Intraductal photothermal ablation: a noninvasive approach for early breast cancer treatment and prevention.

Background: Innovative treatment strategies for early-stage breast cancer (BC) are urgently needed. Tumors originating from mammary ductal cells present an opportunity for targeted intervention. Methods: We explored intraductal therapy via natural nipple openings as a promising non-invasive approach for early BC. Using functional Near-infrared II (NIR-II) nanomaterials, specifically NIR-IIb quantum dots conjugated with Epep polypeptide for ductal cell targeting, we conducted in situ imaging and photothermal ablation of mammary ducts. Intraductal administration was followed by stimulation with an 808 nm laser. Results: This method achieved precise ductal destruction and heightened immunological responses in the microenvironment. The technique was validated in mouse models of triple-negative BC and a rat model of ductal carcinoma in situ, demonstrating promising therapeutic potential for localized BC treatment and prevention. Conclusion: Our study demonstrated the effectiveness of NIR-II nanoprobes in guiding non-invasive photothermal ablation of mammary ducts, offering a compelling avenue for early-stage BC therapy.

Ziyin Bushen Fang improves Diabetic Osteoporosis by Inhibiting Autophagy and Oxidative Stress In vitro and In vivo.

OBJECTIVE: Diabetic osteoporosis (DOP) belongs to the group of diabetes-induced secondary osteoporosis and is the main cause of bone fragility and fractures in many patients with diabetes. The aim of this study was to determine whether Ziyin Bushen Fang (ZYBSF) can improve DOP by inhibiting autophagy and oxidative stress. METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats using a high-fat high-sugar diet combined with streptozotocin. Micro-CT scanning was used to quantitatively observe changes in the bone microstructure in each group. Changes in the serum metabolites of DOP rats were analyzed using UHPLC-QTOF-MS. The DOP mouse embryonic osteoblast precursor cell model (MC3T3-E1) was induced using high glucose levels. RESULTS: After ZYBSF treatment, bone microstructure significantly improved. The bone mineral density, trabecular number, and trabecular thickness in the ZYBSF-M and ZYBSF-H groups significantly increased. After ZYBSF treatment, the femur structure of the rats was relatively intact, collagen fibers were significantly increased, and osteoporosis was significantly improved. A total of 1239 metabolites were upregulated and 1527 were downregulated in the serum of T1DM and ZYBSF-treated rats. A total of 20 metabolic pathways were identified. In cellular experiments, ZYBSF reduced ROS levels and inhibited the protein expression of LC3II / I, Beclin-1, and p-ERK. CONCLUSION: ZYBSF may improve DOP by inhibiting the ROS/ERK-induced autophagy signaling pathway.

Nanoparticle-Based Photothermal Therapy for Breast Cancer Noninvasive Treatment.

Rapid advancements in materials science and nanotechnology, intertwined with oncology, have positioned photothermal therapy (PTT) as a promising noninvasive treatment strategy for cancer. The breast's superficial anatomical location and aesthetic significance render breast cancer a particularly pertinent candidate for the clinical application of PTT following melanoma. This review comprehensively explores the research conducted on the various types of nanoparticles employed in PTT for breast cancer and elaborates on their specific roles and mechanisms of action. The integration of PTT with existing clinical therapies for breast cancer is scrutinized, underscoring its potential for synergistic outcomes. Additionally, the mechanisms underlying PTT and consequential modifications to the tumor microenvironment after treatment are elaborated from a medical perspective. Future research directions are suggested, with an emphasis on the development of integrative platforms that combine multiple therapeutic approaches and the optimization of nanoparticle synthesis for enhanced treatment efficacy. The goal is to push the boundaries of PTT toward a comprehensive, clinically applicable treatment for breast cancer.

Bundle management strategy in reducing hospital-acquired pneumonia in hospitalized patients with mental disorders.

