Multi-step strategies for synergistic treatment of urinary tract infections based on D-xylose-decorated antimicrobial peptide carbon dots.

Urinary tract infections (UTIs) caused by Uropathogenic Escherichia coli (UPEC), often reoccur due to the formation of intracellular bacterial colonies (IBCs) and antibiotic resistance. Given the significance of YadC for UPEC infection in our previous study, we developed D-xylose-decorated ɛ-poly-L-lysine (εPL)-based carbon dots (D-xyl@εPLCDs) that can be traced, and employed multi-step approaches to elucidate the functional roles of D-xyl@εPLCDs in UPEC infection. Compared to undecorated particles, D-xyl@εPLCDs demonstrate YadC-dependent bacterial targeting and exhibit enhanced bactericidal activities both intracellularly and extracellularly. Moreover, pre-treatment of D-xyl@εPLCDs before infection blocked the subsequent adhesion and invasion of UPEC to bladder epithelial cells 5637. Increase of ROS production and innate immune responses were observed in bladder epithelial cells 5637 treated with D-xyl@εPLCDs. In addition, treatment of D-xyl@εPLCDs post-infection facilitated clearance of UPEC in the bladders of the UTI mouse model, and reduced ultimate number of neutrophils, macrophages and inflammatory responses raised by invaded bacteria. Collectively, we presented a comprehensive evaluating system to show that D-xyl@εPLCDs exhibits superior bactericidal effects against UPEC, making them a promising candidate for drug development in clinical UTI therapeutics.

Bacterial indole-3-lactic acid affects epithelium-macrophage crosstalk to regulate intestinal homeostasis.

Tryptophan and its derivatives perform a variety of biological functions; however, the role and specific mechanism of many tryptophan derivatives in intestinal inflammation remain largely unclear. Here, we identified that an Escherichia coli strain (Ec-TMU) isolated from the feces of tinidazole-treated individuals, and indole-3-lactic acid (ILA) in its supernatant, decreased the susceptibility of mice to dextran sulfate sodium-induced colitis. Ec-TMU and ILA contribute to the relief of colitis by inhibiting the production of epithelial CCL2/7, thereby reducing the accumulation of inflammatory macrophages in vitro and in vivo. Mechanistically, ILA downregulates glycolysis, NF-κB, and HIF signaling pathways via the aryl hydrocarbon receptor, resulting in decreased CCL2/7 production in epithelial cells. Clinical evidence suggests that the fecal ILA level is negatively correlated with the progression indicator of inflammatory bowel diseases. These results demonstrate that ILA has the potential to regulate intestinal homeostasis by modulating epithelium-macrophage interactions.

A mouse model to test the anti-inflammatory effect of facultative anaerobes on dextran sulfate sodium-induced colitis.

The role of facultative anaerobic bacteria in colitis remains to be elucidated. We have adapted a mouse model to explore the effect of individual facultative anaerobic bacteria on colitis, focusing on adapting a cocktail of antibiotics and multiple instillations by gavage. Weight, disease activity index, colon length, and histological score are used to assess the severity of colitis. We also describe anaerobic processing protocols of preparing facultative anaerobes. For complete details on the use and execution of this protocol, please refer to Li et al. (2022).1.

Enterobacter ludwigii protects DSS-induced colitis through choline-mediated immune tolerance.

Commensal intestinal bacteria play key roles in regulating host immune tolerance; however, bacterial strains and related metabolites directly involved in this regulation are largely unknown. Here, using a mouse model of dextran sulfate sodium (DSS)-induced colitis combined with different antibiotic treatment, Enterobacter ludwigii, abundant in microbiota of mice treated with metronidazole, is screened out to have prophylactic and therapeutic effects on DSS-induced colitis with or without the presence of complex intestinal bacteria. E. ludwigii is found to induce CD103+DC and regulatory T (Treg)-mediated immune tolerance for colitis remission using in vitro and in vivo experiments. Moreover, choline, one metabolite of E. ludwigii, is identified to increase dendritic cells' (DCs) immune tolerance to promote Treg differentiation. E. ludwigii is found to induce DCs' immune tolerance ability for Treg differentiation through choline and α7nAChR-mediated retinoic acid (RA) and transforming growth factor beta (TGF-ß) upregulation, resulting in protecting mice against DSS-induced colitis. This study suggests potential therapeutic approaches for inflammatory bowel diseases (IBDs).

