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Objective: The purpose of this study is to explore the process and internal mechanism of patients with diabetes falling into the vicious cycle of medication dependence from the perspective of patients' life., Methods: Employing purposive sampling, 23 patients with type 2 diabetes were interviewed individually at a renowned tertiary hospital in South China. Subsequently, interview data underwent content analysis., Results: Analysis of the collected data yielded three overarching themes: "disease limits me everywhere," "the medications make me feel my life again," and "difficult to get rid of the medication dependence.", Conclusions: Our study reveals the process and underlying causes of the vicious cycle of medication dependence among patients with type 2 diabetes. Diabetes patients, in the process of integrating self-management into their daily lives, often view medication as a shortcut to simplify life. They struggle between comprehensive management and dependence on medication, but influenced by immediate gratification and life rationality, they ultimately fall into an inescapable vicious cycle., Practice Implications: This study can provide information for targeted interventions to enhance patients' comprehensive health management abilities, thereby breaking the vicious cycle., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin β receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4 + Foxp3 + Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

It has been 16 years since the world's largest Ulva bloom appeared in the Yellow Sea. However, it remains unclear how the floating Ulva prolifera developed into the immense green tide within two months especially considering that source control measures have been conducted since 2019. In this study, we investigated the growth mechanism of the floating population by examining the production and regeneration of U. prolifera explants and constructing a growth model. The results showed that U. prolifera explants exhibited rapid regeneration mainly through branches at 15, 20 and 25 °C. Algivore feeding and sporulation (at 20-25 °C) contributed to mass production of explants. The growth of floating population could be attributed to the coupling of mass production and rapid regeneration of explants through multiple cycles, which accounted for the outbreak of floating green tide. This finding presented a novel population growth model to elucidate macroalgal bloom occurrences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hepatic ischemia reperfusion (I/R) injury is a common clinical complication. X-box binding protein 1 (XBP1), as a critical regulator of the endoplasmic reticulum stress, has been implicated in a variety of diseases. In this study, we aimed to investigate the effects and the underlying mechanism of XBP1 in the progression of hepatic I/R injury. Hepatocyte-specific XBP1 knockout mice, multiple viral delivery systems and specific pharmacological inhibitors were applied in vivo in a partial hepatic I/R injury mouse model and in vitro in a cell model of hypoxia-reoxygenation (H/R) injury. Mitophagy and autophagic flux were evaluated and fluorescence resonance energy transfer (FRET) as well as immunoprecipitation were performed. The results demonstrated that reperfusion for 6 h represented a critical timepoint in hepatic I/R injury and resulted in significant intracellular mitochondrial dysfunction; led to the breakdown of hepatocytes accompanied by the highest expression levels of XBP1. Hepatocyte-specific XBP1 knockout alleviated hepatic I/R injury via enhanced mitophagy, as demonstrated by the reduction in hepatocellular damage/necrosis and increased expression of mitophagy markers. Mechanistically, XBP1 interacted with FoxO1 directly and catalyzed the ubiquitination of FoxO1 for proteasomal degradation. Targeting XBP1 by genetic or pharmacological techniques potentiated the protein levels of FoxO1, further promoting the activity of the PINK1/Parkin signaling pathway, thus augmenting mitophagy and exerting hepatoprotective effects upon I/R injury. In conclusion, the inhibition of XBP1 potentiated FoxO1-mediated mitophagy in hepatic I/R injury. Specific genetic and pharmacological treatment targeting XBP1 in the perioperative 6 h prior to reperfusion exerted beneficial effects, thus providing a novel therapeutic approach., Competing Interests: Declaration of competing interest The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The world's largest green tide, caused by the nuisance green algae Ulva prolifera, has occurred in the southern Yellow Sea for 16 consecutive years. It is puzzling why the extensive floating green tide occurs exclusively in the southern Yellow Sea, rather than other waters. We speculate that the transition of U. prolifera from a sessile state to a surface-floating one is the underlying cause of the floating green tide. Here we founded that the floating of U. prolifera was attributed to detachment from substrata and appropriate desiccation. The convergence of unreasonable green algae disposal, geographical features and farming patterns of Porphyra (economic red algae) in Subei Shoal contributed to mass production of floating U. prolifera, resulting in the exclusive occurrence of the floating green tides. Inducing the natural inactivation of green algae to prevent the floating of U. prolifera may effectively mitigate the extensive Ulva bloom at zero cost., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The longevity protein sirtuins (SIRTs) belong to a family of nicotinamide adenine dinucleotide (NAD + )-dependent deacetylases. In mammals, SIRTs comprise seven members (SIRT1-7) which are localized to different subcellular compartments. As the most prominent mitochondrial deacetylases, SIRT3 is known to be regulated by various mechanisms and participate in virtually all aspects of mitochondrial homeostasis and metabolism, exerting significant impact on multiple organs. Notably, the kidneys possess an abundance of mitochondria that provide substantial energy for filtration and reabsorption. A growing body of evidence now supports the involvement of SIRT3 in several renal diseases, including acute kidney injury, chronic kidney disease, and diabetic nephropathy; notably, these diseases are all associated with aging. In this review, we summarize the emerging role of SIRT3 in renal diseases and aging, and highlights the intricate mechanisms by which SIRT3 exerts its effects. In addition, we highlight the potential therapeutic significance of modulating SIRT3 and provide valuable insights into the therapeutic role of SIRT3 in renal diseases to facilitate clinical application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oncolytic viruses (OVs) have shown potential in converting a "cold" tumor into a "hot" one and exhibit effectiveness in various cancer types. However, only a subset of patients respond to oncolytic virotherapy. It is important to understand the resistance mechanisms to OV treatment in pancreatic ductal adenocarcinoma (PDAC) to engineer oncolytic viruses. In this study, we used transcriptome RNA sequencing (RNA-seq) to identify Visfatin, which was highly expressed in the responsive tumors following OV treatment. To explore the antitumor efficacy, we modified OV-mVisfatin, which effectively inhibited tumor growth. For the first time, we revealed that Visfatin promoted the antitumor efficacy of OV by remodeling the tumor microenvironment, which involved enhancing CD8 + T cell and DC cell infiltration and activation, repolarizing macrophages towards the M1-like phenotype, and decreasing T reg cells using single-cell RNA sequencing (scRNA-seq) and flow cytometry. Furthermore, PD-1 blockade significantly enhanced OV-mVisfatin antitumor efficacy, offering a promising new therapeutic strategy for PDAC., Competing Interests: Declaration of competing interest We declared that There is No conflict of interest for this paper., (Copyright © 2024. Published by Elsevier Inc.)

