302(8) Å, b = 11.4007(6) Å, c = 10.1791(6) Å, β = 118.4090(10)°, V = 1248.38(13) Å3, and Z = 4. Cu(II) is square planar with nitrogen from BIM ligand and oxygen from the suc in the trans arrangement. Each BIM is bidentate bridging two Cu(II)s to generate a 1-D zigzag chain; the suc bridges two Cu(II)s in a monodentate gauche conformation, which results in the formation of wavy 2-D (4, 4) grid arrays. Complex 2 crystallizes in the monoclinic space group P2(1)/n with a = 10.8042(3) Å, b = 9.1053(2) Å, c = 12.0134(6) Å, β = 96.394(1)°, V = 1174.47(7) Å3, and Z = 4. Cd(II) is coordinated in a distorted decahedral geometry. Each BIM is bidentate bridging two Cd(II)s to form a 1-D infinite zigzag chain; each ox bridges two neighboring Cd(II)s in a distinct zigzag chain in a chelating/chelating coordination mode, which extends the 1-D chain to a 2-D supramolecular network. [ABSTRACT FROM AUTHOR]

The identity of the putative G-protein coupled receptor (GPCR) that mediates the non-genomic effects of androgens is unknown. We present in vitro and in vivo evidence that the orphan GPRC6A receptor, a widely expressed calcium and amino acid sensing GPCR, transduces the non-genomic effects of testosterone and other steroids. Overexpression of GPRC6A imparts the ability of extracellular testosterone to illicit a rapid, non-genomic signaling response in HEK-293 cells lacking the androgen receptor. Conversely, testosterone-stimulated rapid signaling and phosphorylation of ERK is attenuated in bone marrow stromal cells derived from GPRC6A-/- mice and in 22Rv1 prostate cancer cells after siRNA-mediated knockdown of GPRC6A. Compared with wild-type controls, GPRC6A-/- null mice exhibit significantly less ERK activation and Egr-1 expression in both bone marrow and testis in response to pharmacological doses of testosterone in vivo. In addition, testosterone administration results in suppression of luteinizing hormone in wild-type male mice, but paradoxically stimulates serum luteinizing hormone levels in GPRC6A-/- null mice. These results suggest that GPRC6A is functionally important in regulating non-genomic effects of androgens in multiple tissues. [ABSTRACT FROM AUTHOR]