Introduction: The incidence of hospital-acquired pneumonia (HAP) is high in the medical setting for mental disorders. To date, effective measurements for preventing HAP in hospitalized mental disorder patients are unavailable. Methods: This study was conducted at the Large-Scale Mental Health Center of Renmin Hospital of Wuhan University (Wuhan, China) in two phases: baseline phase (January 2017-December 2019) and intervention phase (May 2020-April 2022). In the intervention phase, the HAP bundle management strategy was implemented in the Mental Health Center, and the data on HAP were collected continuously for analysis. Results: A total of 18,795 and 9,618 patients were included in the baseline and intervention phases, respectively. The age, gender, ward admitted to, type of mental disorder, and Charlson comorbidity index did not differ significantly. After intervention, the rate of HAP occurrence decreased from 0.95 to 0.52% (P < 0.001). Specifically, the HAP rate decreased from 1.70 to 0.95% (P = 0.007) in the closed ward and from 0.63 to 0.35% (P = 0.009) in the open ward. The HAP rate in the subgroups was higher in patients with schizophrenia spectrum disorders (1.66 vs. 0.74%) and organic mental disorders (4.92 vs. 1.41%), and in those ≥65 years old (2.82 vs. 1.11%) but decreased significantly after intervention (all P < 0.05). Conclusion: The implementation of the HAP bundle management strategy reduced the occurrence of HAP in hospitalized patients with mental disorders.

Distinct invasive patterns in situ between estrogen receptor-positive and triple-negative breast cancer through the intraductal tracking of carbon nanoparticles.

Given that the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (BC) is crucial during the BC progression, the mechanism involved in the invasion transition behind triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER-positive) subtype has remained elusive. This article detected distinct invasion patterns of BC cells between the ER-positive and TNBC using intraductal murine models with intraductal administration of carbon nanoparticles (CNPs). First, the feasibility of the utility of CNPs as a tracer was proved. The area ratio of CNPs and tumor cells invading the stroma at the late stage was found significantly higher than that in the early stage in MNU-induced ER-positive BC. However, opposite results were obtained in the triple-negative model. Consequently, we proposed that the ER-positive phenotype cells behave differently between different stages during tumor progression while there is no such difference in the invasion process of TNBC cells. The analysis regarding the duct integrity along with immunohistochemical characteristics further explained the distinct invasion features between the ER-positive and triple-negative subtypes. Last, the relationship between the duct thickness and the duct integrity suggested that ER-positive tumors gradually increased in size within the lumen before the invasion. Overall, this study suggested the different invasion characteristics of ER-positive BC and TNBC in vivo.

Ultrasensitive multiplex SERS immunoassay based on porous Au-Ag alloy nanoparticle-amplified Raman signal probe and encoded photonic crystal beads.

An ultrasensitive multiplex surface-enhanced Raman scattering (SERS) immunoassay was developed using porous Au-Ag alloy nanoparticles (p-AuAg NPs) as Raman signal amplification probe coupling with encoded photonic crystal microsphere. p-AuAg NPs were synthesized and modified with the second antibody (Ab2) and Raman tag (mercaptobenzoic acid, MBA) to prepare a Raman signal-amplified probe. The high porosity of the p-AuAg NPs enables significant coupling of the localized surface plasmon resonance and thus abundant inherent hotspots for Raman signal enhancement. 3D-ordered silver nanoparticles-coated silica photonic crystal beads (Ag/SPCBs) were prepared as encoded SERS substrate for multiplex detection using their reflection peaks. The signal-amplified probe was used for multiplex detection of tumor markers carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP). The wide linear ranges of 10-7-103 ng/mL for CEA and 10-4-103 ng/mL for AFP with detection limits of 1.22 × 10-8 ng/mL and 2.47 × 10-5 ng/mL for CEA and AFP at a signal-to-noise ratio of 3 were obtained. The proposed multiplex SERS immunoassay method displays ultrahigh sensitivity, wide linear range, and excellent specificity, which can be successfully applied to measure clinical serum samples with satisfactory results. The research provides a novel SERS signal enhancement strategy for the multiplex bioassay.