The rapid development of the industry has led to the destruction of the earth's ozone layer, resulting in an increasingly serious problem of excessive ultraviolet radiation. Exploring effective measures to address these problems has become a hot topic. Lignin shows promise in the design and preparation of anti-ultraviolet products due to its inherent properties. However, it is important to investigate way to enhance the reactivity of lignin and determine its application form in related products. In this study, phenolic reactions with tea polyphenols were conducted through acid-catalyzed conversion, utilizing organic solvent lignin as the primary material. The phenolic hydroxyl content of the original lignin increased significantly by 218.8 %, resulting in notable improvements in UV resistance and oxidation resistance for phenolic lignin. Additionally, micro-nanocapsule emulsions were formed using phenolic lignin particles as surfactants through ultrasonic cavitation with small-molecule sunscreens. A bio-based sunscreen was prepared with phenolated lignin micro-nanocapsules as the active ingredient, achieving an SPF 100.2 and demonstrating excellent stability. The sunscreen also exhibited strong antioxidant properties and impermeability, ensuring user safety. This research offers a current solution for improving the application of lignin in sunscreens while also broadening the potential uses of plant-based materials in advanced functional products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Evasion of apoptosis is a hallmark of cancer, attributed in part to overexpression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). In a variety of cancer types, including lymphoma, Bcl-2 is overexpressed. Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy. Therefore, the development of co-delivery systems for Bcl-2 targeting agents, such as small interfering RNA (siRNA), and chemotherapeutics, such as doxorubicin (DOX), holds promise for enabling combination cancer therapies. Lipid nanoparticles (LNPs) are a clinically advanced nucleic acid delivery system with a compact structure suitable for siRNA encapsulation and delivery. Inspired by ongoing clinical trials of albumin-hitchhiking doxorubicin prodrugs, here we developed a DOX-siRNA co-delivery strategy via conjugation of doxorubicin to the surface of siRNA-loaded LNPs. Our optimized LNPs enabled potent knockdown of Bcl-2 and efficient delivery of DOX into the nucleus of Burkitts' lymphoma (Raji) cells, leading to effective inhibition of tumor growth in a mouse model of lymphoma. Based on these results, our LNPs may provide a platform for the co-delivery of various nucleic acids and DOX for the development of new combination cancer therapies., Competing Interests: The authors declare the following competing financial interest(s): Michael J. Mitchell, Kamila Butowska, and Xuexiang Han are inventors on a patent related to this work filed by the Trustees of the University of Pennsylvania., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background: Genetically modified dendritic cells (DCs) modulate the alloimmunity of T lymphocytes by regulating antigen presentation., Methods: We generated mice with specific deletion of the X-box-binding protein 1 (XBP1) allele in bone marrow cells and cultured bone marrow-derived DCs (Xbp1 -/- BMDCs) from these animals. We then tested the phenotype of Xbp1 -/- BMDCs, evaluated their capability to activate allogeneic T cells and investigated their mechanistic actions. We developed a mouse model of allogeneic heart transplantation in which recipients received PBS, Xbp1 -/- BMDCs, a suboptimal dose of cyclosporine A (CsA), or Xbp1 -/- BMDCs combined with a suboptimal dose of CsA to evaluate the effects of Xbp1 -/- BMDC transfusion on alloimmunity and on the survival of heart allografts., Results: The deletion of XBP1 in BMDCs exploited the IRE1-dependent decay of TAPBP mRNA to reduce the expression of MHC-I on the cell surface, altered the capability of BMDCs to activate CD8 + T cells, and ultimately suppressed CD8 + T-cell-mediated allogeneic rejection. The adoptive transfer of Xbp1 -/- BMDCs inhibited CD8 + T-cell-mediated rejection. In addition, XBP1-deficient BMDCs were weak stimulators of allogeneic CD4 + T cells despite expressing high levels of MHC-II and costimulatory molecules on their cell surface. Moreover, the adoptive transfer of Xbp1 -/- BMDCs inhibited the production of circulating donor-specific IgG. The combination of Xbp1 -/- BMDCs and CsA treatment significantly prolonged the survival of allografts compared to CsA alone., Conclusions: The deletion of XBP1 induces immunosuppressive BMDCs, and treatment with these immunosuppressive BMDCs prevents alloimmune rejection and improves the outcomes of heart transplantation. This finding provides a promising therapeutic target in combating transplant rejection and expands knowledge of inducing therapeutic DCs., Competing Interests: Declaration of Competing Interest This research was supported by grants from the National Natural Science Foundation of China (grant numbers: 81873623 and 81570678), the Major State Basic Research Development Program of China (grant number: 2013CB530803), the Clinical Research Physician Program of Tongji Medical College, HUST and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences (grant number: 2018PT32018). The authors would like to express their gratitude to EditSprings (https://www.editsprings.com/) for the expert linguistic services provided., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) have poor aqueous solubility, which hinders their clinical application. The reports show that the solubility of many insoluble drugs can be significantly improved through salt formation with the PIP. In this work, we obtained a series of NSAIDs-PIP salts, such as ibuprofen-piperazine (IBU-0.5PIP) salt, indomethacin-piperazine (IND-0.5PIP) salt, sulindac-piperazine (SUL-0.5PIP) salt, phenylbutazone-piperazine (PBZ-0.5PIP) salt, ketoprofen-piperazine (KPF-0.5PIP) salt and flurbiprofen-piperazine (FLB-0.5PIP) salt. The spatial structure, arrangement, interaction and associations were expatiated by single crystal X-ray diffraction. Powder X-ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The six new salts had more than 10 folds of solubility and a faster dissolution rate improved corresponding to the bulk drugs in pure water, and the significant improvement of solubility is closely related to the structure of salts., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2022 American Pharmacists Association. All rights reserved.)

