Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Collaborative Design of MgO/FeOx Nanosheets on Titanium: Combining Therapy with Regeneration.

The repair of bone defects caused by osteosarcoma resection remains a clinical challenge because of the tumor recurrence and bacterial infection. Combining tumor and bacterial therapy with bone regeneration properties in bone implants is a promising strategy for the treatment of osteosarcoma. Here, a layer of MgO/FeOx nanosheet is constructed on the Ti implant to prevent tumor recurrence and bacterial infection, while simultaneously accelerating bone formation. This MgO/FeOx double metal oxide demonstrates good peroxidase activity to catalyze H2 O2 , which is rich in tumor microenvironment, to form reactive oxygen species (ROS), and shows good photothermal conversion capacity to produce photothermal effect, thus synergistically killing tumor cells and eliminating tumor tissue. In addition, it generates a local alkaline surface microenvironment to inhibit the energy metabolism of bacteria to enhance the photothermal antibacterial effect. Furthermore, benefiting from the generation of a Mg ion-containing alkaline microenvironment, this MgO/FeOx film can promote the osteogenic differentiation of osteoblast and angiogenesis of vascular endothelial cells in vitro as well as accelerated bone formation in vivo. This study proposes a multifunctional platform for integrating tumor and bacterial therapy and bone regeneration, which has good application prospects for the treatment of osteosarcoma.

Photo-controllable Luminescence from Radicals Leading to Ratiometric Emission Switching via Dynamic Intermolecular Coupling.

The development of photoinduced luminescent radicals with dynamic emission color is still challenging. Herein we report a novel molecular radical system (TBIQ) that shows photo-controllable luminescence, leading to a wide range of ratiometric color changes via light excitation. The conjugated skeleton of TBIQ is decorated with steric-demanding tertiary butyl groups that enable appropriate intermolecular interaction to make dynamic intermolecular coupling possible for controllable behaviors. We reveal that the helicenic pseudo-planar conformation of TBIQ experiences a planarization process after light excitation, leading to more compactly stacked supermolecules and thus generating radicals via intermolecular charge transfer. The photo-controllable luminescent radical system is employed for a high-level information encryption application. This study may offer unique insight into molecular dynamic motion for optical manufacturing and broaden the scope of smart-responsive materials for advanced applications.

Intramolecular Cyclization: A Convenient Strategy to Realize Efficient BT.2020 Blue Multi-Resonance Emitter for Organic Light-Emitting Diodes.

Rationally tuning the emission position and narrowing the full width at half-maximum (FWHM) of an emitter is of great importance for many applications. By synergistically improving rigidity, strengthening the resonant strength, inhibiting molecular bending and rocking, and destabilizing the HOMO energy level, a deep-blue emitter (CZ2CO) with a peak wavelength of 440 nm and an ultranarrow spectral FWHM of 16 nm (0.10 eV) was developed via intramolecular cyclization in a carbonyl/N resonant core (QAO). The dominant υ0-0 transition character of CZ2CO gives a Commission Internationale de I'Éclairage coordinates (CIE) of (0.144, 0.042), nicely complying with the BT.2020 standard. Moreover, a hyper-fluorescent device based on CZ2CO shows a high maximum external quantum efficiency (EQEmax ) of 25.6 % and maintains an EQE of 22.4 % at a practical brightness of 1000 cd m-2 .

Deep learning-based method for non-uniform motion-induced error reduction in dynamic microscopic 3D shape measurement.

The non-uniform motion-induced error reduction in dynamic fringe projection profilometry is complex and challenging. Recently, deep learning (DL) has been successfully applied to many complex optical problems with strong nonlinearity and exhibits excellent performance. Inspired by this, a deep learning-based method is developed for non-uniform motion-induced error reduction by taking advantage of the powerful ability of nonlinear fitting. First, a specially designed dataset of motion-induced error reduction is generated for network training by incorporating complex nonlinearity. Then, the corresponding DL-based architecture is proposed and it contains two parts: in the first part, a fringe compensation module is developed as network pre-processing to reduce the phase error caused by fringe discontinuity; in the second part, a deep neural network is employed to extract the high-level features of error distribution and establish a pixel-wise hidden nonlinear mapping between the phase with motion-induced error and the ideal one. Both simulations and real experiments demonstrate the feasibility of the proposed method in dynamic macroscopic measurement.

Generic saturation-induced phase error correction for structured light 3D shape measurement.