Uniting tensile ductility with ultrahigh strength via composition undulation.

Metals with nanocrystalline grains have ultrahigh strengths approaching two gigapascals. However, such extreme grain-boundary strengthening results in the loss of almost all tensile ductility, even when the metal has a face-centred-cubic structure-the most ductile of all crystal structures1-3. Here we demonstrate that nanocrystalline nickel-cobalt solid solutions, although still a face-centred-cubic single phase, show tensile strengths of about 2.3 gigapascals with a respectable ductility of about 16 per cent elongation to failure. This unusual combination of tensile strength and ductility is achieved by compositional undulation in a highly concentrated solid solution. The undulation renders the stacking fault energy and the lattice strains spatially varying over length scales in the range of one to ten nanometres, such that the motion of dislocations is thus significantly affected. The motion of dislocations becomes sluggish, promoting their interaction, interlocking and accumulation, despite the severely limited space inside the nanocrystalline grains. As a result, the flow stress is increased, and the dislocation storage is promoted at the same time, which increases the strain hardening and hence the ductility. Meanwhile, the segment detrapping along the dislocation line entails a small activation volume and hence an increased strain-rate sensitivity, which also stabilizes the tensile flow. As such, an undulating landscape resisting dislocation propagation provides a strengthening mechanism that preserves tensile ductility at high flow stresses.

WITHDRAWN: GAS5 enhances natural killer cell-mediated killing by promoting ubiquitination of SESN2 in prostate cancer cells.

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"Lattice Strain Matching"-Enabled Nanocomposite Design to Harness the Exceptional Mechanical Properties of Nanomaterials in Bulk Forms.

Nanosized materials are known to have the ability to withstand ultralarge elastic strains (4-10%) and to have ultrahigh strengths approaching their theoretical limits. However, it is a long-standing challenge to harnessing their exceptional intrinsic mechanical properties in bulk forms. This is commonly known as "the valley of death" in nanocomposite design. In 2013, a breakthrough was made to overcome this challenge by using a martensitic phase transforming matrix to create a composite in which ultralarge elastic lattice strains up to 6.7% are achieved in Nb nanoribbons embedded in it. This breakthrough was enabled by a novel concept of phase transformation assisted lattice strain matching between the uniform ultralarge elastic strains (4-10%) of nanomaterials and the uniform crystallographic lattice distortion strains (4-10%) of the martensitic phase transformation of the matrix. This novel concept has opened new opportunities for developing materials of exceptional mechanical properties or enhanced functional properties that are not possible before. The work in progress in this research over the past six years is reported.

Alpha-hemolysin of uropathogenic Escherichia coli induces GM-CSF-mediated acute kidney injury.

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs), inducing acute pyelonephritis and may result in permanent renal scarring and failure. Alpha-hemolysin (HlyA), a key UPEC toxin, causes serious tissue damage; however, the mechanism through which HlyA induces kidney injury remains unclear. In the present study, granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by renal epithelial cells was upregulated by HlyA in vitro and in vivo, which induced M1 macrophage accumulation in kidney, and ADAM10 was found involved in HlyA-induced GM-CSF. Macrophage elimination or GM-CSF neutralization protected against acute kidney injury in mice, and increased GM-CSF was detected in urine of patients infected by hlyA-positive UPEC. In addition, HlyA was found to promote UPEC invasion into renal epithelial cells by interacting with Nectin-2 in vitro. However, HlyA did not affect bacterial titers during acute kidney infections, and HlyA-induced invasion did not contribute to GM-CSF upregulation in vitro, which indicate that HlyA-induced GM-CSF is independent of bacteria invasion. The role of GM-CSF in HlyA-mediated kidney injury may lead to novel strategies to treat acute pyelonephritis.

HIF1α promotes prostate cancer progression by increasing ATG5 expression.