Accurate detection of microRNA (miRNA) is challenging but essential for disease diagnostics and therapeutics. To meet the high demands of miRNA analysis, we proposed a highly sensitive and specific electrochemical strategy based on duplex-specific nuclease (DSN)-assisted target recycling and DNA self-assembled FeN x C nanocatalytic network for precise quantitation of miRNA-21 as a model. FeN x C nanospherical catalyst with high peroxidase-mimicking activity was synthesized through high-temperature pyrolysis and modified with DNA. The identification of miRNA-21 by elaborately designed capture probe triggered DSN-assisted target recycling. Subsequently, self-assembled FeN x C nanocatalytic network was constructed on the sensor surface through DNA hybridization reaction, whose signal response was demonstrated to be 4.272-fold higher than the single layer of FeN x C. By virtue of such cascade signal amplification, ultrasensitive electrochemical detection of miRNA-21 was realized in a dynamic range of 0.5 fM - 1 pM with a detection limit of 0.2805 fM. Additionally, the proposed strategy exhibited high specificity for miRNA-21 and practical applicability in real sample analysis, demonstrating promising potential for the reliable miRNA analysis in disease diagnosis and therapy applications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Near-infrared (NIR) emitting BiVO 4 :Yb 3+ ,Tm 3+ nanoparticles are synthesized by a new solvothermal strategy using solvents of oleic acid and methanol. The obtained BiVO 4 :Yb 3+ ,Tm 3+ samples show an average particle size of ≈164 nm and exhibit an asymmetry monoclinic crystal structure of BiVO 4 . At NIR excitation of 980 nm, the BiVO 4 :Yb 3+ ,Tm 3+ sample exhibits a nearly single NIR emission at ≈796 nm with extremely weak blue emissions from Tm 3+ ions. These high-energy visible emissions are absorbed by the semiconducting host of BiVO 4 that possesses a bandgap of ≈2.2 eV. Therefore, the NIR excitation to a single intense NIR emission fluorescent BiVO 4 materials could be a potential ideal probe for deep-tissue high-resolution bioimaging. To validate the ability of BiVO 4 materials for bio-applications, we conduct the cytotoxicity experiments. The results show that the cytotoxicity of HeLa cells is negligible at a concentration of 0.2 mg/ml of BiVO 4 :Yb 3+ ,Tm 3+ , and the cell viability approaches 90% at a high dosage of 0.5 mg/ml. The Daphnia magna and Zebrafish treated with nanoparticles (0.5 mg/ml) display bright NIR emission without any background, indicating the excellent in vivo fluorescent imaging capacity of BiVO 4 :Yb 3+ ,Tm 3+ nanoparticles. Our findings offer an environment-friendly strategy to synthesize BiVO 4 UCL nanophosphors and provide a promising new class of fluorescent probes for biological applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Trimethylamine-N-oxide (TMAO), a gut microbiota-produced metabolite, is accumulated in chronic kidney disease (CKD) patients. It is well known to contribute to CKD-related cardiovascular complications. However, the effect of TMAO on peritoneal dialysis (PD)-related peritonitis remains largely unknown. Here, we demonstrate that serum concentrations of TMAO were positively correlated with C-reactive protein levels, and the appearance rate of dialysate IL-6 and PAI-1, in PD patients. During the follow-up period of 28.3 ± 8.0 months, patients with higher TMAO levels (≥50 μM) had a higher risk of new-onset peritonitis (HR, 3.60; 95%CI, 1.18-10.99; P=0.025) after adjusting for sex, age, diabetes, PD duration, BUN, rGFR, C-reactive protein, BMI and β2-M. In CKD rat models, TMAO significantly promoted peritoneal dialysate-induced inflammatory cell infiltration, inflammatory cytokines production in the peritoneum. In vitro study revealed that TMAO directly induced primary peritoneal mesothelial cell necrosis, together with increased production of pro-inflammatory cytokines including CCL2, TNF-α, IL-6, and IL-1β. In addition, TMAO significantly increased TNF-α-induced P-selectin production in mesothelial cells, as well as high glucose-induced TNF-α and CCL2 expression in endothelial cells. In conclusion, our data demonstrate that higher levels of TMAO exacerbate peritoneal inflammation and might be a risk factor of incidence of peritonitis in PD patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It has been 14 years since the world's largest Ulva bloom appeared in the Yellow Sea, China in 2007. Although it is clear that the Ulva bloom originates from the culture system of Porphyra yezoensis (Nori) in the southern Yellow Sea, how to control it is still little understood. Since overwintering banks played a crucial role in the development of spring population of green algae on the cultivation ropes, here, a promising method was presented to prevent the development of Ulva bloom by the inactivation of the overwintering banks of green algae on the P. yezoensis cultivation ropes during February and early March. Chlorine dioxide, an environment-friendly disinfectant was used as algaecide with dosage of no lower than 40 mg/L at the contact time of 1 min. The overwintering green algae gradually disappeared within two weeks after the treatment. Furthermore, the growth of spring population of green algae on the cultivation ropes was effectively inhibited for at least eight weeks, which contribute to prevent the formation of floating populations during cultivation facilities collection. It was expected that the present method, if to be applied in the P. yezoensis cultivation areas in southern Yellow Sea, may mitigate the magnitude of the Ulva blooms in the Yellow Sea at a lower cost., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: MiR-135b is a downstream effector of oncogenic signaling pathways. This study aimed to reveal the underlying regulation and significance of miR-135b in gastric cancer., Materials and Methods: The influence of Wnt and PI3K/AKT signaling pathways on the transcriptional activation of the miR-135b promoter was determined by dual-luciferase reporter assays. In vitro experiments, including the cell counting kit-8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry analysis and malignant phenotype profiles, were conducted to determine the oncogenic role of miR-135b in gastric cancer. To analyze the clinical significance of miR-135b in gastric cancer, the expression profile of miR-135b in tissue specimens and plasma was examined by quantitative real-time PCR (qRT-PCR)., Key Findings: Oncogenic signaling pathways represented by Wnt and PI3K/AKT promoted the transcriptional activation of the miR-135b promoter in gastric cancer. Downregulation of miR-135b inhibited proliferation, promoted apoptosis, and suppressed the migratory, invasive, and adherent abilities as well as the cancer stem cell phenotype of gastric cancer cells. High expression of miR-135b in gastric cancer tissues was tightly associated with poor prognosis and malignant transformation represented by metastasis of gastric cancer. The miR-135b level in the plasma of gastric cancer patients was significantly higher than that in healthy individuals., Significance: MiR-135b is a potential downstream effector of the Wnt and PI3K/AKT signaling pathways in gastric cancer. High expression of miR-135b may predict malignant transformation and poor prognosis of gastric cancer. This study reveals the potential role of miR-135b as a target for the early diagnosis and therapy of gastric cancer., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The implant surface and tissue experience strain when micro-motion occurs at the bone-implant interface under physiological loading. Moreover, strain is also introduced on the surface during mechanical processing of biomedical devices. Both these situations can induce phase transformation depending on the degree of stability of the microstructural constituents. In this regard, we elucidate here the interplay between mechanically-induced phase transformation (strain-induced martensite) in austenitic stainless steel on osteoblast functions. Strain-induced martensite significantly impacted cellular functions, notably, cell attachment, cell-surface interactions, proliferation, and synthesis of prominent proteins (fibronectin, actin, and vinculin). Strain-induced martensite favorably modulated cellular activity and contributed to small differences in hydrophilicity in relation to the non-strained austenitic stainless steel surface. The study provides a pathway for tuning biological functionality via microstructural control facilitated by mechanical strain., Competing Interests: Declaration of competing interest There are no conflicts of interest associated with this publication and there is no significant financial support for this work that could have influenced its outcome., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The occurrence and development of osteoclasts can directly affect the severity of bone destruction in middle ear cholesteatoma. At the same time, cell communication between keratinocytes and fibroblasts can stimulate osteoclast differentiation. However, the molecular mechanism of osteoclast differentiation in cholesteatoma is still poorly understood. In this study, we try to isolate the exosomes of keratinocytes from patients with middle ear cholesteatoma, and explore the effects of keratinocyte-derived exosomes (Ker-Exo) on osteoclast differentiation by co-culturing Ker-Exo with fibroblasts and osteoclast precursor cells. As a result, we confirmed that Ker-Exo primed fibroblasts can up-regulate the expression of RANKL and promote osteoclast differentiation. We revealed that the effect of Ker-Exo depened on its miRNA-17 conponent. Analysis confirmed that miRNA-17 was down-regulated in Ker-Exo, and they can increase RANKL level in fibroblasts, thus promoting the differentiation of osteoclasts. In conclusions, we provide evidence that exosomes miRNA-17 secreted by keratinocytes in patients with middle ear cholesteatoma can up-regulate the expression of RANKL in fibroblasts and induce osteoclast differentiation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Conventional coarse-grained (CG) biomedical austenitic stainless steel with grain size in the micrometer range was subjected to a novel phase reversion concept involving severe cold deformation, followed by annealing, when the cold deformed martensite reverts to austenite with grain size in the nanometer/ultrafine (NG/UFG) regime (~200-400 nm). The mechanical behavior of CG and NG/UFG steels was studied via load-controlled and displacement-controlled experiments using a nanoindentation technique with the aim to simulate micromotion. The plastic zone associated with the indentation-induced deformed region was characterized by post-mortem electron microscopy of the deformed region to elucidate the deformation mechanism. Nanoscale twinning was the deformation mechanism in steel with grain size in the NG/UFG regime, and contributed to the ductility of high strength steel. In contrast, strain-induced martensite contributed to the ductility of low strength CG steel with micrometer grain size. Interestingly, besides the differences in the mechanical behavior, the biological functions of the two steels were remarkably different. Higher cell attachment, proliferation and higher expression level of prominent proteins, fibronection, actin and vinculin were favored by a surface with grain size in the nanometer regime and was in striking contrast with the surface with micrometer grain size. This behavior is attributed to the differences in the fraction of grain boundaries that are high energy two-dimensional defects. The study advances our understanding of the mechanical behavior of biomaterials and their cellular functions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study considered the stability of nickel oxide nanoparticles (nNiO) in seawater including their ability of aggregation and ion release. Furthermore, the relationship between these properties and their toxicity on marine algae Chlorella vulgaris was investigated. The results showed nNiO inhibited the growth of algal cells and decreased their chlorophyll content, which was due to the shading effects by aggregation of nNiO in seawater. Moreover, the release of Ni 2+ depended on concentration of the nNiO solution. About 1.63% Ni 2+ (varied from 0.89 to 3.63%) was detected and it may mediate the generation of ROS under both visible light and ultraviolet (UV) irradiation, which resulted in oxidative stress in algae. Therefore, the stability of nNiO in water affected its toxicity, which should be considered when assessing the nano-pollution risks in aquatic ecosystem., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In the cartilage and synovial microenvironment of osteoarthritis (OA) patients, utmost changes are commonly brought upon by the inflammatory cytokines, leading to cellular dysfunction, particularly in chondrocytes. The regulation of chondrogenesis, a key part is played the microRNAs. Thus, the current study aimed to assess the function of miR-20a in osteoarthritis. The miR-20a expression was observed to increase in the tissues of OA cartilage, when compared with tissues of normal cartilage, and enhanced proliferation of chondrocyte was observed in the presence of miR-20a. Moreover, on treating the chondrocytes with LPS (lipopolysaccharide), an increase in miR-20a level was observed. On transfecting with miR-20a inhibitor, inhibition in production of LPS-induced pro-inflammatory cytokines as well as cell apoptosis were seen. The assay for luciferase activity showed that the expression of IκBβ was impeded on being targeted at its 3'-UTR by miR-20a. The transfection of IκBβ and inhibitor of miR-20a repressed the NF-κB pathway activation and chondrocyte cellular apoptosis. An OA model was established for in vivo studies on rats by ACLT (anterior cruciate ligament transection). In conclusion, the results demonstrate an increase in articular cavity inflammation in rats with OA in the presence of miR-20a by targeting on IκBβ and activating the NF-κB signaling pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Raman spectra of acetic acid-water binary solutions with different concentrations have been measured in order to study molecular association of acetic acid. We find that the symmetric and asymmetric OH stretching vibration of water (3242 and 3443 cm -1 ) have marked changes of Raman shift when the volume fraction of acetic acid (V AA ) is 0.3 and 0.8, respectively, which demonstrates that the hydrogen bonding of the water is affected, causing association molecule (acetic acid-water structure) to undergo two phase transitions. Furthermore, the peak of the HCH bending vibration is blue-shifted at V AA  = 0.8, which shows that the acetic acid-acetic acid structure undergoes a phase transition and the acetic acid side-on dimer is formed. These results also indicate that the CH vibration mode in CH⋯O is HCH bending vibration. Finally, the phase transition process of association molecules (hydrated monomer, linear dimer, acetic acid side-on dimer and water-separated dimer) has been obtained in acetic acid-water binary solutions through theoretical analysis., (Copyright © 2018. Published by Elsevier B.V.)

