Does Antibiotic Use Increase the Risk of Post-Transplantation Diabetes Mellitus? A Retrospective Study of Renal Transplant Patients.

BACKGROUND This study aimed to investigate the incidence of post-transplant diabetes mellitus (PTDM) in renal transplant (RT) patients at our center and to explore new risk factors for PTDM. MATERIAL AND METHODS This retrospective study included RT patients from 2010 to 2022. Clinic data on RT patients were obtained from hospital electronic medical records. CYP3A5*3, POR*28, ABCB1 (3435 C>T), and ABCB1 (1236 C>T) were genotyped in RT patients. The associations between age, BMI, concentration of tacrolimus (TAC), polymorphism of genes, antibiotics (eg, penicillins, cephalosporins, oxazolidinones, quinolones), numbers and days of antibiotic use, and PTDM were analyzed. RESULTS In this study, 409 patients with RT were included. The cumulative incidence of PTDM in the first year after RT was 9.05%. The numbers and days of antibiotic use in PTDM patients were significantly higher than those in non-PTDM patients. Multivariate logistic regression analysis identified age (OR=1.047, P=0.014), body mass index (BMI) (OR=1.178, P=0.007), dose-adjusted trough concentration of TAC (TAC C0/D) at 7 days after RT (OR=1.159, P=0.042), trough concentration of TAC (TAC C0) at 28 days after RT (OR=1.094, P=0.042), and levofloxacin (OR=5.975, P=0.003) as independent risk factors for PTDM. CONCLUSIONS In addition to age, BMI, and TAC concentration after RT, antibiotic use may be a novel factor affecting PTDM. The use of antibiotics may influence the development of PTDM.

Protective effect of ginsenoside Rb1 against aconitine cardiotoxicity studied by myocardial injury, action potential, and calcium signaling.

Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.

Selective Construction and Structural Transformation of Homogeneous Linear Metalla[4]catenane and Metalla[2]catenane Assemblies.

Although the synthesis of mechanically interlocked molecules has been extensively researched, selectively constructing homogeneous linear [4]catenanes remains a formidable challenge. Here, we selectively constructed a homogeneous linear metalla[4]catenane in a one-step process through the coordination-driven self-assembly of a bidentate benzothiadiazole derivative ligand and a binuclear half-sandwich rhodium precursor. The formation of metalla[4]catenanes was facilitated by cooperative interactions between strong sandwich-type π-π stacking and non-classical hydrogen bonds between the components. Moreover, by modulating the aromatic substituents on the binuclear precursor, two homogeneous metalla[2]catenanes were obtained. The molecular structures of these metallacatenanes were unambiguously characterized by single-crystal X-ray diffraction analysis. Additionally, reversible structural transformation between metal-catenanes and the corresponding metallarectangles could be achieved by altering their concentration, as confirmed by mass spectrometry and NMR spectroscopy studies.

Pulmonary manifestations of POEM syndrome: a retrospective analysis of 282 cases.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystemic clonal plasma cell disorder. Pulmonary involvement is frequently found in patients with POEMS syndrome, manifesting various clinical features. Therefore, to improve diagnostic accuracy and provide treatment strategies, a comprehensive analysis of pulmonary manifestations of POEMS syndrome is needed. METHODS: This retrospective study included patients with POEMS syndrome at Peking Union Medical College Hospital, a major referral medical center in China, between June 1, 2013, and June 1, 2023. Demographic data, laboratory findings, pulmonary function test results, echocardiograms, and chest imaging data were extracted. Continuous variables were compared using the t-test or Mann-Whitney method. Pearson's chi-square test or Fisher's exact test was conducted to compare categorical data. RESULTS: Overall, 282 individuals diagnosed with POEMS syndrome were included in this study, of which 56% were male with an average age of 48.7 years. Respiratory symptoms were found in 40.1% of the patients, with dyspnea as the most common symptom (34.4%). Chest computed tomography and echocardiography findings showed that 56.4% of patients exhibited pleural effusion, 62.8% displayed mediastinal or hilar lymphadenopathy, 46.5% presented pleural thickening, 27.3% demonstrated bone lesions of the ribs or thoracic vertebra, 7.8% showed lung interstitial abnormalities, and 35.5% had pulmonary hypertension. Decreased diffuse capacity and restrictive ventilatory patterns were identified in 85.2% (115 cases) and 47.4% (64 cases) of patients, respectively. Patients with respiratory symptoms exhibited higher declined lung function measures than those having no respiratory symptoms. High-risk patients with poor prognosis showed more pulmonary function abnormalities. CONCLUSION: Abnormalities in pulmonary manifestations constitute the significant features of POEMS syndrome. Several patients with POEMS syndrome presented with respiratory symptoms at the initial evaluation. These findings underscore the importance of early identification and accurate diagnosis of POEMS syndrome by clinicians, particularly in cases involving lung and multisystem.