Prostate cancer (PCa) is the most frequently diagnosed cancer among men. However, the major modifiable risk factors for PCa are poorly known and its specific mechanism of progression remains unclear. Here we reported that, in prostate cancer cells, the autophagy level was elevated under hypoxic condition, as well as the mRNA and protein level of ATG5, which is an important gene related to autophagy. Furthermore, we found HIF1α could directly bind to the promoter of ATG5 and promote the expression of ATG5 on transcriptional level by luciferase assay and ChIP assay. Intriguingly, overexpression of HIF1α by HIF1α-M could increase tumor size and the effect could be abolished by knockdown ATG5 by si-ATG5 in BALB/cA-nu/nu nude mice. Importantly, HIF1α could also promote the metastasis of PC-3 cells by upregulating the ATG5 and autophagy level and knockdown ATG5 and inhibition autophagy both could abolish the effect of overexpression of HIF1α on the migration of PC-3 cells. Taken together, our results, for the first time, proved that HIF1α could promote the proliferation and migration of PC-3 cells by direct upregulating ATG5 and autophagy level in PC-3 prostate cancer cells. Our findings not only provide new perspective for the relationship between hypoxia and autophagy, but also add new potential therapeutic regimens for the treatment of prostate cancers.

An Adrenal Hepatoid Adenocarcinoma with Left Renal Vein Thrombosis Extending into the Inferior Vena Cava.

Hepatoid adenocarcinoma (HAC) is an uncommon tumor with morphological resemblance to hepatocellular car-cinoma. HAC of the adrenal glands is extremely rare. Here, we report the case of an 83-year-old man with adrenal HAC who presented with a greatly increased preoperative serum alpha-fetoprotein level (> 24,200 ng/mL). The findings of magnetic resonance imaging and contrast-enhanced abdominal computed tomography revealed a large mass occupying the left adrenal gland region as well as thrombosis of the renal vein extending into the inferior vena cava. Subsequently, the adrenal HAC was treated by surgical resection and targeted sorafenib therapy. How-ever, the patient died 9 months later because of systemic metastasis of the tumor. In conclusion, adrenal HAC with inferior vena cava tumor thrombosis is extremely rare and challenging to diagnose and treat. Pathological and immunohistochemical examination are helpful for diagnosis and surgical excision is the main strategy for treating the tumor.

Lycopene alleviates AFB1-induced immunosuppression by inhibiting oxidative stress and apoptosis in the spleen of mice.

Lycopene (LYC) has been reported to exhibit antioxidant and immunoprotective activities, and our previous studies confirmed that LYC can alleviate multiple tissue damage induced by aflatoxin B1 (AFB1). However, it is unclear whether LYC could relieve the AFB1-induced immunosuppression. Thus, forty-eight male mice were randomly allocated and treated with LYC (5 mg kg-1) and/or AFB1 (0.75 mg kg-1) by intragastric administration for 30 days. We found that LYC alleviated AFB1-induced immunosuppression by relieving splenic structure injury and increasing the spleen weight, spleen coefficient, T lymphocyte subsets, the contents of IL-2, IFN-γ and TNF-α in serum, as well as the mRNA expression of IL-2, IFN-γ and TNF-α in spleen. Furthermore, LYC inhibited oxidative stress induced by AFB1via decreasing the levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and malondialdehyde (MDA), while enhancing the total antioxidant capacity (T-AOC) and antioxidant enzyme activities. In addition, LYC also restrained splenic apoptosis through blocking mitochondria-mediated apoptosis in AFB1 intoxicated mice, presenting as the increase of mitochondrial membrane potential, and the decrease of cytoplasmic Cyt-c protein expression, cleaved Caspase-3 protein expression, Caspase-3/9 activities and mRNA expressions, as well as balancing the mitochondrial protein and mRNA expressions of Bax and Bcl-2. These results indicate that LYC can alleviate AFB1-induced immunosuppression by inhibiting oxidative stress and mitochondria-mediated apoptosis of mice spleen.

Melatonin alleviates aluminium chloride-induced immunotoxicity by inhibiting oxidative stress and apoptosis associated with the activation of Nrf2 signaling pathway.