Solvatomorphism occurred in diosgenin solvates. A series of solvates including DMSO, DMF, DMAC, Methanol of diosgenin were obtained and crystallized in order to compare their structures and properties in the solid state. Single-crystal X-ray diffraction was used to analyze the crystal structures and the solvent types and the stoichiometric ratio of the diosgenin solvates. Hirshfeld surface analyses, especially dnorm surface and fingerprint plots, were used to determine intermolecular interactions in the crystal structure. Powder X-ray diffraction, differential scanning calorimetry, thermogravimetric, Fourier transform Infrared spectroscopy were all used to characterize the diosgenin solvates. And the solvates transformation have been reported for the first time., (Copyright © 2018. Published by Elsevier Inc.)

Aim: To investigate the effects of ALA-PDT on biofilm structure, virulence factor secretion, and quorum sensing (QS) in Pseudomonas aeruginosa., Materials and Methods: We used confocal laser scanning microscopy (CLSM), an XTT assay, scanning electron microscopy (SEM), a virulence factor assay and qRT-PCR in this study., Results: The XTT assay showed that ALA-PDT significantly inhibited the growth of planktonic P. aeruginosa. CLSM and SEM showed that ALA-PDT destroyed both bacterial and biofilm structures. The virulence factor assay showed that pyocyanin and elastase secretion were significantly inhibited in the ALA-PDT groups. qRT-PCR assays demonstrated that ALA-PDT significantly reduced the mRNA expression of QS-related genes., Conclusion: ALA-PDT kills planktonic and viable biofilm-associated P. aeruginosa cells, destroys biofilm structures, reduces virulence factor secretion and affects QS system gene expression., (Copyright © 2018. Published by Elsevier B.V.)