Osthole protects H9c2 cardiomyocytes against trastuzumab-induced damage by enhancing autophagy through the p38MAPK/mTOR signaling pathway.

Trastuzumab (TRZ) is a novel targeted anti-tumor agent that significantly improve the survival of patients with human epidermal growth factor receptor (HER2) positive breast cancer. However, its clinical application is limited due to the side effects of cardiotoxicity. Osthole (OST), a coumarin derivative isolated from Cnidium monnieri (L.) Cusson, has previously demonstrated cardioprotective effects. The aim of this study was to observe the protective effect of OST on TRZ-induced cardiomyocytes damage and to explore its potential mechanism. The results showed that OST pretreatment could significantly inhibit TRZ-induced cardiomyocytes damage, markedly increase the ratio of LC3II/I and Beclin-1 protein expression, and reduce the protein expression of p62. OST pretreatment significantly attenuated oxidative stress and apoptosis induced by TRZ, as evidenced by reducing intracellular ROS level, the Bax/Bcl-2 ratio, and Caspase-3 protein expression. Additionally, OST markedly increased the phosphorylation level of p38MAPK and decreased the mTOR phosphorylation level. However, the effects of OST on enhancing autophagy, reducing oxidative stress, apoptosis, and the phosphorylation level of mTOR were reversed after the addition of 3-MA or SB203580. Molecular docking results indicated that OST exerted a good binding ability with the p38MAPK protein. Our findings suggested that OST could protect TRZ-induced cardiomyocytes damage by enhancing autophagy via the p38MAPK/mTOR signaling pathway.

Feel so bac: is Fusobacterium the suspect causing endometriosis?

Recent work by Muraoka and colleagues reports that the Gram-negative anaerobic bacterium Fusobacterium nucleatum is detected in the uterus of 64% of women with endometriosis. Fusobacterium infection causes macrophage infiltration, transforming growth factor-ß production, and transgelin upregulation in human and mouse endometria as well as endometriotic lesion development in a mouse model of endometriosis.

SIRT1 activation by 2,3,5,6-tetramethylpyrazine alleviates neuroinflammation via inhibiting M1 microglia polarization.

Background: Neuroinflammation has been reported as a potential contributing factor to brain diseases, and is characterized by activated microglia with release of multiple inflammatory mediators. 2,3,5,6-Tetramethylpyrazine (TMP) is an active alkaloid in Ligusticum chuanxiong Hort. and has various biological activities, including anti-inflammatory and neuroprotection properties. However, the anti-neuroinflammatory activity of TMP has been less studied and its potential molecular mechanisms in this field remain unclear. This study aimed to investigate the effects of TMP and its underlying mechanisms in neuroinflammation. Methods: In vitro, lipopolysaccharide (LPS)-stimulated BV2 microglia were used to assess the effects of TMP on inflammatory cytokines as well as the components of the SIRT1/NF-κB signaling pathway, which were measured by using ELISA, western blotting, qRT-qPCR and immunofluorescence. Moreover, LPS-induced acute neuroinflammation model in mice was performed to detect whether TMP could exert anti-neuroinflammatory effects in vivo, and the EX527, a SIRT1 inhibitor, were given intraperitoneally every two days prior to TMP treatment. Serums and spinal trigeminal nucleus (Sp5) tissues were collected for ELISA assay, and the Sp5 tissues were used for HE staining, Nissl staining, immunofluorescence, qRT-PCR and western blotting. Results: In vitro, TMP treatment significantly reduced the secretion of pro-inflammatory cytokines, including TNF-α and IL-6, promoted SIRT1 protein expression and inactivated NF-κB signaling pathway in LPS-induced neuroinflammation. Interestingly, pretreatment with EX527 blocked the therapeutic effects of TMP on neuroinflammation in vitro. Furthermore, TMP reduced the levels of pro-inflammatory cytokines and chemokines, and prevented microglia from polarizing towards a pro-inflammatory state through activating SIRT1 and inhibiting NF-κB activation in LPS-induced neuroinflammation in mice. And EX527 reversed the beneficial effects of TMP against LPS exposure in mice. Conclusion: In summary, this study unravels that TMP could mitigate LPS-induced neuroinflammation via SIRT1/NF-κB signaling pathway.

