Peroxisome proliferator-activated receptor-α (PPARα) regulates wound healing and mitochondrial metabolism in the cornea.

Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mitochondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochondrial function, we found that Peroxisome Proliferator-Activated Receptor-α (PPARα) expression was downregulated in diabetic human corneas. Even without diabetes, global PPARα knockout mice and corneal epithelium-specific PPARα conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPARα agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific PPARα transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPARα agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of PPARα, suggesting a PPARα-dependent mechanism. These findings suggest that downregulation of PPARα plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes.

MlrA, an Essential Enzyme for Microcystins and Nodularin on First Step Biodegradation in Microcystin-Degrading Bacteria.

Microcystin-degrading bacteria first degrade microcystins by microcystinase A (MlrA) to cleave the cyclic structure of microcystins at the Adda-Arg site of microcystin-LR, microcystin-RR, and microcystin-YR, but the cleavage of the other microcystins was not clear. In our study, the microcystin-degrading bacterium Sphingopyxis sp. C-1 as wild type and that of mlrA-disrupting mutant, Sphingopyxis sp. CMS01 were used for microcystins biodegradation. The results showed MlrA degraded microcystin-LA, microcystin-LW, microcystin-LY, microcystin-LF, and nodularin. MlrA could cleave the Adda-L-amino acid site.

Alleviating effect of vagus nerve cutting in Salmonella-induced gut infections and anxiety-like behavior via enhancing microbiota-derived GABA.

The vagus nerve, a pivotal link within the gut-brain axis, plays a critical role in maintaining homeostasis and mediating communication between the gastrointestinal tract and the brain. It has been reported that gastrointestinal infection by Salmonella typhimurium (S. typhimurium) triggers gut inflammation and manifests as anxiety-like behaviors, yet the mechanistic involvement of the vagus nerve remains to be elucidated. In this study, we demonstrated that unilateral cervical vagotomy markedly attenuated anxiety-like behaviors induced by S. typhimurium SL1344 infection in C57BL/6 mice, as evidenced by the open field test and marble burying experiment. Furthermore, vagotomy significantly diminished neuronal activation within the nucleus of the solitary tract and amygdala, alongside mitigating aberrant glial cell activation in the hippocampus and amygdala. Additionally, vagotomy notably decreases serum endotoxin levels, counters the increase in splenic Salmonella concentration, and modulates the expression of inflammatory cytokines-including IL-6, IL-1ß, and TNF-α-in both the gastrointestinal tract and brain, with a concurrent reduction in IL-22 and CXCL1 expression. This intervention also fostered the enrichment of beneficial gut microbiota, including Alistipes and Lactobacillus species, and augmented the production of gamma-aminobutyric acid (GABA) in the gut. Administration of GABA replicated the vagotomy's beneficial effects on reducing gut inflammation and anxiety-like behavior in infected mice. However, blockade of GABA receptors with picrotoxin abrogated the vagotomy's protective effects against gut inflammation, without influencing its impact on anxiety-like behaviors. Collectively, these findings suggest that vagotomy exerts a protective effect against infection by promoting GABA synthesis in the colon and alleviating anxiety-like behavior. This study underscores the critical role of the vagus nerve in relaying signals of gut infection to the brain and posits that targeting the gut-brain axis may offer a novel and efficacious approach to preventing gastrointestinal infections and associated behavioral abnormalities.

Baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating ATP-sensitive potassium channels.

