A Targeted and Responsive Nanoprodrug Delivery System for Synergistic Glioma Chemotherapy.

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood-brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH-responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX-Cur@NPs) are developed. In this system, a disulfide bond-bridged DOX prodrug (PEG-SS-DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P-glycoprotein (P-gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX-Cur@NPs exhibited synergistic anti-tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain-targeting abilities of cRGD/PSDOX-Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

Preparation and efficacy verification of three-dimensional printed partitioned multi-effect precision-care gel facial mask.

OBJECTIVE: A partition multi-effect precision-care gel facial mask conforming to facial skin characteristics was prepared using three-dimensional (3D) printing technology. METHODS: First, the hydrogel matrix and humectant of a 3D-printed gel for facial masks were screened, and three 3D-printed gels of arbutin, hexapeptide, and salicylic acid were prepared with whitening, wrinkle removal, and oil control functions, respectively. Skin irritation tests were performed on the gels. Physicochemical properties such as pH, heat and cold tolerance were evaluated. The efficacy of three 3D-printed gels was assessed by measuring melanin value, wrinkle depression score, and oil secretion. Finally, the facial mask model design and printing parameters were studied, and a partition multi-effect precision-care gel facial mask was printed in line with facial skin characteristics. RESULTS: For the 3D-printed facial mask, the gel prescription with 2% hydroxyethyl cellulose gel as matrix and 7% glycerol as humectant was the best. The prepared 3D-printed gel did not irritate the human skin, and its physicochemical properties met the Chinese facial mask industry standard (QB/T2872-2017). We showed that three types of 3D-printed gels containing arbutin, hexapeptide, and salicylic acid could be applied to the corresponding parts of the face to solve different problems, such as facial skin dullness, wrinkles, and oil secretion. Therefore, according to facial physiological characteristics, the facial mask model was designed for the forehead and nasolabial fold, which needs to be anti-wrinkled; the cheek, which needs to be whitened; and the nose and chin, which need oil control. The optimal printing parameters were 0.26 mm nozzle diameter, 90 mm/s printing speed, 30% filling density, 140% wire extrusion ratio, and 0.25 mm layer height. Different skin care effects can be achieved using a three-nozzle printer to print arbutin, hexapeptide, or salicylic acid gel on the mask's forehead and nasolabial fold, cheek, and nose and chin, respectively. CONCLUSION: The 3D-printed partition multi-effect care gel facial mask prepared according to the skin features of different parts of the face can overcome the problem of the single skincare effect of the mass-produced facial masks.

OBJECTIF: Un masque facial de soin de précision en gel à effets multiples, adapté aux caractéristiques de la peau du visage, a été préparé à l'aide de la technologie d'impression tridimensionnelle (3D). MÉTHODES: Tout d'abord, la matrice d'hydrogel et l'humectant d'un gel imprimé en 3D pour les masques faciaux ont été sélectionnés, et trois gels imprimés en 3D d'arbutine, d'hexapeptide et d'acide salicylique ont été préparés avec des fonctions de blanchiment, d'élimination des rides et de contrôle du sébum, respectivement. Des tests d'irritation cutanée ont été réalisés sur les gels. Les propriétés physicochimiques telles que le pH et la tolérance à la chaleur et au froid ont été évaluées. L'efficacité des trois gels imprimés en 3D a été évaluée en mesurant la valeur de la mélanine, le score de dépression des rides et la sécrétion de sébum. Enfin, la conception du modèle de masque facial et les paramètres d'impression ont été étudiés, et un masque facial de gel de soin de précision à effets multiples a été imprimé en fonction des caractéristiques de la peau du visage. RÉSULTATS: Pour le masque facial imprimé en 3D, la prescription de gel avec 2 % de gel d'hydroxyéthylcellulose comme matrice et 7 % de glycérol comme humectant était la meilleure. Le gel imprimé en 3D n'a pas irrité la peau humaine et ses propriétés physicochimiques sont conformes à la norme industrielle chinoise relative aux masques faciaux (QB/T2872­2017). Nous avons montré que trois types de gels imprimés en 3D contenant de l'arbutine, de l'hexapeptide et de l'acide salicylique pouvaient être appliqués aux parties correspondantes du visage pour résoudre différents problèmes, tels que l'aspect terne de la peau du visage, les rides et la sécrétion de sébum. Par conséquent, en fonction des caractéristiques physiologiques du visage, le modèle de masque facial a été conçu pour le front et le sillon nasogénien, qui doivent être antirides, la joue, qui doit être blanchie, et le nez et le menton, qui ont besoin d'un contrôle du sébum. Les paramètres d'impression optimaux étaient les suivants : diamètre de buse de 0,26 mm, vitesse d'impression de 90 mm/s, densité de remplissage de 30 %, rapport d'extrusion du fil de 140 % et hauteur de couche de 0,25 mm. Différents effets de soin de la peau peuvent être obtenus en utilisant une imprimante à trois buses pour imprimer de l'arbutine, de l'hexapeptide ou du gel d'acide salicylique sur le front et le sillon nasogénien, la joue, le nez et le menton du masque, respectivement. CONCLUSION: Le masque facial en gel de soin à effets multiples imprimé en 3D et préparé en fonction des caractéristiques de la peau des différentes parties du visage peut résoudre le problème de l'effet de soin unique des masques faciaux produits en masse.