[The Change in Subpopulation and Function of Natural Killer Cells in Adult Patients with Infectious Mononucleosis Related Liver Injury].

OBJECTIVE: To investigate the changes of subpopulation and function of natural killer (NK) cells in adult patients with infectious mononucleosis related liver injury. METHODS: Seventeen healthy controls, twenty-six patients of infectious mononucleosis (IM) without liver injury, and twenty-one IM patients with liver injury were enrolled in this study. Peripheral blood was collected. Plasma and peripheral blood mononuclear cells (PBMC) were purified. Plasma interleukin-15 (IL-15) level was measured by enzyme linked immunosorbent assay. Three NK cell subpopulations, including CD56+CD16-, CD56+CD16+, and CD56-CD16+ NK cells, were assessed by flow cytometry. PBMC were co-cultured with 721.221, K562, and P815-Ab cells, respectively. CD107a expression and CD16 mean fluorescence intensity (MFI) in NK cells was investigated by flow cytometry. PBMC from IM patients with liver injury were stimulated with anti-IL-15 neutralizing antibody, and the change of NK cell function was observed. One-way ANOVA and paired t test were used for statistical analysis. RESULTS: The percentage of CD56+CD16- NK cells in IM patients with liver injury (7.36±0.92)% and IM patients without liver injury (10.67±1.37)% were lower than that of controls (12.02±2.51)% (P<0.05). CD56+CD16- NK cell frequency in IM patients with liver injury also was lower than that in IM patients with liver injury (P<0.0001). The percentage of CD56+CD16+ NK cells in IM patients with liver injury (62.03±8.78)% and IM patients without liver injury (44.74±13.03)% were higher than that in controls (40.74±10.15)% (P<0.05). CD56+CD16+ NK cell frequency in IM patients with liver injury also was higher than that in IM patients with liver injury (P<0.0001). There was no statistical difference of CD56-CD16+ NK cell proportion among three groups (P=0.427). Plasma IL-15 level in IM patients with liver injury (309.1±68.00) pg/ml were higher than that in IM patients without liver injury (269.6±53.57) pg/ml and controls (257.4±73.93) pg/ml (P<0.05). NK cells induced target cell death through different receptors upon activation, the ratio of CD107a-positive cells in NK cells of IM patients with liver injury was higher than that in IM patients without liver injury and controls (P<0.05), while CD16 MFI in NK cells in IM patients with liver injury was lower than that in IM patients without liver injury and controls (P<0.05). The percentage of CD107a positive cells in NK cells was significantly reduced in response to anti-IL-15 neutralizing antibody stimulation in IM patients with liver injury (P<0.05). CONCLUSION: IM patients with liver injury presented imbalance of NK cell subpopulation and enhanced NK cell function. The elevation of IL-15 might contribute to promote NK cell cytotoxicity in IM patients with liver injury.

Detachment of Dodecane from Silica Surfaces with Variable Surface Chemistry Studied Using Molecular Dynamics Simulation.