Fluorescence and absorption characteristics of Chlorophyll a (Chl-a) were modulated by the carotenoids (Cars) with different numbers of conjugated carbon‑carbon double bonds in solutions. The Chl-a absorption appears the redshift phenomenon with the effective conjugated of Cars increasing. The absorption of Chl-a and Cars are linearly dependent on intrinsic factors, namely effective conjugate length and functional groups, and on environmental factors, such as the polarizability of the solvent. Cars can be able to quench the Chl-a fluorescence by producing the non-emitting exciplex intermediate. The effective conjugated length of Cars is one of the reasons that effect the fluorescence quenching of Chl-a. According to the Stern-Volmer plots, the Chl-a fluorescence quenching should be predominantly dynamic rather than static., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Recently, lncRNA ZEB2-AS1 was identified as a lncRNA that promoted cancer progression. However, the biological function and the underlying mechanism of ZEB2-AS1 in pancreatic cancer had not been reported. In the current study, we revealed that the expression level of ZEB2-AS1 was elevated in pancreatic cancer cell lines and tissues. ZEB2-AS1 inhibition decreased cell growth and invasion in pancreatic cancer. Mechanismly, ZEB2-AS1 exerted as a ceRNA and negatively regulated miR-204 expression. In addition, HMGB1 was identified as a down-stream target of miR-204. The miR-204/HMGB1 axis mediated ZEB2-AS1's effect on pancreatic cancer. Our findings revealed that lncRNA ZEB2-AS1 may be a candidate prognostic biomarker and a target for new therapies in pancreatic cancer patients., (Copyright © 2018. Published by Elsevier B.V.)

Carboxymethyl-chitosan (CMC)/bentonite composite was prepared by the method of membrane-forming, and characterized by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) techniques. The simultaneous adsorption of Cu 2+ and Acid fuchsin (AF) applying CMC/bentonite composite as an adsorbent in single or binary systems was investigated. The adsorption study was conducted systematically by varying the ratio of CMC to bentonite, adsorbent dosage, initial pH value, initial Cu 2+ (or AF) concentration, contact time and the interaction of two components in binary solutions. The results showed that the presence of Cu 2+ hindered the adsorption of AF, while the presence of AF almost had no influence on the adsorption of Cu 2+ in binary systems. The adsorption data of Cu 2+ and AF were both suitable for Langmuir isotherm model, and the maximum adsorption capacities of CMC/bentonite composite, according to the Langmuir isotherm model were 81.4 mg/g for Cu 2+ and 253.2 mg/g for AF at 298 K. The pseudo-second-order model could better describe the adsorption process of Cu 2+ and AF. Thermodynamic constant values illustrated that the adsorption of Cu 2+ was endothermic, while the adsorption process of AF was exothermic., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Photodynamic therapy (PDT) has been shown to be a very successful therapy in clinical practice, and its usefulness as a treatment for bacterial infections has been gradually recognized by researchers, who believe it has very good clinical prospects. Atypical mycobacterial skin infections are a type of rare refractory infection. The aim of this study was to evaluate the efficacy and safety of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with antibiotics for the treatment of atypical mycobacterial skin infections., Methods: In this study, 4 patients with atypical mycobacterial skin infections were treated with ALA-PDT combined with antibiotic therapy. These patients were diagnosed with atypical mycobacterial skin infections by bacterial culture and microarray analysis, tests that were also useful for identifying the strains responsible for the infections. In addition to being treated with antibiotics, the skin was also treated locally with ALA-PDT (20% ALA was applied to the lesion and incubated in the dark, then, the lesion was irradiated with a red light with an energy density of 100J/cm 2 ) every 10days for a total of 3-5 sessions., Results: All four patients enrolled in the study were cured with 100% efficiency after receiving combination therapy with ALA-PDT and antibiotics for three months. All patients experienced redness and pain during treatment but did not experience any other forms of severe discomfort and were satisfied with the results of their treatments., Conclusion: Local ALA-PDT combined with antibiotics is a safe and effective method of treating atypical mycobacterial skin infections., (Copyright © 2017. Published by Elsevier B.V.)

Four new solvatomorphs of betulin were reported and characterized by X-ray diffractometry as well as thermal and vibrational spectroscopic analyses. Single-crystal X-ray diffraction was used to analyze the X-ray structures of the compounds and confirmed the stoichiometric ratio between the host and guest molecules from thermal data. Results indicated that solvatomorphism occurred in several betulin solvates. Changes in intermolecular arrangements, stoichiometry, and hydrogen-bonding interactions of solvatomorphs were due to solvent incorporation to solvates. Hirshfeld surface analyses, especially d norm surface and fingerprint plots, were used to determine intermolecular interactions in the crystal network. Solvent molecules played an important role in the construction of a 3D architecture. The stabilities of these solvates were evaluated by thermal analyses. Nonisothermal kinetic analysis was used to explain the kinetics of solid-solid phase transition (desolvation) of betulin solvates. The apparent activation energies were evaluated using Kissinger and Ozawa methods. Moreover, phase transitions were visually investigated by hot-stage microscopic analysis., (Copyright © 2017. Published by Elsevier Inc.)

Background: Atypical mycobacterial skin infection is rare in clinical practice. Because atypical mycobacteria are highly hydrophobic, the permeability of the outer membrane of the bacterial wall is very low, which makes it difficult for drugs to cross the barrier. Additionally, atypical mycobacteria are resistant to many drugs, and thus, infection tends to last for a long time and become recurrent and difficult to treat. Thus, it is very important to find new, more effective treatment methods. Mycobacterium fortuitum is a type of fast-growing atypical mycobacterium that is resistant to all of the primary anti-TB drugs and thus is very difficult to treat. Recently, in vivo and in vitro experiments have shown that singlet oxygen generated by photodynamic therapy can kill various microorganisms, including atypical mycobacteria. Herein, we report one case of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with antibiotics for the treatment of multiple skin abscesses in the hands caused by M. fortuitum. The results showed that ALA-PDT combined with antibiotics was very effective for treating multiple skin abscesses caused by M. fortuitum and significantly shortened the treatment time., (Copyright © 2016. Published by Elsevier B.V.)