Insight on genetic features prevalent in five Ipomoea species using comparative codon pattern analysis reveals differences in major codons and reduced GC content at the 5' end of CDS.

Ipomoea plants possess important commercial, medicinal, and ornamental value. Molecular and morphological studies have confirmed that most species of this genus exhibit similar phenotypes but complex phylogenetic relationships. To date, limited information is available on these evolutionary relationships. In this study, systematic analysis of diverse species from Ipomoea was used to elucidate the relationships in this genus. To this end, we employed the concept of codon usage bias (CUB) to analyze the codon usage bias of five Ipomoea species such as effective number of codons (ENC) and GC content at the third synonym codon position (GC3s). Three types of plots including ENC-GC3s, parity rule 2 (PR2) and neutrality plots were employed to discover the factors determining CUB, and the frequency of hydrogen bonds and nucleotide were calculated to dissect changes in GC content at the 5'-end of the coding sequence. Our results showed little distinctness in CUB among the five species, with a reduction of hydrogen bonds content at the 5'-end (with similar changes in cytosines). In addition, optimal codons of Ipomoea aquatica ended with G or C, different from those of the other four species, which ended in A or T. These results may be useful for exploring the evolutionary relationships among this group, and for understanding the reasons for the variation among Ipomoea species.

Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis.

Diabetes has been reported to induce brain metabolic disturbance, but the effect of transient neonatal hyperglycemia (TNH) on brain metabolism remains unclear. Herein the rats were treated with a single intraperitoneal injection of 100 µg/g body weight of streptozotocin within 12 h after birth and displayed a typical clinical characteristic of TNH. Then we used NMR-based metabolomics to examine the metabolic changes in the hippocampus between TNH and normal control (Ctrl) rats at postnatal 7 days (P7) and 21 days (P21). The results show that TNH rats had significantly increased levels of N-acetyl aspartate, glutamine, aspartate and choline in the hippocampus relative to Ctrl rats at P7. Moreover, we found that the levels of alanine, myo-inositol and choline were significantly lower in TNH rats, although their blood glucose levels have been recovered to the normal level at P21. Therefore, our results suggest that TNH may have a long-term effect on hippocampal metabolic changes mainly involving neurotransmitter metabolism and choline metabolism.

Older liver grafts from donation after circulatory death are associated with impaired survival and higher incidence of biliary non-anastomotic structure.

BACKGROUND: Grafts from older donors after circulatory death were associated with inferior outcome in liver transplants in the past. But it has seemed to remain controversial in the last decade, as a result of modified clinical protocols, selected recipients, and advanced technology of organ perfusion and preservation. The present study aimed to examine the impact of older donor age on complications and survival of liver transplant using grafts from donation after circulatory death (DCD). METHODS: A total of 944 patients who received DCD liver transplantation from 2015 to 2020 were included and divided into two groups: using graft from older donor (aged ≥ 65 years, n = 87) and younger donor (age < 65 years, n = 857). Propensity score matching (PSM) was applied to eliminate selection bias. RESULTS: A progressively increased proportion of liver transplants with grafts from older donors was observed from 1.68% to 15.44% during the study period. The well-balanced older donor (n = 79) and younger donor (n = 79) were 1:1 matched. There were significantly more episodes of biliary non-anastomotic stricture (NAS) in the older donor group than the younger donor group [15/79 (19.0%) vs. 6/79 (7.6%); P = 0.017]. The difference did not reach statistical significance regarding early allograft dysfunction (EAD) and primary non-function (PNF). Older livers had a trend toward inferior 1-, 2-, 3-year graft and overall survival compared with younger livers, but these differences were not statistically significant (63.1%, 57.6%, 57.6% vs. 76.9%, 70.2%, 67.7%, P = 0.112; 64.4%, 58.6%, 58.6% vs. 76.9%, 72.2%, 72.2%, P = 0.064). The only risk factor for poor survival was ABO incompatible transplant (P = 0.008) in the older donor group. In the subgroup of ABO incompatible cases, it demonstrated a significant difference in the rate of NAS between the older donor group and the younger donor group [6/8 (75.0%) vs. 3/14 (21.4%); P = 0.014]. CONCLUSIONS: Transplants with grafts from older donors (aged ≥ 65 years) after circulatory death are more frequently associated with inferior outcome compared to those from younger donors. Older grafts from DCD are more likely to develop NAS, especially in ABO incompatible cases.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