The adsorption and detachment processes of n-dodecane (C12H26) molecules were studied on silica surfaces with variable surface chemistry (Q2, Q3, Q4 environments), using molecular dynamics simulations. The area density of the silanol groups varied from 9.4 to 0 per nm2. The shrinking of the oil-water-solid contact line was a key step for the oil detachment, due to water diffusion on the three-phase contact line. The simulation results showed that oil detachment was easier and faster on a perfect Q3 silica surface which had (≡Si(OH))-type silanol groups, due to the H-bond formation between the water and silanol groups. When the surfaces contained more Q2 crystalline type which had (≡Si(OH)2)-type silanol groups, less oil detached, due to the formations of H-bonds among the silanol groups. There were no silanol groups on the Si-OH 0 surface. Water cannot diffuse on the water-oil-silica contact line, and oil cannot detach from the Q4 surface. The detachment efficiency of oil from the silica surface not only depended on the area density, but also on the types of silanol groups. The density and type of silanol groups depend on the crystal cleavage plane, particle size, roughness, and humidity.

Engineering MMP-2 Activated Nanoparticles Carrying B7-H3 Bispecific Antibodies for Ferroptosis-Enhanced Glioblastoma Immunotherapy.

Administration of bispecific antibodies (biAbs) in tumor therapy is limited by their short half-life and off-target toxicity. Optimized strategies or targets are needed to overcome these barriers. B7-H3 (CD276), a member of the B7 superfamily, is associated with poor survival in glioblastoma (GBM) patients. Moreover, a dimer of EGCG (dEGCG) synthesized in this work enhanced the IFN-γ-induced ferroptosis of tumor cells in vitro and in vivo. Herein, we prepared recombinant anti-B7-H3×CD3 biAbs and constructed MMP-2-sensitive S-biAb/dEGCG@NPs to offer a combination treatment strategy for efficient and systemic GBM elimination. Given their GBM targeted delivery and tumor microenvironment responsiveness, S-biAb/dEGCG@NPs displayed enhanced intracranial accumulation, 4.1-, 9.5-, and 12.3-fold higher than that of biAb/dEGCG@NPs, biAb/dEGCG complexes, and free biAbs, respectively. Furthermore, 50% of GBM-bearing mice in the S-biAb/dEGCG@NP group survived longer than 56 days. Overall, S-biAb/dEGCG@NPs can induce GBM elimination by boosting the ferroptosis effect and enhancing immune checkpoint blockade (ICB) immunotherapy and may be successful antibody nanocarriers for enhanced cancer therapy.

Rational Design of PDI-Based Linear Conjugated Polymers for Highly Effective and Long-Term Photocatalytic Oxygen Evolution.

Constructed through relatively weak noncovalent forces, the stability of organic supramolecular materials has shown to be a challenge. Herein, the designing of a linear conjugated polymer is proposed through creating a chain polymer connected via bridging covalent bonds in one direction and retaining π-stacked aromatic columns in its orthogonal direction. Specifically, three analogs of linear conjugated polymers through tuning the aromatic core and its covalently linked moiety (bridging group) within the building block monomer are prepared. Cooperatively supported by strong π-π stacking interactions from the extended aromatic core of perylene and favorable dipole-dipole interactions from the bridging group, the as-expected high crystallinity, wide light absorption, and increased stability are successfully achieved for Oxamide-PDI (perylene diimide) through ordered molecular arrangement, and present a remarkable full-spectrum oxygen evolution rate of 5110.25 µmol g-1  h-1 without any cocatalyst. Notably, experimental and theoretical studies reveal that large internal dipole moments within Oxamide-PDI together with its ordered crystalline structure enable a robust built-in electric field for efficient charge carrier migration and separation. Moreover, density functional theory (DFT) calculations also reveal oxidative sites located at carbon atoms next to imide bonds and inner bay positions based on proven spatially separated photogenerated electrons and holes, thus resulting in highly efficient water photolysis into oxygen.

Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice.

Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca2+-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.

Cultivation of algal-bacterial granular sludge and degradation characteristics of tetracycline.