The present study aimed to investigate whether melatonin (MT) treatment can attenuate immunotoxicity induced by aluminum chloride (AlCl3) in rat spleen. Forty-eight healthy male Wistar rats were randomly allocated and treated with AlCl3 and/or MT. Rats were orally administered with AlCl3 for 90 days, from 61st days, rats were injected intraperitoneally with MT for 30 days. Firstly, we found that MT relieved the AlCl3-induced immunosuppression by improving spleen structural damage, CD3+ and CD4+ T lymphocyte subsets, IL-2 and TNF-α mRNA expressions and decreasing CD8+ T lymphocyte subsets. Secondly, MT attenuated the AlCl3-induced oxidative stress in rat spleen by decreasing the levels of ROS and MDA, while increasing the activities of SOD and CAT. Thirdly, MT relieved the AlCl3-induced apoptosis in rat spleen by increasing the MMP and Bcl-2 mRNA and protein expressions, while decreasing apoptosis rates, activity of Caspase-3 and pro-apoptotic gene expression. Finally, MT increased Nrf2 nuclear translocation, and Nrf2 target genes (HO-1, NQO1, SOD1 and CAT) mRNA expressions in the spleen of AlCl3-exposed rat. These results suggest that MT may alleviate AlCl3-induced immunotoxicity by inhibiting oxidative stress and apoptosis associated with the activation of Nrf2 signaling pathway, which could lay the foundation for the treatment of AlCl3 immunotoxicity.

Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells.

Many reports demonstrated that aluminum maltolate (Almal) has potential toxicity to human and animal. Our study has demonstrated that Almal can induce oxidative damage and apoptosis in PC12 cells and SH-SY5Y Cells, two in vitro models of neuronal cells. Hyperforin (HF) is a well-known antioxidant, anti-inflammatory, anti-amyloid and anti-depressant compound extracted from Hypericum perforatum extract. Here, we investigated the neuroprotective effect of HF against Almal-induced neurotoxicity in cultured PC12 cells and SH-SY5Y cells, mainly caused by oxidative stress. In the present study, HF significantly inhibited the formation of reactive oxygen species (ROS), decreased the level of lipid peroxide and enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) compared with Almal group in PC12 cells and SH-SY5Y cells. Additionally, HF suppressed the reduction of the mitochondrial membrane potential (MMP), cytochrome c (Cyt-c) release, activation of caspase-3, and the down-regulation of Bcl-2 expression and up-regulation of Bax expression induced by Almal in PC12 cells and SH-SY5Y cells. In summary, HF protects PC12 cells and SH-SY5Y cells from damage induced by Almal through reducing oxidative stress and preventing of mitochondrial-mediated apoptosis.

MiR-10a functions as a tumor suppressor in prostate cancer via targeting KDM4A.

Deregulation of microRNAs contributes to the abnormal cell growth which is frequently observed in cancer. In the current study, we detected the expression and regulatory relationship between miR-10a and Lysine-specific demethylase 4A (KDM4A) to reveal their function in prostate cancer (PCa) progression. We found that miR-10a levels were significantly decreased in PCa cell lines in comparison with the normal epithelial cell line RWPE-1. Downregulation of miR-10a levels was also observed in tumor tissues from PCa patients compared with the adjacent normal tissues. Enhanced expression of miR-10a inhibited cell proliferation and colony forming capability of PCa cells. In addition, quantitative real-time polymerase chain reaction and Western blot analysis showed a significant decrease of KDM4A in response to miR-10a elevation in PCa cells. Using dual luciferase assay, we confirmed that KDM4A was a target gene for miR-10a. Furthermore, Western blot analysis indicated that miR-10a overexpression inactivated YAP signaling and suppressed transcription of YAP target genes. Additionally, cell growth arrest and colony forming capacity inhibition induced by miR-10a overexpression could be reversed by YAP overexpression in PCa cells. More importantly, miR-10a mimics inhibited PC-3 tumor growth in nude mice accompanied with a remarkable reduction of KDM4A and YAP expression. In conclusion, our results uncovered a tumor suppressor role of miR-10a in PCa via negative regulation of KDM4A and its downstream Hippo-YAP pathway.

Lycopene attenuates AFB1-induced renal injury with the activation of the Nrf2 antioxidant signaling pathway in mice.