Betulin (BE), a triterpene found in many plant species, has recently attracted the attention of researchers because of its important physiological and pharmacological properties, such as anti-HIV and anticancer activities. Studies have revealed the solvatomorphism of BE (I with dimethyl sulfoxide and III with ethanol, named by author), which means more solvatomorphs may be obtained when different solvents are used during crystallization. After solid-form screening tests, 3 new solvatomorphs of BE with methanol (II), n-propanol (IV), and isopropanol (V) were obtained. In this work, 5 BE solvatomorphs were characterized by X-ray powder diffractometric, thermogravimetric, and Fourier transform infrared spectroscopic analyses. Single-crystal X-ray diffraction was used to analyze the X-ray structures of the compounds, and all 5 solvatomorphs were proven to be isostructral. Change in the crystal symmetry, intermolecular arrangements, stoichiometry, and hydrogen bonding interactions of the solvatomorphs resulted from solvent incorporation to the solvates. Solvatomorphs II, IV, and V, along with their single-crystal structures, were reported for the first time., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

7-hydroxyisoflavone has been crystallized, identified, and characterized as 2 solvent-free conformational polymorphs and 5 solvates, which differ from each other in the mode of packing and in molecular conformation. All the 7 crystal structures were previously unreported. The conformational polymorphs and solvates were compared by Hirshfeld surface and fingerprint plot analysis and were spectroscopically characterized by powder X-ray diffraction, differential scanning calorimetry, and thermal gravimetric analysis. Hydrogen bond played an important role in the formation of polymorphs. From this study, we can predict that more solvates could be cultivated in other polarity solvents such as isopropanol or 2-butanol at appropriate conditions., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Both peptidic agonist exenatide and herbal agonist catalpol of the glucagon-like peptide-1 receptor (GLP-1R) are neuroprotective. We have previously shown that activation of spinal GLP-1Rs expresses β-endorphin in microglia to produce antinociception. The aim of this study was to explore whether exenatide and catalpol exert neuroprotection via activation of the hippocampal GLP-1R/β-endorphin pathway. The rat middle cerebral artery occlusion model was employed, and the GLP-1R immunofluorescence staining and β-endorphin measurement were assayed in the hippocampus and primary cultures of microglia, neurons and astrocytes. The immunoreactivity of GLP-1Rs on microglia in the hippocampus was upregulated after ischemia reperfusion. Intracerebroventricular (i.c.v.) injection of exenatide and catalpol produced neuroprotection in the rat transient ischemia/reperfusion model, reflected by a marked reduction in brain infarction size and a mild recovery in neurobehavioral deficits. In addition, i.c.v. injection of exenatide and catalpol significantly stimulated β-endorphin expression in the hippocampus and cultured primary microglia (but not primary neurons or astrocytes). Furthermore, exenatide and catalpol neuroprotection was completely blocked by i.c.v. injection of the GLP-1R orthosteric antagonist exendin (9-39), specific β-endorphin antiserum, and selective opioid receptor antagonist naloxone. Our results indicate, for the first time, that the neuroprotective effects of catalpol and exenatide are GLP-1R-specific, and that these effects are mediated by β-endorphin expression probably in hippocampal microglia. We postulate that in contrast to the peripheral tissue, where the activation of GLP-1Rs in pancreas islet β-cells causes secretion of insulin to perform glucoregulation, it leads to β-endorphin expression in microglial cells to produce neuroprotection and analgesia in the central nervous system., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The difference in immunoregulatory effects between sirolimus and tacrolimus on kidney transplantation remains unclear. In this study, a total of 18 living-donor-related kidney transplant recipients received sirolimus (n=8) or tacrolimus (n=10) treatment. Kidney function, acute rejection, peripheral blood CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs), CD19(+)CD5(+)CD1d(+) regulatory B cells (Bregs), and panel reactivity antibody were analyzed after one and three years. Th1/2 cell polarization was also determined at one year. The proportion of Tregs in the recipients receiving tacrolimus significantly decreased to 3.69% and 2.49% at one and three years, respectively, compared to 6.59% in controls, whereas the proportion in the recipients receiving sirolimus remained at 6.67% and 5.66%, respectively. However, no differences in kidney function, acute rejection, proportion of Bregs, panel reactivity antibody, or the frequencies of Th1/2 cells were identified. In conclusion, unlike tacrolimus, sirolimus maintains the proportion of Tregs in kidney transplant recipients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study compares the results of three certified methods, namely differential scanning calorimetry (DSC), the mass balance (MB) method and coulometric titrimetry (CT), in the purity assessment of ferulic acid certified reference material (CRM). Purity and expanded uncertainty as determined by the three methods were respectively 99.81%, 0.16%; 99.79%, 0.16%; and 99.81%, 0.26% with, in all cases, a coverage factor (k) of 2 (P=95%). The purity results are consistent indicating that the combination of DSC, the MB method and CT provides a confident assessment of the purity of suitable CRMs like ferulic acid.

Cabazitaxel is an anticancer drug and its marketed product (form A) is acetone solvate (1:1) (Didier E, Perrin MA. 2005. Patent WO2005/028462 A1). This work describes three crystal structures of cabazitaxel 1:1 solvates with isopropyl alcohol (B), 2-butanol (C), and dioxane (D). These solvates are isostructural with cabazitaxel forming a host framework through hydrogen bonds and the guest solvent molecules located in channels from which they can escape. The host is hydrogen bonded to each other through hydroxyl O1 and sec-amide N3 ', whereas the hydroxyl O2 ' plays an important role in connecting the host to the guest. Moreover, because of the existence of channels in the crystal structure, the solvent-replacement method was established to prepare four new solvates of cabazitaxel with dimethyl formamide (E), cyclohexane (F), n-hexane (G), and ethyl ether (H). All the seven solvates involved in this work were proven to be isostructural by methods of X-ray crystallography and contain the same amount of solvents by thermogravimetric analysis. The single-crystal structures of solvate C-E and the solvates prepared by solvent-replacement method have been reported for the first time., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Alzheimer's disease (AD) is a complicated, neurodegenerative disorder involving multifactorial pathogeneses and still lacks effective clinical treatment. Recent studies show that lithium exerts disease-modifying effects against AD. However, the intolerant side effects at conventional effective dosage limit the clinical use of lithium in treating AD. To explore a novel AD treatment strategy with microdose lithium, we designed and synthesized a new chemical, tri-lithium pyrroloquinoline quinone (Li3PQQ), to study the synergistic effects of low-dose lithium and pyrroloquinoline quinone, a native compound with powerful antioxidation and mitochondrial amelioration. The results showed that Li3PQQ at a relative low dose (6 and 12 mg/kg) exhibited more powerful effects in restoring the impairment of learning and memory, facilitating hippocampal long-term potentiation, and reducing cerebral amyloid deposition and phosphorylated tau level in APP/PS1 transgenic mice than that of lithium chloride at both low and high dose (5 and 100 mg/kg). We further found that Li3PQQ inhibited the activity of glycogen synthase kinase-3 and increased the activity of β-amyloid-binding alcohol dehydrogenase, which might underlie the beneficial effects of Li3PQQ on APP/PS1 transgenic mice. Our study demonstrated the efficacy of a novel AD therapeutic strategy targeting at multiple disease-causing mechanisms through the synergistic effects of microdose lithium and pyrroloquinoline quinone., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Certified reference materials (CRMs) can be used as a valuable tool to validate the trueness of measurement methods and to establish metrological traceability of analytical results. Diosgenin has been selected as a candidate reference material. Characterization of the material relied on two different methods, mass balance method and Coulometric titration method (CT). The certified value of diosgenin CRM is 99.80% with an expanded uncertainty of 0.37% (k=2). The new CRM of diosgenin can be used to validate analytical methods, improve the accuracy of measurement data and control the quality of diosgenin in relevant pharmaceutical formulations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Five solvates of betulinic acid with dimethyl sulfoxide (I), methanol (II), ethanol (III), isopropyl alcohol (IV), and 2-butanol (V) have been described in this work. Methods of X-ray crystallography, thermal analysis, and Fourier transform infrared spectroscopy were introduced for solvatomorphic identifications and characterizations. The orientation of isopropenyl and carboxylic groups might differ because of single-bonding rotations. The incorporation of solvents resulted in changes of the crystal symmetry, intermolecular arrangements, stoichiometry, hydrogen bonding interactions, and so on. Adducted solvents contributed most to the stability of crystal lattices and led to the formation of crystalline forms. Solvates II-V with their single-crystal structures determined have been reported for the first time., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

