Removal of particulate matter and dissolved organic matter from sedimentation sludge water during pre-sedimentation process: Performances and mechanisms.

Sedimentation sludge water (SSW), a prominent constituent of wastewater from drinking water treatment plants, has received limited attention in terms of its treatment and utilization likely due to the perceived difficulties associated with managing SSW sludge. This study comprehensively evaluated the water quality of SSW by comparing it to a well-documented wastewater (filter backwash water (FBW)). Furthermore, it investigated the pollutant variations in the SSW during pre-sedimentation process, probed the underlying reaction mechanism, and explored the feasibility of employing a pilot-scale coagulation-sedimentation process for SSW treatment. The levels of most water quality parameters were generally comparable between SSW and FBW. During the pre-sedimentation of SSW, significant removal of turbidity, bacterial counts, and dissolved organic matter (DOM) was observed. The characterization of DOM components, molecular weight distributions, and optical properties revealed that the macromolecular proteinaceous biopolymers and humic acids were preferentially removed. The characterization of particulates indicated that high surface energy, zeta potential, and bridging/adsorption/sedimentation/coagulation capacities in aluminum residuals of SSW, underscoring its potential as a coagulant and promoting the generation and sedimentation of inorganic-organic complexes. The coagulation-sedimentation process could effectively remove pollutants from low-turbidity SSW ([turbidity]0 < 15 NTU). These findings provide valuable insights into the water quality dynamics of SSW during the pre-sedimentation process, facilitating the development of SSW quality management and enhancing its reuse rate.

An ultrasensitive free-of-electronic sacrificial agent photoelectrochemical aptasensor for the detection of dibutyl phthalate based on Z-scheme p-n Bi-doped BiOI/Bi2S3 heterojunction.

Dibutyl phthalate (DBP), a common and outstanding plasticizer, exhibits estrogenic, mutagenic, carcinogenic, and teratogenic properties. It is easily liberated from plastic materials and pollutes aquatic ecosystems, endangering human health. Therefore, highly sensitive and selective DBP detection methods are necessary. In this work, a free-of-electronic sacrificial agent photoelectrochemical (PEC) aptasensor for DBP detection was constructed using a novel Z-scheme Bi-doped BiOI/Bi2S3 (Bi-BIS) p-n heterojunction. The Bi-BIS composites had higher visible-light absorption, charge transfer, and separation efficiency. This is attributed to the synergistic effect of the formation of Z-scheme p-n heterojunction between BiOI and Bi2S3, the plasma resonance effect of metallic Bi and photosensitization of Bi2S3, thus exhibiting large and stable photocurrent response in the absence of electron sacrificial agent, that was 10.4 and 6.4 times higher than that of BiOI and Bi2S3, respectively. Then, a DBP PEC aptasensor was constructed by modifying the DBP aptamer on the surface of the ITO/Bi-BIS electrode. The aptasensor demonstrated a broad linear range (2-500 pM) and a low detection limit (0.184 pM). What's more, because there is no interference from electronic sacrificial agent, the aptasensor exhibited excellent selectivity in real water samples. Therefore, the proposed PEC has considerable potential for DBP monitoring.

NF-κB/miR-455-5p/SOCS3 axis aggravates sepsis induced acute kidney injury through promoting renal inflammation.

INTRODUCTION: Sepsis is the leading contributor to acute kidney injury (AKI), responsible for 45% to 70% of AKI occurrences. Despite this, septic AKI is a highly multifactorial and complex condition, and our grasp of its pathogenesis is still not fully developed. Consequently, there remains a significant gap in effective diagnostic and therapeutic strategies for septic AKI. METHODS: In the in vitro experiments, BUMPT cells were exposed to lipopolysaccharides (LPS). In vivo experiments involved inducing sepsis in mice through administration of LPS injections. Additionally, in certain experiments, either a miR-455-5p mimic or an anti-miR-455-5p LAN was administered to the mice via injections into the tail vein. The mice were then sacrificed 24 hours following LPS administration for subsequent analysis. RESULTS: We observed a significant elevation in miR-455-5p levels within renal tubular cells following LPS-induced septic AKI. Our investigation revealed that NF-κB plays a crucial role in the upregulation of miR-455-5p. Inhibition of NF-κB using TPCA-1 prevented the rise in miR-455-5p levels in BUMPT cells (mouse proximal tubular cells from Boston University) cultured in vitro. ChIP assays confirmed that NF-κB directly interacts with the promoter region of the miR-455-5p gene in response to LPS treatment. Functionally, introducing miR-455-5p mimics intensified cell apoptosis, kidney damage, and the production of inflammatory cytokines, while silencing miR-455-5p had protective effects in septic mice. Notably, administering anti-miR-455-5p enhanced SOCS3 expression, whereas miR-455-5p mimics reduced SOCS3 levels following LPS exposure. Furthermore, our luciferase reporter assays demonstrated that SOCS3 is a direct target of miR-455-5p. CONCLUSION: This study indicates a NF-κB/miR-455-5p/SOCS3 axis which can exacerbate kidney damage by enhancing renal inflammation. This process highlights potential therapeutic targets for managing septic AKI.