Intensity saturation is a challenging problem in structured light 3D shape measurement. Most of the existing methods achieve high dynamic range (HDR) measurement by sacrificing measurement speed, making them limited in high-speed dynamic applications. This Letter proposes a generic efficient saturation-induced phase error correction method for HDR measurement without increasing any fringe patterns. We first theoretically analyze the saturated signal model and deduce the periodic characteristic of saturation-induced phase error. Based on this, we specially design a saturation-induced phase error correction method by joint Fourier analysis and Hilbert transform. Furthermore, the relationship among phase error, saturation degree, and number of phase-shifting steps is established by numerical simulation. Since the proposed method requires no extra captured images or complicated intensity calibration, it is extremely convenient in implementation and is applicable to performing high-speed 3D shape measurements. Simulations and experiments verify the feasibility of the proposed method.

Efficient Pyrazolo[5,4-f]quinoxaline Functionalized Os(II) Based Emitter with an Electroluminescence Peak Maximum at 811†nm.

Upon fusing the pyrazinyl pyrazole entity in giving pyrazolo[3,4-f]quinoxaline chelate, the corresponding Os(II) based NIR emitter exhibited "invisible" and efficient electroluminescence with a peak maximum at 811 nm. A maximum external quantum efficiency of 0.97 % and a suppressed efficiency roll-off till a current density of 300 mA cm-2 was also exhibited.

Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway.

Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1-10 µM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5-90 mg·kg-1·d-1, i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.

Zerumbone attenuates house dust mite extract-induced epithelial barrier dysfunction in 16HBE14o- cells.

CONTEXT: The airway epithelial barrier can be disrupted by house dust mite (HDM) allergens leading to allergic airway inflammation. Zerumbone, a natural monocyclic sesquiterpene, was previously found to possess anti-asthmatic effect by modulating Th1/Th2 cytokines. However, the protective role of zerumbone on epithelial barrier function remains to be fully explored. OBJECTIVE: To investigate the effect of zerumbone on HDM extract-induced airway epithelial barrier dysfunction. MATERIALS AND METHODS: Human bronchial epithelial cells 16HBE14o- were incubated with 100 µg/mL HDM extract and treated with non-cytotoxic concentrations of zerumbone (6.25 µM, 12.5 µM, and 25 µM) for 24 h. The epithelial junctional integrity and permeability were evaluated through transepithelial electrical resistance (TEER) and fluorescein isothiocynate (FITC)-Dextran permeability assays, respectively. The localization of junctional proteins, occludin and zona occludens (ZO)-1, was studied using immunofluorescence (IF) while the protein expression was measured by western blot. RESULTS: Zerumbone inhibited changes in junctional integrity (6.25 µM, p ≤ .05; 12.5 µM, p ≤ .001; 25 µM, p ≤ .001) and permeability (6.25 µM, p ≤ .05; 12.5 µM, p ≤ .01; 25 µM, p ≤ .001) triggered by HDM extract in a concentration-dependent manner. This protective effect could be explained by the preservation of occludin (12.5 µM, p ≤ .01 and 25 µM, p ≤ .001) and ZO-1 (12.5 µM, p ≤ .05 and 25 µM, p ≤ .001) localization, rather than the prevention of their cleavage. DISCUSSION AND CONCLUSION: Zerumbone attenuates HDM extract-induced epithelial barrier dysfunction which supports its potential application for the treatment of inflammation-driven airway diseases such as asthma.

Cryptic species and grey zone speciation of the Barbodes binotatus complex (Teleostei, Cyprinidae) in Sundaland.

Morphology-based taxonomy of freshwater fish is effective when there are representative specimens covering large regions. However, in Sundaland, where the presence of cryptic species is high, the technique has its limitations. This is compounded by uncritical descriptions of holotypes in old literature. We demonstrate the problem using Barbodes binotatus first described from an ink drawing. Several species in the Barbodes genus of Sundaland exhibit morphological similarity to B. binotatus. We applied new DNA sequences of 16S, cytochrome c oxidase subunit I (COI), cytochrome b (Cytb) and recombination-activating gene 1 (RAG1), and pigmentation markers to clarify species complex boundaries in the Malay Peninsula, namely B. aff. binotatus "Malay Peninsula", Barbodes cf. banksi and Barbodes rhombeus. Results suggest B. binotatus-like specimens in the Malay Peninsula are B. rhombeus based on a threshold of 3% COI genetic divergence. B. aff. binotatus recorded in Sumatra, Borneo and the Philippines are likely valid but undescribed species. However, if the 2% COI threshold is applied, some populations in the northern Malay Peninsula would qualify as new and undescribed species. The implications of the 2% threshold and the likelihood of "grey zone" incipient populations are discussed. We further found a rapid visual method, not reported previously, to delineate B. aff. binotatus and B. cf. banksi, but it requires further validation. Additionally, we offer fresh perspectives by discussing the roles of biological species concept, morphological species concept, genetic species concept and mate recognition concept in the B. binotatus complex. Our findings reinforce the standpoint that species delineation is not entirely a binary process, but there is a spectrum to consider, especially in biogeography intersection regions.