Due to the increasing use of antibiotics, tetracycline was frequently detected in wastewater. As a novel technology, algal-bacterial granular sludge process is expected to be widely used in wastewater treatment. However, the degradation effect of tetracycline by algal-bacterial granular sludge process and its degradation path is still unknown. In this study, mature and stable algal-bacterial granular sludge was cultured and the degradation of tetracycline by it was investigated. The results showed that the removal amount of 1-25 mg/L tetracycline by algal-bacterial granular sludge was 0.09-1.45 mg/g volatile suspended solids (VSS), in which the adsorption amount was 0.06-0.17 mg/g VSS and the degradation amount was 0.03-1.27 mg/g VSS. Tetracycline biosorption was dominant at its concentration of 1-3 mg/L, while biodegradation was predominant at 5-25 mg/L of tetracycline. At tetracycline concentration of 3-5 mg/L, the contribution of biosorption and biodegradation to tetracycline removal by algal-bacterial granular sludge process was almost equal. Algal-bacterial granular sludge could effectively degrade tetracycline through demethylation, dehydrogenation, deacylation, and deamination or their combination. In addition, the degradation products were nontoxic and hardly pose a threat to environmental health. The research results of this paper provide a solid theoretical basis for tetracycline removal by algal-bacterial granular sludge and a reference for the development of algal-bacterial granular sludge process for wastewater treatment in the presence of tetracycline. PRACTITIONER POINTS: Mature and stable algal-bacterial granular sludge was cultured. Tetracycline was removed by algal-bacterial granular sludge through biosorption and biodegradation. Algal-bacterial granular sludge could degrade tetracycline through demethylation, dehydrogenation, deacylation, and deamination or their combination. The degradation products were nontoxic.

Exploring the potential molecular mechanism of trastuzumab-induced cardiotoxicity based on RNA sequencing and bioinformatics analysis.

The cardiotoxicity of trastuzumab (TRZ) seriously affects the prognosis of breast cancer patients, but the underlying mechanisms remains to be elucidated. This study aimed to investigate the potential molecular mechanisms of TRZ-induced cardiotoxicity based on RNA sequencing (RNA-Seq) and bioinformatics analysis. Kunming mice were exposed to 10 mg/kg TRZ for 6 and 10 days, followed by echocardiography, histopathology and serum biochemical analysis to evaluate the cardiotoxicity model. The results showed no significant changes after 6 days administration of TRZ. After 10 days administration of TRZ, the mice showed cardiac dysfunction, myocardial injury and fibrosis, and the serum levels of LDH, CK, CK-MB and cTnI were increased compared to the control [CON (Day 10)] group, indicating the cardiotoxicity model was successfully established. We compared gene expression levels in mice cardiac tissues by RNA-Seq and screened out 593 differentially expressed genes (DEGs). Results based on Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network analysis and RT-PCR revealed that the CD74/STAT1 signaling pathway might play an important role in TRZ-induced cardiotoxicity. In the TRZ group, the protein expressions of CD74, p-STAT1 (Tyr) and p-STAT1 (Ser) were increased. The TUNEL staining showed increased apoptosis of cardiomyocytes. In addition, an increased expressions of Bax, Caspase-3, IFN-γ and TNF-α and a decreased expression of Bcl-2 were observed in Western blot results, indicating the apoptosis and inflammation levels were increased. These findings suggested that TRZ may induce cardiotoxicity in mice by activating the CD74/STAT1 signaling pathway, which might be related to the induction of apoptosis and inflammation.

[Variation Characteristics of Surface Water Quality in China in Recent Years].