Expected Eight-Week Prenatal Versus Twelve-Week Perinatal Tenofovir Alafenamide Prophylaxis to Prevent Mother-To-Child Transmission of Hepatitis B Virus: A Multicenter, Prospective, Open-label, Randomized Controlled Trial.

INTRODUCTION: The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study. METHODS: In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected eight-week) or to four-week postpartum (expected twelve-week) were randomly enrolled at a 1:1 ratio and followed until six-month postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary endpoint was the safety of mothers and infants. The secondary endpoint was infants' HBV-MTCT rate at seven months of age. RESULTS: Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in two groups completed the study. Overall, TAF was well tolerated, no one discontinued therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n=231) and at seven months (n=222) were normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at seven months of age. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) versus 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the two groups had mildly elevated alanine aminotransferase levels at three-month and six-month postpartum, respectively (P=0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] versus 0% [0/120, 0%-3.1%]). DISCUSSION: Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected eight-week prenatal duration is feasible. ClinicalTrials.gov, NCT04850950.

Evaluation of a new classification system for measuring the progression of ocular cystinosis: an analysis of 64 patients.

AIMS: To analyse the correlation between the physician categories defined by the 3C classification (crystal-complication-compliance) and the ocular manifestations of nephropathic cystinosis. METHODS: The last visit data of 64 patients aged between 2 and 64 attending the centre for management of cystinosis were reviewed. Each patient had been placed into one of four categories by the clinician based on disease severity. The correlation between these categories and markers of the disease was assessed using Pearson's correlation. RESULTS: Photophobia (0.647, p<0.001), visual acuity (-0.695, p<0.001), Gahl's score (0.603, p<0.001), optical coherence tomography (OCT)% (0.713, p<0.001) and in vivo confocal microscopy (IVCM)% (0.845, p<0.001), showed a strong, highly significant correlation between key signs and symptoms and the 3C classification. Corneal complications were strongly correlated with the 3C classification with scores of 0.802 (p<0.001), 0.634 (p<0.001), 0.726 (p<0.001) and 0.677 (p<0.001) for band keratopathy, keratitis, neovascularisation and corneal ulceration, respectively. 75% of those classified as most severe had all four complications. The use of artificial tears and ciclosporin strongly correlated with the categorisation, 0.574 (p<0.001) and 0.631 (p<0.001), respectively. With all cystinosis markers, the 3C classification showed a stronger correlation than age and crystal scores by Gahl's and OCT. Category and age were strongly correlated (0.656, p<0.001). There was a moderate negative correlation with therapeutic compliance with cysteamine eye-drops and categorisation (-0.422, p<0.001). The compliance pattern observed may help to explain why the disease progresses in some patients. CONCLUSION: 3C classification is a reliable tool to categorise ocular cystinosis and can support clinical management decisions allowing more reliable comparison of datasets.

Sm(â ¢), Gd(â ¢), and Eu(â ¢) complexes with 8-hydroxyquinoline derivatives as potential anticancer agents via inhibiting cell proliferation, blocking cell cycle, and inducing apoptosis in NCI-H460 cells.

Four lanthanide complexes with 8-hydroxyquinoline-2-aldehyde-2-hydrazinopyridine (H-L1), 8-hydroxyquinoline-2-aldehyde-2-hydrazimidazole (H-L2): [Sm(L1)2][Sm(L1)(NO3)3]·CHCl3·2CH3OH (1), [Gd(L1)2][Gd(L1)(NO3)3]·CHCl3·2CH3OH (2), [Sm(L2)(NO3)2]2·CH3OH (3), and [Eu(L2)(NO3)2]2·CH3OH (4) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex 1 showed the best antiproliferative activity against NCI-H460 tumor cells. Mechanistic studies demonstrated that complex 1 arrested the cell cycle of NCI-H460 cells in G1 phase and induced mitochondria-mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca2+ levels and reactive oxygen species generation. In addition, complex 1 affected the expression levels of intracellular apoptosis-related proteins and activated the caspase-3/9 in NCI-H460 cells. Therefore, complex 1 is a potential anticancer agent.