Gut Microbiota and Lung Injury.

Gut microbiota are known to impact multiple organs including the lung. The cross talk between gut microbes and lungs, termed as the "gut-lung axis," is vital for immune response and homeostasis in the airways. In this chapter, we summarized the coordinated development of microorganisms in the gut and lung, exogenous and endogenous factors related to the cross talk, the mechanisms of the gut-lung axis and their dysbiosis in lung diseases. Although the current understanding of the gut-lung axis is in its infancy, several gut microbiota-associated strategies have been designed to treat and prevent lung diseases.

Cardioprotection of post-ischemic moderate ROS against ischemia/reperfusion via STAT3-induced the inhibition of MCU opening.

Enhanced reactive oxygen species (ROS) at the beginning of reperfusion activated signal transducer and activator of transcription 3 (STAT3) in intermittent hypobaric hypoxia (IHH)-afforded cardioprotection against ischemia/reperfusion (I/R). However, its mechanism remains largely unknown. This study aimed to investigate the role and the downstream of STAT3 in exogenous enhanced post-ischemic ROS-induced cardioprotection using the model of moderate hydrogen peroxide postconditioning (H2O2PoC) mimicking endogenous ROS in IHH. Moderate H2O2PoC not only improved the post-ischemic myocardial contractile recovery and reduced the infarct size in isolated rat I/R hearts, but also alleviated mitochondrial calcium overload and ameliorated Ca2+ transients, cell contraction, and mitochondrial membrane potential in rat I/R cardiomyocytes. However, the cardioprotective effects of moderate H2O2PoC were abrogated by Janus kinase 2 (JAK2)/STAT3 inhibitor AG490 in rat hearts as well as adenovirus-delivered short hairpin RNA specific for STAT3 and the opener of mitochondrial calcium uniporter (MCU) spermine in rat cardiomyocytes. Notably, the moderate H2O2PoC-afforded cardioprotection abrogated by spermine could be rescued by STAT3 over-expression with adenovirus in rat I/R cardiomyocytes. Besides, moderate H2O2PoC enhanced mitochondrial STAT3 expression during I/R. A co-localization/interaction of STAT3 or phospho-STAT3ser727 and MCU was observed in rat cardiomyocytes with moderate H2O2PoC at 5 and 30 min of reperfusion but not in rat I/R cardiomyocytes. Further, STAT3 interacted with the N-terminal domain (NTD) of MCU in rat cardiomyocytes with moderate H2O2PoC. These findings indicated that post-ischemic moderate ROS activate STAT3 against cardiac I/R by inhibiting MCU opening via its interaction with the NTD of MCU to alleviate mitochondrial calcium overload.

Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) via attenuation of IgE-mediated mast cell activation and inhibition of passive systemic anaphylaxis.

tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (ß-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D2 and leukotriene C4). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future.

Neuroprotective Effects of Biochanin A against ß-Amyloid-Induced Neurotoxicity in PC12 Cells via a Mitochondrial-Dependent Apoptosis Pathway.

Alzheimer's disease is considered one of the major neurodegenerative diseases and is characterized by the production of ß-amyloid (Aß) proteins and progressive loss of neurons. Biochanin A, a phytoestrogen compound found mainly in Trifolium pratense, was used in the present study as a potential alternative to estrogen replacement therapy via the investigation of its neuroprotective effects against Aß25-35-induced toxicity, as well as of its potential mechanisms of action in PC12 cells. Exposure of these cells to the Aß25-35 protein significantly increased cell viability loss and apoptosis. However, the effects induced by Aß25-35 were markedly reversed in the present of biochanin A. Pretreatment with biochanin A attenuated the cytotoxic effect of the Aß25-35 protein by decreasing viability loss, LDH release, and caspase activity in cells. Moreover, we found that expression of cytochrome c and Puma were reduced, alongside with the restoration of Bcl-2/Bax and Bcl-xL/Bax ratio in the presence of biochanin A, which led to a decrease in the apoptotic rate. These data demonstrate that mitochondria are involved in the protective effect of biochanin A against Aß25-35 and that this drug attenuated Aß25-35-induced PC12 cell injury and apoptosis by preventing mitochondrial dysfunction. Thus, biochanin A might raise a possibility as a potential therapeutic agent for Alzheimer's disease and other related neurodegenerative diseases.

ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca(2+) overload and contractile dysfunction via the JAK2/STAT3 pathway.

Moderate enhanced reactive oxygen species (ROS) during early reperfusion trigger the cardioprotection against ischemia/reperfusion (I/R) injury, while the mechanism is largely unknown. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) contributes to the cardioprotection but whether it is activated by ROS and how it regulates Ca(2+) homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca(2+) overload and contractile dysfunction via the activation of JAK2/STAT3 signaling pathway by using a cardioprotective model of intermittent hypobaric hypoxia (IHH) preconditioning. IHH improved the postischemic recovery of myocardial contractile performance in isolated rat I/R hearts as well as Ca(2+) homeostasis and cell contraction in simulated I/R cardiomyocytes. Meanwhile, IHH enhanced I/R-increased STAT3 phosphorylation at tyrosine 705 in the nucleus and reversed I/R-suppressed STAT3 phosphorylation at serine 727 in the nucleus and mitochondria during reperfusion. Moreover, IHH improved I/R-suppressed sarcoplasmic reticulum (SR) Ca(2+)-ATPase 2 (SERCA2) activity, enhanced I/R-increased Bcl-2 expression, and promoted the co-localization and interaction of Bcl-2 with SERCA2 during reperfusion. These effects were abolished by scavenging ROS with N-(2-mercaptopropionyl)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca(2+) homeostasis as well as cell contraction were reversed after Bcl-2 knockdown by short hairpin RNA. In addition, the reversal of the I/R-suppressed mitochondrial membrane potential by IHH was abolished by 2-MPG and AG490. These results indicate that during early reperfusion the ROS/JAK2/STAT3 pathways play a crucial role in (i) the IHH-maintained intracellular Ca(2+) homeostasis via the improvement of postischemic SERCA2 activity through the increase of SR Bcl-2 and its interaction with SERCA2; and (ii) the IHH-improved mitochondrial function.

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood.

Association Between Serum Uric Acid and Prevalence of Type 2 Diabetes Diagnosed using HbA1c Criteria Among Chinese Adults in Qingdao, China.

OBJECTIVE: To determine whether elevated serum uric acid (UA) levels are associated with type 2 diabetes diagnosed using HbA1c levels among Chinese adults. METHODS: We conducted two population-based cross-sectional studies in Qingdao in China in 2006 and 2009. A total of 6894 (39.4% men) subjects aged 35-74 years were included in the data analysis. Newly diagnosed diabetes was defined as HbA1c level of ⋝6.5%, and prediabetes was classified as HbA1c level between 5.7% and 6.4% according to the International Diabetes Federation criteria. Multivariate logistic regression was employed to assess the association between UA and prevalence of type 2 diabetes defined using Glycated hemoglobin A1c (HbA1c) levels. RESULTS: Subjects with prediabetes had higher UA levels than those with normal glucose tolerance, newly diagnosed diabetes, and known diabetes, with corresponding values of 325.1 (82.5) µmol/L, 310.9 (84.2) µmol/L, 291.3 (81.7) µmol/L, 305.2 (83.6) µmol/L, respectively (P<0.001 for all comparisons). Binary logistic regression analysis showed that UA was a possible predictor for the prevalence of type 2 diabetes diagnosed using HbA1c levels, and the second quartile of UA levels had a higher odds ratio (OR: 4.088; 95% CI: 2.900-5.765) for HbA1c than the other quartiles after adjusting for age, body mass index, sex, marital status, education, income, alcohol consumption, smoking, and cardiometabolic parameters. CONCLUSION: Serum UA is significantly associated with type 2 diabetes diagnosed using HbA1c levels, independent of other cardiometabolic parameters.

Genetic and environmental effects on the bone development of the hand and wrist in Chinese young twins.

We assessed genetic and environmental effects on bone development of the hand and wrist, and on key anthropometric measures in Chinese young twins. In total, 139 monozygotic and 95 dizygotic twin pairs aged from 5 to 18 years were recruited. The twin correlations of total hand and wrist scores for monozygotic (MZ) and dizygotic (DZ) twins were 0.71 and 0.36, respectively. Bivariate model analysis showed moderate genetic correlations only for total skeletal maturity vs. weight and total skeletal maturity vs. waist circumference (r, 0.51 and 0.46, respectively). Our findings demonstrated that genetic factors played important roles in bone development of the hand and wrist in Chinese young twins, and that these genetic effects might be distinct from those influencing anthropometric measures.