Based on data from 839 comparable sections (sites) of the national surface water environmental quality monitoring network from 2012 to 2020, the variation tendency of surface water environmental quality over the past nine years was analyzed. The results showed that the environmental quality of surface water in China has continuously improved, the proportion of Grade Ⅰ-Ⅲ water quality increased steadily, and the proportion of inferior Grade Ⅴ water quality decreased in succession. The annual average concentration of ammonia nitrogen, total phosphorus, and permanganate index all showed a decreasing trend annually; compared with those in 2012, the three indicator concentrations respectively declined 75.9%, 48.2%, and 17.5% by 2020. In Guangxi, Hainan, and Ningxia, the proportion of Grade Ⅰ-Ⅲ water quality sections was maintained at 100%, whereas Hubei and Jiangxi showed a consecutive decreasing trend, and the other provinces showed a consecutive increasing trend. In Guangxi, Hainan, Ningxia, Hunan, and Fujian, the proportion of inferior Grade Ⅴ water quality sections remained at 0, and the other provinces showed a decreasing trend yearly. The annual average concentration of total phosphorus in Guangxi and Jiangxi and the permanganate index in Hubei, Hainan, and Liaoning increased annually, whereas that in the other provinces decreased to varying degrees. The proportion of Grade Ⅰ-Ⅲ water quality sections in Ten Major basins showed a fluctuating upward trend. The proportion of inferior Grade Ⅴ water quality in the Zhejiang and Fujian Slice Rivers was maintained at 0, and the other river basins showed a fluctuating and declining trend. The annual average of the main pollution indicators all decreased to varying degrees. In 2020, 53% of 32 important lakes were eutrophic, which increased 12% compared to that in 2012. On the whole, surface water quality has generally improved in China during the past nine years; especially since the 13th Five-Year Plan period, remarkable achievements have been made in the prevention and control of water pollution. However, there are differences among various provinces and basins, the improvement in water environmental quality is unbalanced and uncoordinated, water resources are distributed unevenly, and the eutrophication trend of lakes and reservoirs is not optimistic. In the future, water resources, water environment, and water ecology should be overall managed, and great attention should be focused on precise pollution control and ecological restoration of surface water.

Targeting the Akt/PI3K/mTOR signaling pathway for complete eradication of keloid disease by sunitinib.

Keloid disease is a nodular lesion, tumor-like but not cancerous, and characterized of excessive proliferation of fibroblasts and deposition of extracellular matrix (ECM) components. This condition often causes itching, pain and cosmetic disfigurement, significantly reducing patient quality of life. To date, no universally effective therapies are available, possibly due to inadequate understanding of keloid pathogenesis. As an oral small-molecule inhibitor of certain tyrosine kinase receptors, sunitinib has shown significant therapeutic effects in renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). However, it has never been tested if keloid therapy can be effective for the management of keloids. This study thus aims to explore the potential of sunitinib for keloid treatment. Keloid-derived fibroblasts (KFs) were successfully isolated and demonstrated proliferative advantage to normal skin-derived fibroblasts (NFs). Additionally, sunitinib showed specific cytotoxicity and inhibition of invasion, and induced cell cycle arrest and significant apoptosis in KFs. These effects were accompanied by complete suppression of ECM component expression, including collagen types 1 and 3, upregulation of autophagy-associated LC3B and significant suppression of the Akt/PI3K/mTOR pathway. Moreover, a keloid explant culture model was successfully established and used to test the therapeutic efficacy of sunitinib on keloid formation in nude mice. Sunitinib was found to induce complete regression of keloid explant fragments in nude mice, showing significantly higher therapeutic efficacy than the most commonly used intralesional drug triamcinolone acetonide (TAC). These data suggest that sunitinib effectively inhibits keloid development through suppression of the Akt/PI3K/mTOR pathway and thus can be potentially developed as a monotherapy or combination therapy for the effective treatment of keloid disease.

Adaptation responses of microalgal-bacterial granular sludge to polystyrene microplastic particles in municipal wastewater.

Microplastics are frequently detected in wastewater treatment plants, but the knowledge of their effects on microalgal-bacterial granular sludge (MBGS) is still unknown. This study investigated the performance and adaptive response of MBGS exposed in municipal wastewater in the presence of polystyrene (PS) microplastic particles with different sizes (i.e., 100 nm, 5 µm, and 10 µm). Results indicated that the average removal efficiency of influent organics, ammonia, and phosphorus by MBGS process was stable at above 85%, showing insignificant difference between three sizes of microplastic particles. The community richness of MBGS was reduced by nano-sized (i.e., 100 nm) and micro-sized (i.e., 5 µm) PS microplastic particles, while the community diversity decreased in all types. Although filamentous cyanobacteria were broken by PS microplastic particles, the performance of MBGS process was insignificantly affected due to the stimulated extracellular polymeric substances, which could act as adaptive responses and protect MBGS from stress damage. This study proves that MBGS process can be operated in the presence of prevalent PS microplastic particles.