Dopaminergic neurons in the substantia nigra (SN) expressing SUR1/Kir6.2 type ATP-sensitive potassium channels (K-ATP) are more vulnerable to rotenone or metabolic stress, which may be an important reason for the selective degeneration of neurons in Parkinson's disease (PD). Baicalein has shown neuroprotective effects in PD animal models. In this study, we investigated the effect of baicalein on K-ATP channels and the underlying mechanisms in rotenone-induced apoptosis of SH-SY5Y cells. K-ATP currents were recorded from SH-SY5Y cells using whole-cell voltage-clamp recording. Drugs dissolved in the external solution at the final concentration were directly pipetted onto the cells. We showed that rotenone and baicalein opened K-ATP channels and increased the current amplitudes with EC50 values of 0.438 µM and 6.159 µM, respectively. K-ATP channel blockers glibenclamide (50 µM) or 5-hydroxydecanoate (5-HD, 250 µM) attenuated the protective effects of baicalein in reducing reactive oxygen species (ROS) content and increasing mitochondrial membrane potential and ATP levels in rotenone-injured SH-SY5Y cells, suggesting that baicalein protected against the apoptosis of SH-SY5Y cells by regulating the effect of rotenone on opening K-ATP channels. Administration of baicalein (150, 300 mg·kg-1·d-1, i.g.) significantly inhibited rotenone-induced overexpression of SUR1 in SN and striatum of rats. We conducted surface plasmon resonance assay and molecular docking, and found that baicalein had a higher affinity with SUR1 protein (KD = 10.39 µM) than glibenclamide (KD = 24.32 µM), thus reducing the sensitivity of K-ATP channels to rotenone. Knockdown of SUR1 subunit reduced rotenone-induced apoptosis and damage of SH-SY5Y cells, confirming that SUR1 was an important target for slowing dopaminergic neuronal degeneration in PD. Taken together, we demonstrate for the first time that baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating K-ATP channels.

Occurrence and seasonal variation of Perkinsus sp. Infection in wild mollusk populations from coastal waters of Qingdao, northern China.

Perkinsosis has been recognized as one of the major threats to natural and farmed bivalve populations, many of which are of commercial as well as environmental significance. Three Perkinsus species have been identified in China, and the Manila clam (Ruditapes philippinarum) was the most frequently infected species in northern China. Although the occurrence and seasonal variation of Perkinsus spp. have previously been examined, the pathological characteristics of these infections in wild Manila clams and sympatric species in China have seldom been reported. In the present study, the prevalence and intensity of Perkinsus infection in wild populations of Manila clams and 10 sympatric species from three sites were investigated by Ray's fluid thioglycolate medium (RFTM) assay seasonally across a single year. Perkinsus infection was only identified in Manila clams, with a high prevalence (274/284 = 96.48 %) and low intensity (89.8 % with a Mackin value ≤ 2, suggesting generally low-intensity infections) throughout the year. Heavily infected clams were mainly identified in Tianheng in January, which displayed no macroscopic signs of disease. An overview of the whole visceral mass section showed that the trophozoites mostly aggregated in gills and connective tissue of the digestive tract, to a lesser extent in the mantle and foot, and even less frequently in adductor muscle and connective tissues of the gonad. PCR and ITS-5.8S rRNA sequencing of 93 representative RFTM-positive samples revealed a 99.69 to 100 % DNA sequence identity to Perkinsus olseni. Unexpectedly, significantly higher infection intensities were usually identified in January and April when the Condition Index (CI) was relatively high. We propose that factors associated with the anthropogenic harvesting pressure and irregular disturbances should be responsible for the uncommon seasonal infection dynamics of perkinsosis observed in the present study.

Antitumor Mechanism and Therapeutic Potential of Cordycepin Derivatives.

Cordycepin has good antitumor activity, but its clinical application is limited due to the easy deamination of N6 in structure. In this study, a large lipolysis group was introduced at the cordycepin N6 to improve the problem, cordycepin derivatives (3a-4c) were synthesized, and biological evaluation of compounds was studied. In this study, the vitro antitumor activity of the compounds against MCF7 cells, HepG2 cells and SGC-7901 cells was evaluated by MTT assay. In the results, compound 4a showed the most obvious inhibitory effect on MCF7 cells with an IC50 value of 27.57 ± 0.52 µM, which was much lower than cordycepin. Compound 4a showed high selectivity between MCF7 and normal MCF-10A cells. Further biological evaluation showed that compound 4a promoted apoptosis and blocked the cell cycle in the G0/G1 phase. Then, Western Blot was used to detect related apoptotic proteins. It was found that Compound 4a could down-regulate the expression of Bcl-2 protein and up-regulate the expression of p53, Bax, Caspase-3 and Caspase-9 proteins. The mitochondrial membrane potential decreased continuously and the positive expression rate decreased. It was speculated that compound 4a induced the apoptosis of MCF7 cells through the mitochondrial pathway.