Amelioration of Obesity-Related Disorders in High-Fat Diet-Fed Mice following Fecal Microbiota Transplantation from Inulin-Dosed Mice.

The role of inulin in alleviating obesity-related disorders has been documented; yet, its underlying mechanisms still need to be further investigated. This study attempted to elucidate the causative link between the gut microbiota and the beneficial effect of inulin on obesity-related disorders via transferring the fecal microbiota from inulin-dosed mice to high-fat diet (HFD)-induced obese recipient mice. The results show that inulin supplementation can decrease body weight, fat accumulation, and systemic inflammation and can also enhance glucose metabolism in HFD-induced obese mice. Treatment with inulin reshaped the structure and composition of the gut microbiota in HFD-induced obese mice, as characterized by increases in the relative abundances of Bifidobacterium and Muribaculum and decreases in unidentified_Lachnospiraceae and Lachnoclostridium. In addition, we found that these favorable effects of inulin could be partially transferable by fecal microbiota transplantation, and Bifidobacterium and Muribaculum might be the key bacterial genera. Therefore, our results suggest that inulin ameliorates obesity-related disorders by targeting the gut microbiota.

Liver transplantation in patients with liver failure: Twenty years of experience from China.

Liver transplantation (LT) is the only effective method of treating end-stage liver disease, such as various types of liver failure. China has the largest number of patients with hepatitis B virus-related disease, which is also the main cause of liver failure. From the first LT performed in 1977, and especially over the past two decades, LT has experienced rapid development as a result of continuous research and innovation in China. China performs the second-highest number of LTs every year worldwide, and the quality of LT continues to improve. Starting January 1, 2015, all donor's livers have been from deceased donors and familial donors. Thus, China entered into a new era of LT. However, LT is still a challenging procedure in China. In this review, we introduced the brief history of LT in China, the epidemiology, aetiology and clinical outcomes of LT for liver failure in China and summarized the experience of LT from Chinese LT surgeons and scholars. The future perspectives of LT were also discussed, and it is expected that China's LT research could be further integrated elsewhere in the world.

Ultra-sensitive H2S sensor based on sunflower-like In-doped ZnO with enriched oxygen vacancies.

Metal oxide sensors face the challenge of high response and fast recovery at low operating temperatures for the detection of toxic and flammable hydrogen sulfide (H2S) gases. Herein, novel In-doped ZnO with a sunflower-like structure and tunable surface properties was rationally synthesized. The substitutional In atom in the ZnO crystal can dramatically enhance the concentration of oxygen vacancies (Ov), the In-ZnO sites are responsible for fast recovery, and the formation of sub-stable sulfide intermediates gives rise to the high response towards H2S. As a result, the response of the optimized 4In-ZnO sensor is 3538.36 to 50 ppm H2S at a low operating temperature of 110 °C, which is 106 times higher than that of pristine ZnO. Moreover, the response time and recovery time to 50 ppm H2S are 100 s and 27 s, respectively, with high selectivity and stability. First-principles calculations revealed that 4In-ZnO with rich Ov exhibited higher adsorption energy for the H2S molecule than pristine ZnO, resulting in effortless H2S detection. Our work lays the foundation for the rational design of highly sensitive gas sensors through precise doping of atoms in oxygen-rich vacancies in semiconductor materials.

Potential Therapeutic Mechanism of Traditional Chinese Medicine on Diabetes in Rodents: A Review from an NMR-Based Metabolomics Perspective.