GSH responsive AuNRs@TFF nanotheranostic for NIR-II photoacoustic imaging-guided CDT/PTT synergistic cancer therapy.

Gold nanorods (AuNRs) are important photothermal therapeutic agents; however, a single therapy does not achieve satisfactory outcomes, and the synthesis process often leads to the adsorption of cetyltrimethylammonium bromide on the surface of AuNRs, which reduces its biocompatibility. Natural polyphenols are abundant in natural plants and have good biocompatibility. The metal-polyphenol network is formed by the coordination of metal ions and polyphenols, which has good drug loading, surface adhesion, and biocompatibility. In this study, the metal-polyphenol network structure formed by a transition metal (iron) and natural polyphenol tannic acid was used to modify the surface of gold nanorods (AuNRs@TF). Additionally, the surfaces of AuNRs were modified using the targeted functional molecule mercapto folic acid (AuNRs@TFF). The constructed composite nanomaterials AuNRs@TFF has good biocompatibility and tumor targeting ability. Tannic acid­iron degrades in the tumor microenvironment and releases iron ions that catalyze the Fenton reaction, thereby facilitating chemodynamic therapy. The good photo-thermal ability of AuNRs generate good photoacoustic signals to facilitate photoacoustic imaging mediation and enhances photothermal and chemodynamic therapy performance. This study expands on the application of AuNRs in the field of nanomedicine. The simple and effective design of AuNRs@TFF provides a strategy for the development of synergistic therapeutic agents for photothermal therapy and chemodynamic therapy.

Antifungal Activity of Phloroglucinol Derivatives against Botrytis cinerea and Monilinia fructicola.

Naturally derived compounds show promise as treatments for microbial infections. Polyphenols, abundantly found in various plants, fruits, and vegetables, are noted for their physiological benefits including antimicrobial effects. This study introduced a new set of acylated phloroglucinol derivatives, synthesized and tested for their antifungal activity in vitro against seven different pathogenic fungi. The standout compound, 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one (2b), exhibited remarkable fungicidal strength, with EC50 values of 1.39 µg/mL against Botrytis cinerea and 1.18 µg/mL against Monilinia fructicola, outperforming previously screened phenolic compounds. When tested in vivo, 2b demonstrated effective antifungal properties, with cure rates of 76.26% for brown rot and 83.35% for gray mold at a concentration of 200 µg/mL, rivaling the commercial fungicide Pyrimethanil in its efficacy against B. cinerea. Preliminary research suggests that 2b's antifungal mechanism may involve the disruption of spore germination, damage to the fungal cell membrane, and leakage of cellular contents. These results indicate that compound 2b has excellent fungicidal properties against B. cinerea and holds potential as a treatment for gray mold.

Developing a Rhodium(III) Complex to Reprogram the Tumor Immune and Metabolic Microenvironments: Overcoming Multidrug Resistance and Metastasis in Non-Small Cell Lung Cancer.

To effectively inhibit the growth and metastasis of non-small cell lung cancer (NSCLC) and overcome its multidrug resistance (MDR), we designed and synthesized a series of rhodium (Rh, III) 2-benzoylpyridine thiosemicarbazone complexes. Through studying their structure-activity relationships, we identified the Rh(III) complex (Rh4) with excellent cytotoxicity against multidrug-resistant lung cancer cells (A549/ADR cells). Additionally, we successfully constructed an apoferritin (AFt) nanoparticle (NP) delivery system (AFt-Rh4 NPs). Importantly, AFt-Rh4 NPs not only exhibited excellent antitumor and antimetastatic capabilities against multidrug-resistant NSCLC in vivo but also demonstrated enhanced targeting ability and reduced systemic toxicity and adverse effects. Furthermore, we confirmed and elucidated the mechanisms by which Rh4/AFt-Rh4 NPs inhibit tumor metastasis and reverse MDR in NSCLC. This was achieved by reprogramming the immune and metabolic tumor microenvironments through induction of immunogenic cell death and inhibition of dual-energy metabolism.