Identification of novel biomarkers of ferroptosis involved in keloid based on bioinformatics analysis.

Keloid is a fibroproliferative disease of unknown aetiology, which has a significant impact the quality of life of patients. Ferroptosis plays an important role in the occurrence and development of fibrosis, but there is still a lack of research related to keloids. The objective of this work was to identify the hub genes related to ferroptosis in keloid to better understand the keloid process. The microarray data (GSE7890 GSE145725, and GSE44270) (23 keloid and 22 normal fibroblast) were analysed via the gene expression comprehensive database (GEO). Only GSE7890 met the FerrDB database. Cell cycle and pathway analysis were performed with gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to differentially expressed genes (DEG). The differential genes were confirmed in other GEO datasets (GSE145725 and GSE44270), and multi-fibrosis-gene correlation analysed. To validate these hub genes, quantitative real-time PCR (qRT-PCR) was conducted. A total of 581 DEGs were screened, with 417 genes down-regulated and 164 genes up-regulated, with 11 ferroptosis genes significantly up-regulated in both keloid and normal tissue, and 6 genes are consistent with our findings and are associated with multiple fibrosis genes. The qRT-PCR results and tissues of normal skin and keloid agreed with our predictions. Our findings provide new evidence for the ferroptosis-related molecular pathways and biomarker of keloid.

Distinct Contributions of Genes and Environment to Visual Size Illusion and the Underlying Neural Mechanism.

As exemplified by the Ebbinghaus illusion, the perceived size of an object can be significantly biased by its surrounding context. The phenomenon is experienced by humans as well as other species, hence likely evolutionarily adaptive. Here, we examined the heritability of the Ebbinghaus illusion using a combination of the classic twin method and multichannel functional near-infrared spectroscopy. Results show that genes account for over 50% of the variance in the strength of the experienced illusion. Interestingly, activations evoked by the Ebbinghaus stimuli in the early visual cortex are explained by genetic factors whereas those in the posterior temporal cortex are explained by environmental factors. In parallel, the feedforward functional connectivity between the occipital cortex and the temporal cortex is modulated by genetic effects whereas the feedback functional connectivity is entirely shaped by environment, despite both being significantly correlated with the strength of the experienced illusion. These findings demonstrate that genetic and environmental factors work in tandem to shape the context-dependent visual size illusion, and shed new light on the links among genes, environment, brain, and subjective experience.

Exposure to okadaic acid could disrupt the colonic microenvironment in rats.

Okadaic acid (OA) is one of the most prevalent marine phycotoxin with complex toxicity, which can lead to toxic symptoms such as diarrhea, vomiting, nausea, abdominal pain, and gastrointestinal discomfort. Studies have shown that the main affected tissue of OA is digestive tract. However, its toxic mechanism is not yet fully understood. In this study, we investigated the changes that occurred in the epithelial microenvironment following OA exposure, including the epithelial barrier and gut bacteria. We found that impaired epithelial cell junctions, mucus layer destruction, cytoskeletal remodeling, and increased bacterial invasion occurred in colon of rats after OA exposure. At the same time, the gut bacteria decreased in the abundance of beneficial bacteria and increased in the abundance of pathogenic bacteria, and there was a significant negative correlation between the abundance of pathogenic bacteria represented by Escherichia/Shigella and animal body weight. Metagenomic analysis inferred that Escherichia coli and Shigella spp. in Escherichia/Shigella may be involved in the process of cytoskeletal remodeling and mucosal layer damage caused by OA. Although more evidence is needed, our results suggest that opportunistic pathogens may be involved in the complex toxicity of OA during OA-induced epithelial barrier damage.

Mathematical Optimisation of Magnetic Nanoparticle Diffusion in the Brain White Matter.