Traditional Chinese medicine (TCM) has been used to treat diabetes for a long time, but its application has not been widely accepted due to unstandardized product quality and complex pharmacological mechanisms. The modernization of TCM is crucial for its further development, and in recent years the metabolomics technique has largely driven its modernization. This review focuses on the application of NMR-based metabolomics in diabetic therapy using TCM. We identified a series of metabolic pathways that altered significantly after TCM treatment, providing a better understanding of the metabolic mechanisms of TCM for diabetes care.

[High quality standard of Scutellariae Radix based on plant metabolomics and index components].

Scutellariae Radix(SR), derived from the dried root of Scutellaria baicalensis in the family Lamiaceae, commonly serves as Chinese medicinal material. Affected by producing areas, growing years, and harvesting periods, the quality of SR fluctuates in the market. However, baicalin≥9% in SR required in the Chinese Pharmacopoeia(2020 edition) can only determine the qualified SR but cannot identify high-quality SR. To improve the quality control methods of SR, the present study analyzed the accumulation of metabolites in SR of different growth years by plant metabolomics, and identified 28 metabolites increasing with growth years(1-3 years). Subsequently, 14 main metabolites were quantitatively analyzed by ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry(UPLC-QQQ-MS). Among them, baicalin, wogonoside, baicalein, and wogonin with high content and good activity were selected as the index components of SR for quality evaluation. A high-performance liquid chromatography(HPLC) method was established to determine the content of four index components in 32 batches of SR from different producing areas, harvesting perio-ds, and growth years. The results showed that the growth years could greatly affect the content of index components. The total content of four index components in 2-year SR was the highest, followed by the 3-/4-year SR and 1-year SR. Based on HPLC data and verification results by enterprises, baicalin ≥12.0%, wogonoside ≥2.3%, baicalein ≥0.1%, and wogonin ≥0.03% were proposed as the evaluation criteria for the high-quality SR. The findings of this study are expected to provide a basis for improving the quality of SR.

The regulatory effect of acetylation of HMGN2 and H3K27 on pyocyanin-induced autophagy in macrophages by affecting Ulk1 transcription.

Pyocyanin (PYO) is a major virulence factor secreted by Pseudomonas aeruginosa, and autophagy is a crucial homeostatic mechanism for the interaction between the pathogens and the host. It remains unknown whether PYO leads to autophagy in macrophages by regulating histone acetylation. The high mobility group nucleosomal binding domain 2 (HMGN2) has been reported to regulate the PYO-induced autophagy and oxidative stress in the epithelial cells; however, the underlying molecular mechanism has not been fully elucidated. In this study, PYO was found to induce autophagy in macrophages, and the mechanism might be correlated with the up-regulation of HMGN2 acetylation (HMGN2ac) and the down-regulation of H3K27 acetylation (H3K27ac) by modulation of the activities of acetyltransferases and deacetylases. Moreover, we further demonstrated that the up-regulated HMGN2ac enhances its recruitment to the Ulk1 promoter, while the down-regulation of H3K27ac reduces its recruitment to the Ulk1 promoter, thereby promoting or inhibiting the transcription of Ulk1. In conclusion, HMGN2ac and H3K27ac play regulatory roles in the PYO-induced autophagy in macrophages.

Nitrogen removal characteristics of a novel heterotrophic nitrification and aerobic denitrification bacteria, Alcaligenes faecalis strain WT14.

Alcaligenes faecalis strain WT14 is heterotrophic nitrification and aerobic denitrification bacterium, newly isolated from a constructed wetland, and its feasibility in nitrogen removal was investigated. The result showed sodium citrate was more readily utilized by WT14 as a carbon source. The response surface methodology model revealed the highest total nitrogen removal by WT14 occurred at 20.3 °C, 113.5 r·min-1, C/N 10.8, and pH 8.4. Under adapted environmental conditions, up to 55.9 mg·L-1·h-1 of ammonium nitrogen (NH4+-N) was removed by WT14, and its NH4+-N tolerance ability reached 2000 mg·L-1. In addition to the reported high NH4+-resistance of Alcaligenes faecalis, WT14 multiplied fast and had strong nitrate or nitrite removal capacity when high strength nitrate or nitrite was provided as the single nitrogen source; which differed from other Alcaligenes faecalis species. These results show WT14 is a novel strain of Alcaligenes faecalis and its nitrogen removal pathway will be carried out in the further study.

Glutaredoxin 1 up-regulates deglutathionylation of α4 integrin and thereby restricts neutrophil mobilization from bone marrow.