Oxidative stress is an important molecular mechanism for kidney injury in aflatoxin B1 (AFB1) nephrotoxicity. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor for regulating the cellular oxidative stress response, which has been confirmed in animal models. Lycopene (LYC), a natural carotenoid, has received extensive attention due to its antioxidant effect with the activation of Nrf2. However, the role of LYC in protecting against AFB1-induced renal injury is unknown. To evaluate the chemoprotective effect of LYC on AFB1-induced renal injury, forty-eight male mice were randomly divided into 4 groups and treated with LYC (5 mg per kg of bodyweight) and/or AFB1 (0.75 mg per kg of bodyweight) by intragastric administration for 30 days. AFB1 and LYC were respectively dissolved in olive oil. We found that AFB1 exposure significantly increased the serum concentrations of blood urea nitrogen (BUN) and serum creatinine (SCR), and caused damage to the renal structure. Notably, LYC potentially alleviated AFB1-induced kidney lesions through attenuating AFB1-induced oxidative stress. Renal nuclear factor-erythroid 2-related factor 2 (Nrf2) and its downstream target gene (CAT, NQO1, SOD1, GSS, GCLM and GCLC) translation and protein expression were ameliorated by pretreatment with LYC in AFB1-exposed mice. These results suggested that LYC potentially alleviates AFB1-induced renal injury. This effect may be attributed to the enhancement of renal antioxidant capacity with the activation of the Nrf2 antioxidant signaling pathway.

Percutaneous nephrostomy via the central venous catheter in combination with selective ureteroscopic lithotripsy for the treatment of ureteral stones in the middle-upper segment.

OBJECTIVE: To explore the therapeutic outcome and significance of preoperative percutaneous nephrolithotomy (PCNL) via the central venous catheter in combination with two-step hard ureteroscopic lithotripsy for the treatment of ureteral stones in the middle-upper segment. METHODS: The success rate and the occurrence of severe infection and perirenal hematoma were analyzed retrospectively in 37 patients who received preoperative PCNL via the central venous catheter in combination with two-step hard ureteroscopic lithotripsy for the treatment of ureteral stones in the middle-upper segment in our hospital between July 2012 and November 2014. RESULTS: The operation duration was 12-38 min with a mean of 18.5 min. The procedure was performed successfully in all patients without the postoperative occurrence of perirenal hematoma in any patient. No severe infection occurred in any patient according to the Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis (2012). CONCLUSION: Preoperative PCNL via the central venous catheter can significantly improve the success rate of ureteroscopic lithotripsy for the treatment of ureteral stones in the middle-upper segment, and reduce postoperative occurrences of severe infection and perirenal hematoma.

HIF-1α induces immune escape of prostate cancer by regulating NCR1/NKp46 signaling through miR-224.

BACKGROUND: Metastasis of prostate cancer (PCa) is largely affected by natural killer (NK) cells. This study aimed to clarify the mechanisms underlying tumor cells escaping from NK cells mediated by HIF-1α. METHODS: MiR-224 expression in lymphocytes and HIF-1α protein level in NK cells were determined by qRT-PCR and western blot, respectively. The amount of NKp46+ NK cells was detected with flow cytometry. The IFN-γ level was examined by enzyme linked immunosorbent assay (ELISA). NK cells were tested for cytolytic activity with a Non-Radioactive Cytotoxicity Assay, and treated with oxygenglucose deprivation (OGD) for hypoxia simulation. Interaction between miR-224 and NCR1 was evaluated with dual luciferase reporter assay. RESULTS: MiR-224 was down-regulated in lymphocytes isolated from prostate cancer tissues (n = 10). Overexpression of miR-224 protected prostate cancer from NK cells. HIF-1α increased miR-224 to inhibit the killing capability of NK cells on prostate cancer. MiR-224 controlled the expression of NCR1. Overexpression of miR-224 protected prostate cancer from NK cells through NCR1/NKp46 signaling. Suppression of HIF-1α enhanced the cytotoxicity of NK cells on prostate cancer via miR-224/NCR1 pathway. CONCLUSION: HIF-1α inhibits NCR1/NKp46 pathway through up-regulating miR-224, which affects the killing capability of NK cells on prostate cancer, thus inducing immune escape of tumor cells.