Magnetic nanoparticles (MNPs) are a promising drug delivery system to treat brain diseases, as the particle transport trajectory can be manipulated by an external magnetic field. However, due to the complex microstructure of brain tissues, particularly the arrangement of nerve fibres in the white matter (WM), how to achieve desired drug distribution patterns, e.g., uniform distribution, is largely unknown. In this study, by adopting a mathematical model capable of capturing the diffusion trajectories of MNPs, we conducted a pilot study to investigate the effects of key parameters in the MNP delivery on the particle diffusion behaviours in the brain WM microstructures. The results show that (i) a uniform distribution of MNPs can be achieved in anisotropic tissues by adjusting the particle size and magnetic field; (ii) particle size plays a key role in determining MNPs' diffusion behaviours. The magnitude of MNP equivalent diffusivity is reversely correlated to the particle size. The MNPs with a dimension greater than 90 nm cannot reach a uniform distribution in the brain WM even in an external magnitude field; (iii) axon tortuosity may lead to transversely anisotropic MNP transport in the brain WM; however, this effect can be mitigated by applying an external magnetic field perpendicular to the local axon track. This study not only advances understanding to answer the question of how to optimise MNP delivery, but also demonstrates the potential of mathematical modelling to help achieve desired drug distributions in biological tissues with a complex microstructure.

An all-organic conditioning method to achieve deep dewatering of waste activated sludge and the underlying mechanism.

Among the common treatment/disposal routes of excessive activated sludge from municipal wastewater treatment plant, dewatering process functions as an essential pre-/post-treatment for volume minimization and transportation facilitation. Since inorganic coagulants have long been criticized for their high dosage and solid residue in sludge cake, there is an urgent need for investigations regarding the potential of applying organic chemicals as the conditioner. In this study, combined use of poly dimethyldiallylammonium chloride (PDMD) and tannic acid (TA) were investigated as an all-organic co-conditioning method for sewage sludge pre-treatment. Results showed that this all-organic conditioning strategy can effectively improve the dewaterability of sewage sludge. The capillary suction time reduced from 128.8 s to 23.1 s, and the filtration resistance reduced from 1.24 × 1012 cm/g to 7.38 × 1010 cm/g. The moisture content of dewatered sludge cake decreased to as low as 55.83%, showing the highest dewatering efficiency reported so far. In addition, the combination of PDMD and TA maximized the treating efficiency with very limited consumption of conditioners (added up to 4% of total solid). Based on the physic-chemical and rheological property investigation, it was proposed that the intermediate molecular weight polymer-based flocculation process and the TA agent-based protein precipitation process, could remarkably strengthen the compactness and structure robustness of sludge. In all, this PDMD-TA-based conditioning method suggested practical significance in consideration of its cost-effectiveness and disposal convenience of sludge cake.

Exosome derived from human adipose-derived stem cell improve wound healing quality: A systematic review and meta-analysis of preclinical animal studies.

Excellent capability of exosome derived from human adipose-derived stem cell (ADSC) manifested in improving the quality of wound healing with SMD (STD Mean Difference). However, it is still in the preclinical stage and its efficacy remains uncertain. Emphasised the need for a systematic review of preclinical studies to the validity of it in ameliorate wound healing quality which accelerate the clinical application translation. We performed a systematic literature review to identify all published controlled and intervention studies comparing exosome derived from human ADSC with placebo in animal models of wound closure during wound healing. PubMed, Embase and Cochrane were employed. Risk of bias assessed by the SYRCLE tool aimed at preclinical animal studies. Administration of exosome derived from human ADSC extremely improved wound closure compared with controls, which is primary outcome (SMD 1.423, 95% confidence interval (CI) 1.137-1.709 P < .001), the same effect as ADSC. The therapeutic effect is further enhanced by modified ADSC-EV. Other outcomes: density and the number of blood vessels: (SMD 1.593 95% CI 1.007-2.179 P < .001)；Fibrosis-related protein expression was highly expressed in the early term of wound healing, decreased in shaping period, which automatically regulates wound collagen deposition. Scar size, number of fibroblast and epithelial cell migration and proliferation expressed were ranked as follows: modified adipose stem cell exosomes > adipose stem cell exosomes > controls. Exosome derived from human ADSC, especially after enrichment for specific non-coding RNA, is a promising approach to improve healing efficiency.