EV-T synergizes with AZD5582 to overcome TRAIL resistance through concomitant suppression of cFLIP, MCL-1, and IAPs in hepatocarcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy, and its effective treatment has been hampered by drug resistance. Extracellular vesicle (EV) delivery of TNF-related apoptosis-inducing ligand (TRAIL) (EV-T) was demonstrated to be superior to recombinant TRAIL (rTRAIL) for cancer treatment previously. And AZD5582, a potent antagonist of inhibitors of apoptosis proteins (IAPs) can potentiate apoptosis-based cancer therapies. However, the combination of EV-T and AZD5582 has never been examined for their possible apoptosis inducing synergism in cancers. In this study, we proposed and tested the combination of EV-T and AZD5582 as a potential novel therapy for effective treatment of HCC. Two HCC lines Huh7 and HepG2 that are both resistant to rTRAIL were examined. The results confirmed that AZD5582 and EV-T are synergistic for apoptosis induction in some cancer lines including Huh7 and HepG2 while sparing normal cells. More importantly, this study revealed that TRAIL sensitization by AZD5582 is mediated through the concomitant suppression of anti-apoptotic factors including cFLIP, MCL-1, and IAPs (XIAP, Survivin and cIAP-1). Particularly the downregulation of cFLIP and IAP's appeared to be essential and necessary for the synergism between AZD5582 and TRAIL. In vivo, we first time demonstrated that the combined therapy with low doses of AZD5582 and EV-Ts triggered drastically enhanced apoptosis leading to the complete eradication of Huh7 tumor development without any apparent adverse side effects examined. We thus have unraveled the important molecular mechanism underlying TRAIL sensitization by AZD5582, rationalizing the next development of a combination therapy with AZD5582 and EV-T for HCC treatment. KEY MESSAGES: It confirmed the TRAIL sensitization by AZD5582, a potent antagonist of IAPs in hepatocarcinoma. It revealed that the sensitization is via the concomitant suppression of antiapoptotic factors including cFLIP, MCL-1, and IAPs. The downregulation of cFLIP and IAPs like Survivin appeared to be essential and necessary for the synergism between AZD5582 and nanosomal TRAIL. In vivo the combined therapy with AZD5582 and nanosomal TRAIL led to complete eradication of hepatocarcinoma tumors. This study has rationalized the next development of a combination therapy with AZD5582 and nanosomal TRAIL for cancer treatment.

USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aß generation.

Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted ß cleavage of APP and Aß generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.

Diffuse large B-cell lymphoma presenting as reversible intrapulmonary arteriovenous shunts with hypoxia, fever and progressive jaundice: a case report and literature review.

BACKGROUND: Intrapulmonary arteriovenous shunts is rare seen in a patient without lung involvement. CASE PRESENTATION: This is the first report of reversible intrapulmonary arteriovenous shunts secondary to extrapulmonary lymphoma as one initial symptom. The patient presented as fever of unknown origin and dyspnea, and examinations of infection were negative. Diagnosis of DLBCL was finally confirmed through bone marrow and splenic biopsies. Intrapulmonary arteriovenous shunts were diagnosed through 100% oxygen inhalation test and transthoracic contrast echocardiography (TTCE). After the treatment of lymphoma, his respiratory failure was relieved. We rechecked the 100% oxygen inhalation test and TTCE, which both indicated that his intrapulmonary arteriovenous shunts had resolved. CONCLUSIONS: We speculated the prominent inflammation from active DLBCL was the most possible mechanism associated with the reversible intrapulmonary shunt in this patient. These findings will assist us to better understand the mechanism of intrapulmonary shunts.