Bone impairment caused by AlCl3 is associated with activation of the JNK apoptotic pathway mediated by oxidative stress.

Exposure to aluminum (Al) inhibits bone formation, the principal mechanism possibly due to oxidative stress. However, little data is available that establishes the precise relationship. In this study, Wistar rats were exposed to 0 (GC), 0.4 (GL), 0.8 (GM) or 1.6 (GH) mg/L aluminum trichloride (AlCl3) in drinking water for 90 days, respectively. The concentrations of Al in serum and bone, serum markers of bone metabolism, bone mineral density (BMD) and body weight were measured. Histological changes within femurs were observed by H&E, ALP, and TRACP staining. Oxidative stress markers and JNK apoptotic pathway were detected in bone. The results indicate that AlCl3 exposure decreased BMD, numbers of ALP-positive osteoblasts and serum levels of bone formation markers (B-ALP, PICP and BGP), and caused damaged to the trabecular structure. Serum levels of bone resorption markers (TRACP-5b, CTX-I) and numbers of TRACP-positive osteoclasts increased in GL, but conversely, they decreased in GM and GH. In addition, AlCl3 caused oxidative stress, up-regulated expression of c-Jun and pro-apoptotic factors with increased p-JNK/JNK ratio and down-regulated expression of anti-apoptotic factor Bcl-2 in bone. Taken together, these results indicate that bone impairment caused by AlCl3 is associated with activation of the oxidative stress-mediated JNK apoptotic pathway.

Aluminum trichloride-induced hippocampal inflammatory lesions are associated with IL-1ß-activated IL-1 signaling pathway in developing rats.

Aluminum (Al) is a recognized environmental pollutant that causes neuroinflammatory lesions, leading to neurodegenerative diseases. Interleukin-1 (IL-1) signaling pathway is responsible for regulating inflammatory lesions. However, it remains unclear whether IL-1 signaling pathway is involved in neuroinflammatory lesions induced by Al exposure. In the present study, one hundred and twenty Wistar rats were orally exposed to 0, 50, 150 and 450 mg/kg BW/d aluminum trichloride (AlCl3) for 90 days, respectively. We found that AlCl3 exposure increased hippocampal Al concentration, reduced hippocampus coefficient, impaired cognitive ability, deteriorated microstructure of hippocampal CA1 and CA3 regions, increased reactive oxygen species (ROS) level, activated astrocytes and microglia, increased pro-inflammatory cytokines contents and mRNA expressions, and decreased anti-inflammatory cytokines contents and mRNA expressions in the hippocampus. These results indicated that AlCl3 induced the hippocampal inflammatory lesion (HIL). Moreover, AlCl3 exposure increased the mRNA and protein expression of IL-1 signaling pathway core components in the hippocampus, demonstrating that AlCl3 activated IL-1 signaling pathway. Furthermore, the correlation between interleukin-1ß (IL-1ß) content and HIL and activation of the IL-1 signaling pathway was analyzed. Results showed that IL-1ß content was positively correlated with pro-inflammatory cytokines contents and mRNA expressions and activation of IL-1 signaling pathway, and was negatively correlated with hippocampus coefficient, anti-inflammatory cytokines contents and mRNA expressions, and the number of hippocampal neurons. The above results demonstrate that AlCl3-induced HIL is associated with IL-1 signaling pathway, in which IL-1ß is a link.

Detwinning through migration of twin boundaries in nanotwinned Cu films under in situ ion irradiation.

The mechanism of radiation-induced detwinning is different from that of deformation detwinning as the former is dominated by supersaturated radiation-induced defects while the latter is usually triggered by global stress. In situ Kr ion irradiation was performed to study the detwinning mechanism of nanotwinned Cu films with various twin thicknesses. Two types of incoherent twin boundaries (ITBs), so-called fixed ITBs and free ITBs, are characterized based on their structural features, and the difference in their migration behavior is investigated. It is observed that detwinning during radiation is attributed to the frequent migration of free ITBs, while the migration of fixed ITBs is absent. Statistics shows that the migration distance of free ITBs is thickness and dose dependent. Potential migration mechanisms are discussed.