α4 integrin plays a crucial role in retention and release of neutrophils from bone marrow. Although α4 integrin is known to be a potential target of reactive oxygen species (ROS)-induced cysteine glutathionylation, the physiological significance and underlying regulatory mechanism of this event remain elusive. Here, using in vitro and in vivo biochemical and cell biology approaches, we show that physiological ROS-induced glutathionylation of α4 integrin in neutrophils increases the binding of neutrophil-associated α4 integrin to vascular cell adhesion molecule 1 (VCAM-1) on human endothelial cells. This enhanced binding was reversed by extracellular glutaredoxin 1 (Grx1), a thiol disulfide oxidoreductase promoting protein deglutathionylation. Furthermore, in a murine inflammation model, Grx1 disruption dramatically elevated α4 glutathionylation and subsequently enhanced neutrophil egress from the bone marrow. Corroborating this observation, intravenous injection of recombinant Grx1 into mice inhibited α4 glutathionylation and thereby suppressed inflammation-induced neutrophil mobilization from the bone marrow. Taken together, our results establish ROS-elicited glutathionylation and its modulation by Grx1 as pivotal regulatory mechanisms controlling α4 integrin affinity and neutrophil mobilization from the bone marrow under physiological conditions.

Characterization of a novel HDAC/RXR/HtrA1 signaling axis as a novel target to overcome cisplatin resistance in human non-small cell lung cancer.

BACKGROUND: Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance. METHODS: A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway. RESULTS: HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis. CONCLUSION: Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.

HMGN2 regulates non-tuberculous mycobacteria survival via modulation of M1 macrophage polarization.

Non-tuberculous mycobacteria (NTM), also known as an environmental and atypical mycobacteria, can cause the chronic pulmonary infectious diseases. Macrophages have been suggested as the main host cell to initiate the innate immune responses to NTM infection. However, the molecular mechanism to regulate the antimicrobial immune responses to NTM is still largely unknown. Current study showed that the NTM clinical groups, Mycobacterium abscessus and Mycobacterium smegmatis, significantly induced the M1 macrophage polarization with the characteristic production of nitric oxide (NO) and marker gene expression of iNOS, IFNγ, TNF-α, IL1-ß and IL-6. Interestingly, a non-histone nuclear protein, HMGN2 (high-mobility group N2), was found to be spontaneously induced during NTM-activated M1 macrophage polarization. Functional studies revealed that HMGN2 deficiency in NTM-infected macrophage promotes the expression of M1 markers and the production of NO via the enhanced activation of NF-κB and MAPK signalling. Further studies exhibited that HMGN2 knock-down also enhanced IFNγ-induced M1 macrophage polarization. Finally, we observed that silencing HMGN2 affected the survival of NTM in macrophage, which might largely relevant to enhanced macrophage polarization into M1 phenotype under the NTM infection. Collectively, current studies thus suggested a novel function of HMGN2 in regulating the anti-non-tuberculous mycobacteria innate immunity of macrophage.

High-mobility group protein N2 induces autophagy by activating AMPK/ULK1 pathway and thereby boosts UPEC proliferation within bladder epithelial cells.

Urinary tract infection is one of the most common bacterial infections which is mainly caused by Escherichia coli (UPEC). Autophagy plays a key role in immune response to eliminate invading pathogens. Exploring the effect of autophagy on UPEC infection and the molecular mechanisms will be benefit for the treatment of urinary tract infection. High-mobility group protein N2 (HMGN2), a highly conserved nuclear protein and an antibacterial peptide, has been associated with bacterial infection induced immune response; however, whether this function is due to the regulation of autophagy remains unclear. In this study, we demonstrate for the first time that HMGN2 is upregulated in UPEC infection of bladder epithelial cell line 5637 (BEC 5637). Furthermore, HMGN2 enhances autophagy in BEC 5637 via activation of AMPK and ULK1, whereas UPEC suppresses autophagy. In addition, the enhanced autophagy activity by HMGN2 overexpression or rapamycin boosts the proliferation of UPEC J96 in BEC 5637. In summary, our data indicate that HMGN2 activates autophagy via AMPK/ULK1 pathway which can be utilized by UPEC J96 for their proliferation within bladder epithelial cells.

Highly enhanced photocatalytic H2 evolution of Cu2O microcube by coupling with TiO2 nanoparticles.