Developing a Palladium(II) Agent to Overcome Multidrug Resistance and Metastasis of Liver Tumor by Targeted Multiacting on Tumor Cell, Inactivating Cancer-Associated Fibroblast and Activating Immune Response.

To targeted overcome the multidrug resistance (MDR) and metastasis of liver tumors, we proposed to develop a palladium (Pd) agent based on a specific residue of human serum albumin (HSA) for multiacting on tumor cell and other components in the tumor microenvironment. To this end, a series of Pd(II) 2-acetylpyridine thiosemicarbazone compounds were optimized to obtain a Pd(II) compound (5b) with significant cytotoxicity against HepG2/ADM cells. Subsequently, we constructed a HSA-5b complex delivery system and revealed the structural mechanism of HSA delivering 5b. Importantly, 5b/HSA-5b effectively inhibited the growth and metastasis of multidrug resistant liver tumors, and HSA enhanced the targeting ability of 5b and reduced its side effects in vivo. Furthermore, we confirmed the mechanisms of 5b/HSA-5b integrating to overcome MDR and metastasis of liver tumors: multiacting on cancer cell, activating immune response, and inactivating cancer-associated fibroblasts.

Aggregated health risk assessment of perfluoroalkyl acids migrated from convenience food contact materials.

Ingestion of perfluoroalkyl acids (PFAAs) via contaminated food contact materials (FCMs) is an important human exposure source. This study adopts a toxicity equivalent approach to evaluate the collective health risk of multiple PFAAs in FCMs. A comprehensive extraction and analysis of 21 PFAAs in FCMs was performed. Among the analyzed substances, 15 PFAAs were detected. Migration experiment using three food simulants revealed the migration range of seven PFAAs from FCMs into the simulant to be 0.47-46.7 ng/cm2. The hazard quotient results suggest minimal health risk, except for 9% of packaged samples where perfluorooctanoic acid (PFOA) poses a higher risk. Utilizing PFOA toxic equivalent concentrations, comprehensive risk calculations showed ∼77% of samples potentially posing elevated health risks due to PFAA exposure. This emphasizes the substantial contribution of PFAAs beyond PFOA and underscores the importance of considering them in related assessments. The aggregated risk assessment reflects actual exposure circumstances more accurately.

Enhanced nitrogen removal and microbial community of the mainstream deammonification treating fluctuating influent C/N wastewater by the novel functional carriers.

The plug-flow fixed bed reactors with zeolite/tourmaline-modified polyurethane carriers (PFBRZTP) and polyurethane carriers (PFBRPU) were operated to assess the fluctuating influent C/N impact on the system performance and the carrier effect on the enhancing the system operation. Result suggested that fluctuations in influent C/N and variations in operational temperature reduced the removal performance and system stability within PFBRPU. The negative impact of C/N fluctuation could be effectively mitigated by effluent reflux. In contrast, PFBRZTP performance and operational stability of maintained at high level with a greater nitrogen removal rate (0.18 kg N·(m³·d)-1). Redundancy analyses showed that the fluctuations in influent C/N dramatically affected the microbiome structure in PFBRPU, and the leading influencing factor was shifted to the fluctuating amount of influent C/N, which in turn reduced the system performance and stability. ZTP carriers could maintain the balance of main functional bacterial activity and abundance and promote the partial denitrification process with a higher Thauera abundance of 0.48%.

Kidney Biopsy Findings Among Patients With Diabetes in the Cleveland Clinic Kidney Biopsy Epidemiology Project.