An enriched environment reduces chronic stress-induced visceral pain through modulating microglial activity in the central nucleus of the amygdala.

Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders; however, the underlying mechanisms of CBT remain to be explored. Previously, we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We stereotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days after CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment, and the expression of synaptic pruning-related signals complement component 1q (C1q), complement component 3 (C3), and C3 receptor (C3R) were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared with control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.NEW & NOTEWORTHY Clinical studies show that cognitive behavioral therapy (CBT) is effective in ameliorating visceral pain in patient with irritable bowel syndrome (IBS), yet the underlying mechanisms remain unexplored. By using environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, we demonstrated that microglia-mediated synaptic plasticity in the CeA explains, plays a role, at least in part, in the positive effects of EE to reduce visceral hypersensitivity.

Internal Social Attention: Gaze Cues Stored in Working Memory Trigger Involuntary Attentional Orienting.

Previous research has shown that social cues, including eye gaze, can readily guide our focus of attention-a phenomenon referred to as social attention. Here, we demonstrated that internally maintained social cues in working memory (WM) can produce an analogous attentional effect (N = 57). Using the delayed-match-to-sample paradigm combined with the dot-probe task, we found that holding irrelevant gaze cues in WM can induce attentional orienting in college-age adults. Importantly, this WM-induced attention effect could not be explained simply by the perceptual-attentional process, because the identical gaze cues that were only passively viewed and not memorized in WM could not trigger attentional orienting beyond the typical time window of social attention. Furthermore, nonsocial cues (i.e., arrows) held in WM failed to elicit the attentional-orienting effect. These findings provide new evidence for the conceptualization of WM as internally directed attention and highlight the uniqueness of social attention compared with nonsocial attention.

Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.

Immunity and inflammation in pulmonary arterial hypertension: From pathophysiology mechanisms to treatment perspective.

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary dysfunctional disease, characterized by progressive vascular remodeling. Inflammation is an increasingly recognized feature of PAH, which is important for the initiation and maintenance of vascular remodeling. High levels of various inflammatory mediators have been documented in both PAH patients and experimental models of PAH. Similarly, multiple immune cells were found to accumulate in and around the wall of remodeled pulmonary vessels and in the vicinity of plexiform lesions, respectively. On the other hand, inflammation is also a bridge from autoimmune diseases to PAH. Autoimmune diseases always lead to chronic inflammation, characterized by the low-level persistent infiltration of immune cells, and elevated levels of several pro-inflammatory cytokines and chemokines. In addition, circulating autoantibodies are found in the peripheral blood of patients, indicating a possible role of autoimmunity in the pathogenesis of PAH. Thus, anti-inflammatory and immunotherapy might be new strategies to prevent or even reverse the process of PAH. Many anti-inflammatory agents and immunotherapies have been confirmed in animal models while some clinical trials employing immunotherapies are completed or currently underway. Here, we review pathological mechanisms associated with inflammation and immunity in the development of PAH, and discuss potential interventions for the treatment of PAH.

Effect of Particle Size and Surface Charge on Nanoparticles Diffusion in the Brain White Matter.

PURPOSE: Brain disorders have become a serious problem for healthcare worldwide. Nanoparticle-based drugs are one of the emerging therapies and have shown great promise to treat brain diseases. Modifications on particle size and surface charge are two efficient ways to increase the transport efficiency of nanoparticles through brain-blood barrier; however, partly due to the high complexity of brain microstructure and limited visibility of Nanoparticles (NPs), our understanding of how these two modifications can affect the transport of NPs in the brain is insufficient. METHODS: In this study, a framework, which contains a stochastic geometric model of brain white matter (WM) and a mathematical particle tracing model, was developed to investigate the relationship between particle size/surface charge of the NPs and their effective diffusion coefficients (D) in WM. RESULTS: The predictive capabilities of this method have been validated using published experimental tests. For negatively charged NPs, both particle size and surface charge are positively correlated with D before reaching a size threshold. When Zeta potential (Zp) is less negative than -10 mV, the difference between NPs' D in WM and pure interstitial fluid (IF) is limited. CONCLUSION: A deeper understanding on the relationships between particle size/surface charge of NPs and their D in WM has been obtained. The results from this study and the developed modelling framework provide important tools for the development of nano-drugs and nano-carriers to cure brain diseases.