A Cu2O/TiO2 p-n heterojunction composite was created via a facile, controllable, one-pot hydrothermal method based on cubic Cu2O and TiO2 nanoparticles in the presence of dioctyl sulfosuccinate sodium salt (AOT) surfactant. The TiO2 nanoparticles with an average edge length of ∼10.1 nm were uniformly distributed on the crystal surface of a Cu2O cube {100}. The photocatalytic performance of the composite was effectively tuned by controlling the amount of TiO2. The Cu2O/TiO2 (60 wt%, labeled as CT-60) exhibits the highest enhanced photocatalytic activity in hydrogen production with H2 evolution of 3002.5 µmol g-1. The yield remained around 92.6% after three cycles. Hydrogen production of the CT-60 is 103 and 8.5 fold higher than the cubic Cu2O and TiO2 nanoparticles, respectively. The improvement in photocatalytic performance could be attributed to the formation of p-n heterojunction. Furthermore, the interface effect of Cu2O and TiO2 caused a broader absorbance in the visible-light region and the lower recombination of photogenerated electron-hole pairs. It is believed that the Cu2O/TiO2 p-n heterojunction composites could provide an alternative method to design highly efficient photocatalysts for solar energy.

Vitamin D deficiency in connective tissue disease-associated interstitial lung disease.

OBJECTIVES: To determine and compare the prevalence of vitamin D deficiency in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). METHODS: The level of vitamin D was determined by the serum levels of 1,25(OH)2D3. We evaluated 144 patients in our study, including 53 subjects in the CTD-ILD group and 91 subjects in the CTD group without ILD. CTD was diagnosed following the American College of Rheumatology criteria, and ILD was diagnosed by high-resolution computed tomography. Patients with other known causes of ILD and other pulmonary diseases were excluded. Vitamin D deficiency level was <20 ng/ml. This is a retrospective study. RESULTS: Serum vitamin D levels were significantly lower in CTD-ILD patients (p<0.0001). Vitamin D deficiency was lower in the CTD-ILD group (mean±SD: 11.5±4.1 ng/ml) than in the control group (13.9±4.8 ng/ml, p=0.004). The CTD-ILD group was older (p=0.002), had higher levels of fibrinogen (p=0.028) and positive anti-CCP (p=0.026), faster ESR (p=0.001), lower serum levels of serum calcium (p=0.002), and more immunosuppressive therapies (p=0.011). Decreased serum albumin and higher positive antinuclear antibodies (ANA) were associated with reduced vitamin D levels in the vitamin D subgroups. When the odds ratio was adjusted for CTD-ILD, vitamin D deficiency was also a risk factor for CTD-ILD, whereas serum levels of calcium was a protective factor for CTD-ILD. CONCLUSIONS: Serum vitamin D deficiency is associated with CTD-ILD and is a risk factor. Therefore, vitamin D may play a role in the pathogenesis of CTD-ILD.

Research on the treatment effects and drug resistances of long-term second-line antiretroviral therapy among HIV-infected patients from Henan Province in China.

BACKGROUND: HIV/AIDS patients who fail to respond to first-line treatment protocols are switched to second-line ART. Identifying factors that influence effective second-line treatment can improve utilization of limited medical resources. We investigated the efficacy of long-term second-line anti-retroviral therapy (ART) after first-line virologic failure as well as the impact of non-nucleotide reverse transcriptase inhibitor (NNRTI), nucleotide reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) resistance mutations and medication adherence on ineffective viral suppression. METHODS: A total of 120 patients were evaluated at 6, 12, 18, 24, and 48 months after initiation of second-line ART; a paper questionnaire was administered via a face-to-face interview and venous blood samples were collected. CD4+ T cell count, viral load, and drug resistance genotypes were quantified. RESULTS: CD4+ T cell counts increased from 170 cells/µL (IQR 100-272) at baseline to 359 cells/µL (IQR 236-501) after 48 months of second-line treatment. Viral load (log10) decreased from 4.58 copies/mL (IQR 3.96-5.17) to 1.00 copies/mL (IQR 1.00-3.15). After switching to second-line ART, nine patients newly acquired the NRTI drug-resistant mutation, M184 V/I. No major PI resistance mutations were detected. Logistical regression analysis indicated that medication adherence < 90% in the previous month was associated with ineffective viral suppression; baseline high/low/moderate level resistance to 3TC/TDF was protective towards effective viral suppression. CONCLUSIONS: Long-term second line ART was effective in the Henan region of China. Drug resistance mutations to NRTIs were detected in patients receiving second-line ART, suggesting that drug resistance surveillance should be continued to prevent the spread of resistant strains. Patient medication adherence supervision and management should be strengthened to improve the efficacy of antiviral treatment.