Rationale & Objectives: Diabetic kidney disease (DKD) is a significant complication of diabetes mellitus, often leading to kidney failure. The absence of well-defined factors prevents distinguishing DKD from non-diabetic kidney disease (non-DKD; alternative primary diagnosis identified on kidney biopsy). Study Design: Retrospective cohort study. Setting & Participants: This study assessed 1,242 patients with a history of diabetes from the Cleveland Clinic Kidney Biopsy Epidemiology Project between January 2015 and September 2021. Exposure: Proteinuria, retinopathy, A1c levels, and estimated glomerular filtration rate. Outcomes: Non-DKD, defined as an alternative primary diagnosis identified on kidney biopsy other than DKD. Analytical Approach: Multivariate logistic regression model with backward elimination method. Results: At the time of biopsy, the median (IQR) age was 63 (53-71 years) years, and 58.8% were men. The median hemoglobin A1c value was 6.7% (6.0%-8.1%), and the median serum creatinine level was 2.5 (1.6-3.9 mg/dL) mg/dL. Among 1,242 patients, 462 (37.2%) had DKD alone, and 780 (62.8%) had non-DKD. Among those with non-DKD, the most common diagnoses were focal segmental glomerulosclerosis (24%), global glomerulosclerosis otherwise not specified (13%), acute tubular necrosis (9%), IgA nephropathy (8%), antineutrophil cytoplasmic antibody vasculitis (7%), and membranous nephropathy (5%). Factors associated with having non-DKD on biopsy were having no retinopathy (vs retinopathy) (adjusted odds ratio [aOR], 3.98; 95% CI, 2.69-5.90), lower A1c levels (<7% vs ≥7%) (aOR, 3.08; 95% CI, 2.16-4.39), higher estimated glomerular filtration rate (≥60 vs <60 mL/min/1.73 m2) (aOR, 2.39; 95% CI 1.28-4.45), microalbuminuria (<300 vs macroalbuminuria ≥300 [mg/g]) (aOR; 2.94; 95% CI, 1.84-4.72), and lower protein-creatinine ratio on random urine sample (<3 vs ≥3 mg/mg) (aOR; 1.80; 95% CI, 1.24-2.61). Limitations: Selection bias of clinically indicated biopsies, not protocol biopsies, which likely represent a ceiling (maximum) for non-DKD. Conclusions: Among patients with diabetes undergoing kidney biopsy, 63% have findings in addition to DKD on biopsy. We identified clinical parameters associated with non-DKD in the setting of diabetes. This provides valuable information for clinicians when kidney biopsy should be considered among patients with diabetes to capture all etiologies of proteinuria and kidney dysfunction.

Our study aimed to better understand when to perform kidney biopsies in patients with diabetes. Often, nephrologists diagnose diabetes-related kidney disease based on clinical parameters without a biopsy. We sought to look at what the spectrum of kidney biopsy findings were in patients with a clinical history of diabetes to see how many patients had diabetic kidney disease or other findings. Given the advent of several new medications that treat and slow the progression of diabetic kidney disease, we also sought to see what clinical factors were more likely to suggest a finding of nondiabetic kidney disease on biopsy to help guide clinicians when to biopsy in this population.

A tartaric acid (TA)-coated iron-based biochar as heterogeneous fenton catalyst for enhanced degradation of dibutyl phthalate.

Iron-biochar composite is a promising catalyst in Fenton-like system for removal of organic pollutants. Nevertheless, low cycling rate of Fe(III)/Fe(II), high iron leaching and low H2O2 utilization efficiency impedes its application. Herein, a iron-based biochar (C-Fe) coated with tartaric acid (TA) was synthesized. The specific structure of inherent graphitized carbon and TA coating improved the removal efficiency of dibutyl phthalate (DBP) to 93%, promoted 2-fold increase in HO• production in H2O2 activation, improved the cycling rate of Fe(III)/Fe(II), and mitigated Fe leaching significantly. The developed HO• and 1O2 dominated Fenton-like system had an excellent pH universality and anti-interference to inorganic ions and real water matrixes. Moreover, C-Fe-TA has been shown to efficiently degrade DBP by using the dissolved oxygen in water to generate HO•. This work provided a novel insight for sustainable and efficient HO• and 1O2 generation, which motivated the development of new water treatment technology based on efficient iron-biochar catalyst.

Anticancer Tetranuclear Cu(I) Complex Catalyzes a Click Reaction to Synthesize a Chemotherapeutic Agent in situ to Achieve Targeted Dual-Agent Combination Therapy for Cancer.

To develop next-generation metal-based drugs and dual-drug combination therapy for cancer, we proposed to develop a copper (Cu) complex that exerts anticancer function by integrating chemotherapy, immunotherapy and catalyzes a click reaction for the in situ synthesis of a chemotherapeutic agent, thereby achieving targeted dual-agent combination therapy. We designed and synthesized a tetranuclear Cu(I) complex (Cu4) with remarkable cytotoxicity and notable catalytic ability for the in situ synthesis of a chemotherapeutic agent via Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition (CuAAC). We also constructed an apoferritin (AFt)-Cu4 nanoparticles (NPs) delivery system. AFt-Cu4 NPs not only showed an enhanced performance of tumor growth inhibition, but also improved the targeting ability and reduced the systemic toxicity of Cu4 in vivo. Importantly, the anticancer effect was enhanced by combining the AFt-Cu4 NPs with the resveratrol analogue obtained from the CuAAC reaction in situ. Finally, we revealed the anticancer mechanism of the Cu4/AFt-Cu4 NPs, which involves both cuproptosis and cuproptosis-induced systemic immune response.