We studied the hypothesis that spinal d-amino acid oxidase (DAAO) that is expressed in astrocytes and that has been reported to promote tonic pain in various pathophysiological conditions plays a role in 'physiological' pain hypersensitivity induced by rapid eye movement sleep deprivation (REMSD). The experiments were performed in healthy rats with a chronic intrathecal (i.t.) catheter. Pain behavior was assessed by determining limb withdrawal response to repetitive stimulation of the hind paw with a calibrated series of monofilaments. REMSD of 48 h duration produced a significant mechanical hypersensitivity. At 48 h of REMSD, the animals were treated i.t. with a DAAO inhibitor or vehicle. Three structurally different DAAO inhibitors were tested in this study: 6-chlorobenzo[d]isoxazol-3-ol (CBIO), sodium benzoate, and 5-methylpyrazole-3-carboxylic acid (AS-057278). CBIO (1-3 μg), sodium benzoate (30-100 μg) and AS-057278 (3-10 μg) produced dose-related antihypersensitivity effects in sleep-deprived animals. In control animals (with no sleep deprivation), the currently used doses of DAAO inhibitors failed to produce significant changes in mechanically evoked pain behavior. The results indicate that among spinal pain facilitatory mechanisms that contribute to the sleep deprivation-induced mechanical pain hypersensitivity is DAAO, presumably due to production of reactive oxygen species, such as hydrogen peroxide, an endogenous agonist of the pronociceptive TRPA1 ion channel., (© 2013.)

Polysaccharides with different molecular weights were extracted from Ulva pertusa and fractionated by ultrafiltration. Iron(III) complex of the low molecular-weight U. pertusa polysaccharides were synthesized. Atomic absorption spectrum showed that the iron content of iron(III)-polysaccharide complex was 27.4%. The comparison between U. pertusa polysaccharides and their iron(III) complex showed that iron chelating altered the structural characteristics of the polysaccharides. The bioactivity analysis showed that polysaccharide with low molecular weight was more effective than polysaccharide with high molecular weight in protecting mice from radiation induced damages on bone marrow cells and immune system. Results also proved that the anti-radiation and anti-oxidative activity of iron(III) complex of low molecular-weight polysaccharides were not less than that of low molecular-weight polysaccharides., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background & Aims: Missense mutations in human Krüppel-like factor 11 (KLF11) lead to the development of diabetes, as a result of impaired insulin synthesis in the pancreas. However, the role of KLF11 in peripheral tissues is largely unknown. The aim of this study is to evaluate the role of KLF11 in the regulation of hepatic lipid homeostasis using different mouse models., Methods: Adenoviruses expressing KLF11 (Ad-KLF11) or KLF11-specific shRNA (Ad-shKLF11) were injected into db/db diabetic, high-fat diet-induced obese (DIO), or normal C57BL/6J mice. Histological analysis of the fatty liver phenotype and biochemical analysis of hepatic and serum TG levels in these mice were performed. The molecular mechanism by which KLF11 regulates lipid metabolism in primary hepatocytes and mouse livers was explored., Results: The expression of the transcription factor KLF11 gene is dysregulated in the livers of db/db and DIO mice. Adenovirus-mediated overexpression of KLF11 in the livers of db/db and DIO mice activates the PPARα signaling pathway, subsequently markedly improving the fatty liver phenotype. Conversely, knockdown of KLF11, by adenovirus (Ad-shKLF11) in livers of wild type C57BL/6J and db/m mice, increases hepatic triglyceride (TG) levels, owing to decreased fatty acid oxidation. Finally, the treatment of diabetic mice with Ad-shPPARα abolishes KLF11 stimulatory effects on the expression of genes involved in fatty acid oxidation and inhibitory effects on hepatic TG content. In contrast, PPARα rescue restores the increased hepatic TG levels in Ad-shKLF11-infected db/m mice to normal levels., Conclusions: KLF11 is an important regulator of hepatic lipid metabolism., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Epithelial-mesenchymal transition (EMT) plays an important role in progress of renal allograft fibrosis. The adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 (Adanti-ERK2) gene therapy was used to block ERK signaling pathway, and its effect on EMT and renal allograft fibrosis both in vivo and in vitro was explored., Methods: We first generated an in vitro EMT model by connective tissue growth factor (CTGF) stimulation in a HK-2 cell culture system, and then applied Adanti-ERK2 gene therapy on it. The transition of epithelial marker (E-cadherin) to mesenchymal markers (α-SMA, Vimentin) and the cell mobility function alteration were monitored for the observation of EMT progress. In vivo, a rat renal transplant model with Fisher-Lewis combination was employed and the Adanti-ERK2 gene therapy was given. The tubular EMT changes and pathology of allograft fibrosis were examined., Results: In vitro, Adanti-ERK2 gene therapy inhibited CTGF-induced tubular EMT and attenuated the cell motility function induced by CTGF. In vivo, Adanti-ERK2 gene therapy attenuated tubular EMT, modulated the infiltration of macrophages and CD8(+), CD4(+)T lymphocytes, and ameliorated fibrosis effectively in the renal allografts 24weeks after transplantation., Conclusions: Adanti-ERK2 gene therapy inhibits tubular EMT and attenuates renal allograft fibrosis. It is possible to develop promising molecular drug(s) in the future based on ERK signaling pathway., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance. We now demonstrate that cocaine induces MCP-1 in rodent microglia through translocation of the sigma receptor to the lipid raft microdomains of the plasma membrane. Sequential activation of Src, mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3' kinase (PI3K)/Akt and nuclear factor kappaB (NF-kappaB) pathways resulted in increased MCP-1 expression. Furthermore, conditioned media from cocaine-exposed microglia increased monocyte transmigration, and thus was blocked by antagonists for CCR2 or sigma receptor. These findings were corroborated by demonstrating increased monocyte transmigration in mice exposed to cocaine, which was attenuated by pretreatment of mice with the sigma receptor antagonist. Interestingly, cocaine-mediated transmigratory effects were not observed in CCR2 knockout mice. We conclude that cocaine-mediated induction of MCP-1 accelerates monocyte extravasation across the endothelium. Understanding the regulation of MCP-1 expression and functional changes by cocaine/sigma receptor system may provide insights into the development of potential therapeutic targets for HIV-1-associated neurocognitive disorders.