Puerarin-V prevents the progression of hypoxia- and monocrotaline-induced pulmonary hypertension in rodent models.

Pulmonary hypertension (PH) is a cardiopulmonary disease characterized by a progressive increase in pulmonary vascular resistance. One of the initial pathogenic factors of PH is pulmonary arterial remodeling under various stimuli. Current marketed drugs against PH mainly relieve symptoms without significant improvement in overall prognosis. Discovering and developing new therapeutic drugs that interfere with vascular remodeling is in urgent need. Puerarin is an isoflavone compound extracted from the root of Kudzu vine, which is widely used in the treatment of cardiovascular diseases. In the present study, we evaluated the efficacy of puerarin in the treatment of experimental PH. PH was induced in rats by a single injection of MCT (50 mg/kg, sc), and in mice by exposure to hypoxia (10% O2) for 14 days. After MCT injection the rats were administered puerarin (10, 30, 100 mg · kg-1 · d-1, i.g.) for 28 days, whereas hypoxia-treated mice were pre-administered puerarin (60 mg · kg-1 · d-1, i.g.) for 7 days. We showed that puerarin administration exerted significant protective effects in both experimental PH rodent models, evidenced by significantly reduced right ventricular systolic pressure (RVSP) and lung injury, improved pulmonary artery blood flow as well as pulmonary vasodilation and contraction function, inhibited inflammatory responses in lung tissues, improved resistance to apoptosis and abnormal proliferation in lung tissues, attenuated right ventricular injury and remodeling, and maintained normal function of the right ventricle. We revealed that MCT and hypoxia treatment significantly downregulated BMPR2/Smad signaling in the lung tissues and PPARγ/PI3K/Akt signaling in the lung tissues and right ventricles, which were restored by puerarin administration. In addition, we showed that a novel crystal type V (Puer-V) exerted better therapeutic effects than the crude form of puerarin (Puer). Furthermore, Puer-V was more efficient than bosentan (a positive control drug) in alleviating the abnormal structural changes and dysfunction of lung tissues and right ventricles. In conclusion, this study provides experimental evidence for developing Puer-V as a novel therapeutic drug to treat PH.

Insights into Infusion-Based Targeted Drug Delivery in the Brain: Perspectives, Challenges and Opportunities.

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity; however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain.

Potential application of a hydrotalcite-like compound for reduction of toxicity to aquatic organisms via rapid and efficient removal of hydrogen sulfide.

Hydrogen sulfide (H2S) is known to have wide ranging toxicities not only as a gas but also as dissolved forms in aquatic environments. The diversity of aquatic organisms can be severely affected by hydrogen sulfide at very low concentrations, indicating the urgent necessity to develop an efficient method for removal of hydrogen sulfide in water. In this study, the removal capacity for hydrogen sulfide of our originally developed hydrotalcite-like compound composed of magnesium and iron (MF-HT) was investigated and its potential application for reduction of toxicity to aquatic organisms was evaluated. The MF-HT experimentally showed a high adsorption capacity of 146.5 mg/g with a fast adsorption equilibrium time of 45 min, both of which are top-class compared with those of other adsorbents previously reported. In fact, removal of hydrogen sulfide (1.2-152.5 mg/L) at an average rate of >97.6% was achieved in groundwater samples (n = 16) by the MF-HT within 60 min. The toxicities of groundwater, indicated by inhibition rate for microalgae (primary producers) and immobilization rate for crustaceans (secondary consumers), were reduced by 96.1% and 82.5% in 2-fold and 4-fold diluted groundwater, respectively, after treatment with the MF-HT for 60 min. These results indicate that MF-HT has an excellent safety record for aquatic organisms. After clarifying the adsorption mechanism, excellent reusability of MF-HT was also confirmed after regeneration using 1 M Na2CO3 solution. Considering the efficacy, speed, safety and cost of MF-HT, it could be a novel promising material for solving the problem of hydrogen sulfide pollution in the hydrosphere.