Enzymatic bioremediation of polycyclic aromatic hydrocarbons (PAHs) in contaminated soil: a study on the recombinant laccase TVL.

Polycyclic aromatic hydrocarbons (PAHs) are pervasive and persistent pollutants in contaminated soil, posing a severe health and environmental threat. Enzymatic bioremediation presents a viable solution for the remediation of PAH-contaminated soil. In this study, a recombinant laccase with the encoding gene originating from Trametes villosa and recombinantly expressed in Aspergillus oryzae, designated as TVL, was discovered to possess strong PAH reduction capabilities. The specific enzyme activity of TVL was 73485 and 5102 LAMU/g enzyme protein at pH 5.0/7.0 and 37°C. Furthermore, it exhibited significant benzo[a]pyrene degradation, with 100% and 90.48% degradation at pH 5.0/7.0 after 24 h in the liquid phase. The degradation process of benzo[a]pyrene in soil was thoroughly investigated. Optimal conditions were identified as 15 mg/g NK-BSoil-3 and 1.35 mg/g HBT, resulting in a removal rate of 37.54% within 7 days when 0.01 U/g of TVL was applied. The potential mechanisms were investigated using molecular docking simulation. The binding energy between benzo[a]pyrene and TVL protein is notably robust, suggesting a higher propensity for enzyme binding. The TVL protein pocket contains nine amino acids that can interact most strongly with benzo[a]pyrene. Consequently, the recombinant laccase TVL holds considerable practical significance in bioremediation.

Reversible chemoresistance of pancreatic cancer grown as spheroids.

Better in vitro models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

Rational Design of a Hetero-multinuclear Gadolinium(III)-Copper(II) Complex: Integrating Magnetic Resonance Imaging, Photoacoustic Imaging, Mild Photothermal Therapy, Chemotherapy and Immunotherapy of Cancer.

For more accurate diagnosis and effective treatment of cancer, we proposed to develop a hetero-multinuclear metal complex based on the property of apoferritin (AFt) for targeting tumor theranostics by integrating dual-modality imaging diagnosis and multimodality therapy. To this end, we rational designed and synthesized a trinuclear Gd(III)-Cu(II) thiosemicarbazone complex (Gd-2Cu) and then constructed a Gd-2Cu@AFt nanoparticle (NP) delivery system. Gd-2Cu/Gd-2Cu@AFt NPs not only had significant T1-weighted magnetic resonance imaging and photoacoustic imaging of the tumor but also effectively inhibited tumor growth through a combination of mild photothermal therapy, chemotherapy, and immunotherapy. Gd-2Cu@AFt NPs optimized the behavior of imaging diagnosis and therapy of Gd-2Cu, improved its targeting ability, and reduced the side effects in vivo. Besides, we revealed and clarified the anticancer mechanism of Gd-2Cu: interrupting energy metabolism of the tumor cell, inducing apoptosis of the tumor cell, and activating a systemic immune response by inducing immunogenic cell death of cancer cells.

Carboxypeptidase inhibitor Latexin (LXN) regulates intestinal organogenesis and intestinal remodeling involved in intestinal injury repair in mice.

The self-renewal and regeneration of intestinal epithelium are mainly driven by intestinal stem cells resided in crypts, which are crucial for rapid recovery intestinal tissue following injury. Latexin (LXN) is a highly expressed stem cell proliferation and differentiation related gene in intestinal tissue. However, it is still ambiguous whether LXN participates in intestine regeneration by regulating intestinal stem cells (ISCs). Here, we report that LXN colocalizes with Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) in intestinal crypts, and deletion of LXN upregulates the expression of Lgr5 in intestinal crypts. LXN deficiency promotes the proliferation of ISCs, thereby enhances the development of intestinal organoids. Mechanically, we show that LXN deficiency enhances the expression of Lgr5 in ISCs by activating the Yes-associated protein (YAP) and wingless (Wnt) signal pathways, thus accelerating intestinal normal growth and regeneration post-injury. In summary, these findings uncover a novel function of LXN in intestinal regeneration post-injury and intestinal organogenesis, suggesting the potential role of LXN in the treatment of inflammatory bowel diseases.