Degradation of cardiac myosin light chain kinase by matrix metalloproteinase-2 contributes to myocardial contractile dysfunction during ischemia/reperfusion.

Although ischemia/reperfusion (I/R)-induced myocardial contractile dysfunction is associated with a prominent decrease in myofilament Ca(2+) sensitivity, the underlying mechanisms have not yet been fully clarified. Phosphorylation of ventricular myosin light chain 2 (MLC-2v) facilitates actin-myosin interactions and enhances contractility, however, its level and regulation by cardiac MLC kinase (cMLCK) and cMLC phosphatase (cMLCP) in I/R hearts are debatable. In this study, the levels and/or effects of MLC-2v phosphorylation, cMLCK, cMLCP, and proteases during I/R were determined. Global myocardial I/R-suppressed cardiac performance in isolated rat hearts was concomitant with decreases of MLC-2v phosphorylation, myofibrillar Ca(2+)-stimulated ATPase activity, and cMLCK content, but not cMLCP proteins. Consistently, simulated I/R in isolated cardiomyocytes inhibited cell shortening, Ca(2+) transients, MLC-2v phosphorylation, and myofilament sensitivity to Ca(2+). These observations were reversed by cMLCK overexpression, while the specific cMLCK knockdown by short hairpin RNA (shRNA) had the opposite effect. Moreover, the inhibition of matrix metalloproteinase-2 (MMP-2, a zinc-dependent endopeptidase) reversed IR-decreased cMLCK, MLC-2v phosphorylation, myofibrillar Ca(2+)-stimulated ATPase activity, myocardial contractile function, and myofilament sensitivity to Ca(2+), while the inhibition or knockdown of cMLCK by ML-9 or specific shRNA abolished MMP-2 inhibition-induced cardioprotection. Finally, the co-localization in cardiomyocytes and interaction in vivo of MMP-2 and cMLCK were observed. Purified recombinant rat cMLCK was concentration- and time-dependently degraded by rat MMP-2 in vitro, and this was prevented by the inhibition of MMP-2. These findings reveal that the I/R-activated MMP-2 leads to the degradation of cMLCK, resulting in a reduction of MLC-2v phosphorylation, and myofibrillar Ca(2+)-stimulated ATPase activity, which subsequently suppresses myocardial contractile function through a decrease of myofilament Ca(2+) sensitivity.

Incorporation of natural and synthetic polymers into honey hydrogel for wound healing: A review.

Background and Aims: The difficulty in treating chronic wounds due to the prolonged inflammation stage has affected a staggering 6.5 million people, accompanied by 25 billion USD annually in the United States alone. A 1.9% rise in chronic wound prevalence among Medicare beneficiaries was reported from 2014 to 2019. Besides, the global wound care market values were anticipated to increase from USD 20.18 billion in 2022 to USD 30.52 billion in 2030, suggesting an expected rise in chronic wounds financial burdens. The lack of feasibility in using traditional dry wound dressings sparks hydrogel development as an alternative approach to tackling chronic wounds. Since ancient times, honey has been used to treat wounds, including burns, and ongoing studies have also demonstrated its wound-healing capabilities on cellular and animal models. However, the fluidity and low mechanical strength in honey hydrogel necessitate the incorporation of other polymers. Therefore, this review aims to unravel the characteristics and feasibility of natural (chitosan and gelatin) and synthetic (polyvinyl alcohol and polyethylene glycol) polymers to be incorporated in the honey hydrogel. Methods: Relevant articles were identified from databases (PubMed, Google Scholar, and Science Direct) using keywords related to honey, hydrogel, and polymers. Relevant data from selected studies were synthesized narratively and reported following a structured narrative format. Results: The importance of honey's roles and mechanisms of action in wound dressings were discussed. Notable studies concerning honey hydrogels with diverse polymers were also included in this article to provide a better perspective on fabricating customized hydrogel wound dressings for various types of wounds in the future. Conclusion: Honey's incapability to stand alone in hydrogel requires the incorporation of natural and synthetic polymers into the hydrogel. With this review, it is hoped that the fabrication and commercialization of the desired honey composite hydrogel for wound treatment could be brought forth.