GABA transporter-1 (GAT1) plays a key role in GABA reuptake, and deletion of GAT1 leads to a largely increased GABA-induced tonic conductance in the GAT1(-/-) mice. We hypothesized that homeostatic plasticity of GABA(A) receptor-mediated inhibition takes place to balance the increased tonic inhibition and maintains stability of the nervous system. In this study, we employed the loss of righting reflex assay and compared the behavioral difference of three animal models, mice with acute, partial, and permanent GAT1 deficiency, to confirm our hypothesis. Our data demonstrated that both acute and partial block of GAT1 increased the sensitivity of mice to GABAergic sedative/hypnotic drugs, whereas permanent GAT1 dysfunction in the GAT1(-/-) mice decreased the sensitivity to some extent. These results confirmed our presumption about the down-regulation of phasic GABAergic transmission in the GAT1 knockout mice. Moreover, electrophysiological measurements performed on slices from motor cortex suggested that it was the reduced GABA release, but not change of postsynaptic GABA receptors, which led to the down-regulation of phasic inhibition in GAT1(-/-) mice.

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial and rate-limiting step in glycerolipid synthesis. Several mammalian GPAT activities have been recognized, including N-ethylmaleimide (NEM)-sensitive isoforms in microsomes and mitochondria and an NEM-resistant form in mitochondrial outer membrane (GPAT1). We have now cloned a second mitochondrial isoform, GPAT2 from mouse testis. The open-reading frame encodes a protein of 798 amino acids with a calculated mass of 88.8kDa and 27% amino acid identity to GPAT1. Testis mRNA expression was 50-fold higher than in liver or brown adipose tissue, but the specific activity of NEM-sensitive GPAT in testis mitochondria was similar to that in liver. When Cos-7 cells were transiently transfected with GPAT2, NEM-sensitive GPAT activity increased 30%. Confocal microscopy confirmed a mitochondrial location. Incubation of GPAT2-transfected Cos-7 cells with trace (3 microM; 0.25 microCi) [1-(14)C]oleate for 6h increased incorporation of [(14)C]oleate into TAG 84%. In contrast, incorporation into phospholipid species was lower than in control cells. Although a polyclonal antibody raised against full-length GPAT1 detected an approximately 89-kDa band in liver and testis from GPAT1 null mice and both 89- and 80-kDa bands in BAT from the knockout animals, the GPAT2 protein expressed in Cos-7 cells was only 80 kDa. In vitro translation showed a single product of 89 kDa. Unlike GPAT1, GPAT2 mRNA abundance in liver was not altered by fasting or refeeding. GPAT2 is likely to have a specialized function in testis.

The loss of corneal endothelial cells plays a critical role in many corneal diseases and is a common phenomenon following cornea transplantation. In addition, the non-regenerative capacity of human corneal endothelial cells (HCEC) ultimately requires appropriate protection of corneal tissues during ex vivo storage to ensure vitality of the cells. However, only 70% of donor corneas can be used for grafting because of endothelial deficiencies. Corneal endothelial cell loss during storage is mainly induced by apoptotic cell death. This study was undertaken, for proof of principle, to investigate whether over-expression of cyto-protective molecules Bcl-x(L), Bag-1, and HO-1 prevents the loss of corneal endothelial cells both in vitro and in vivo. We demonstrate that gene transfer of both Bcl-x(L) and HO-1 has cyto-protective effects on HCEC in vitro. However, gene transfer of a single cyto-protective molecule does not prevent its rejection upon transplantation in a MHC class I/II disparate rat model.

GABAergic synaptic inhibition plays a critical role in regulating long-term potentiation (LTP) of glutamatergic synaptic transmission and circuit output. The K(+)-Cl(-) cotransporter 2 (KCC2) is an important factor in determining inhibitory GABAergic synaptic strength besides the contribution of GABA(A) receptor. Although much knowledge has been gained regarding activity-dependent downregulation of KCC2 in many pathological conditions, the potential change and contribution of KCC2 in LTP expression is still unknown. In this study, we found that downregulation of KCC2 was accompanied with the occurrence of LTP but not that of long-term depression in hippocampal CA1 region. Meanwhile, KCC2 level in CA3/DG and adjacent cortex was stable in the process of LTP expression in Schaffer collateral synapses. Blockade of NMDA receptor with APV not only prevented LTP induction also abolished the reduction of KCC2. Furthermore, the inhibition of KCC2 function with furosemide directly induced EPSP-spike (E-S) potentiation, an important component of LTP in hippocampus. The present data suggest a novel mechanism that LTP formation is accompanied by the downregulation of KCC2, which is underlying GABAergic strength and most likely contributes to the E-S potentiation following LTP.

Pseudonaja textilis, an Australian Elapid, is known to produce a highly toxic venom. Both protein profiling and N-terminal sequence analysis showed the presence of four new phospholipases A(2) in this venom. Besides being non-lethal, the phospholipase A(2) proteins were found to be moderately active enzymes and they showed procoagulant property. cDNA cloning and characterization indicated the presence of two isoforms of PLA(2) proteins in a single snake, each containing the "pancreatic loop," characteristic of group IB phospholipase A(2). The genomic cloning also confirmed the presence of two genes each containing four exons that are interrupted by three introns. Phylogenetic analysis showed that the venom group IB PLA(2) gene is primitive and could have evolved from the same ancestor as the mammalian and venom group IA PLA(2) genes. In the present study, we report that the Pt-PLA2 gene could be responsible for the production of PL1, 2, and 3 possibly via RNA editing process.