In situ Injection of pH- and Temperature-Sensitive Nanomaterials Increases Chemo-Photothermal Efficacy by Alleviating the Tumor Immunosuppressive Microenvironment.

Purpose: Triple-negative breast cancer (TNBC) is challenging to treat with traditional "standard of care" therapy due to the lack of targetable biomarkers and rapid progression to distant metastasis. Methods: We synthesized a novel combination regimen that included chemotherapy and photothermal therapy (PTT) to address this problem. Here, we tested a magnetic nanosystem (MNs-PEG/IR780-DOX micelles) loaded with the near-infrared (NIR) photothermal agent IR780 and doxorubicin (DOX) to achieve chemo-photothermal and boost antitumor immunity. Intraductal (i.duc) administration of MNs-PEG/IR780-DOX could increase the concentration of the drug in the tumor while reducing systemic side effects. Results: We showed more uptake of MNs-PEG/IR780-DOX by 4T1-luc cells and higher penetration in the tumor. MNs-PEG/IR780-DOX exhibited excellent photothermal conversion in vivo and in vitro. The release of DOX from MNs-PEG/IR780-DOX is pH- and temperature-sensitive. Facilitated by i.duc administration, MNs-PEG/IR780-DOX displayed antitumor effects and prevented distant organs metastasis under NIR laser (L) irradiation and magnetic field (MF)while avoiding DOX-induced toxicity. More importantly, MNs-PEG/IR780-DOX alleviated tumor immunosuppressive microenvironment by increasing tumor CD8+ T cells infiltration and reducing the proportion of myeloid-derived suppressor cells (MDSCs) and Tregs. Conclusion: Intraductal administration of pH- and temperature-sensitive MNs-PEG/IR780-DOX with L and MF had the potential for achieving minimally invasive, targeted, and accurate treatment of TNBC.

Comparative study of degradation of ketoprofen and paracetamol by ultrasonic irradiation: Mechanism, toxicity and DBP formation.

The present study comparatively investigated the ultrasonic degradation of ketoprofen (KET) and paracetamol (PCT) in water. Ultrasonic irradiation at 555 kHz achieved rapid degradation of KET and PCT in water, the removal efficiencies of KET (2.5-80 µM) and PCT (2.5-80 µM) reached 87.7%-100% and 50.6%-86.9%, respectively, after 10 min of reaction under an ultrasonic power of 60 W. The degradation behaviors of both KET and PCT followed the Langmuir-Hinshelwood model. KET was eliminated faster than PCT because of its higher hydrophobicity. Acidic media favored ultrasonic degradation of KET and PCT. Organic compounds in water matrices exerted a great negative effect on the ultrasonic degradation rates of KET and PCT major by competing with target compounds with the generated radicals at the bubble/water interfacial region. The effects of anions were species dependent. The introduction of ClO4- and Cl- enhanced KET and PCT degradation to different extents, while the introduction of HCO3- posed a negative effect on both KET and PCT. KET and PCT degradation are accompanied by the generation of several transform intermediates, as identified via LC/MS/MS analysis, and corresponding reaction pathways have been proposed. A human umbilical vein endothelial cell (HUVEC) toxicity evaluation indicated that ultrasonic treatment was capable of controlling the toxicity of KET or PCT degradation. Of note, the enhanced formation of disinfection byproducts (DBPs), i.e., trichloromethane (TCM) and trichloronitromethane (TCNM), was found due to chlorination after ultrasonic treatment for both KET and PCT.

Electrochemically activated peroxymonosulfate for the abatement of chloramphenicol in water: performance and mechanism.

In this study, electrochemically activated peroxymonosulfate (EC/PMS) with a sacrificial iron electrode was used for the removal of chloramphenicol (CAP) from water. Compared to electrolysis alone, peroxymonosulfate (PMS) alone, and Fe2+/PMS, EC/PMS significantly enhanced the CAP degradation. Various parameters, such as the applied current, electrolyte concentration, and PMS dose, were investigated to optimize the process. In addition, acidic conditions facilitated the CAP degradation. The presence of Cl- slightly enhanced the CAP degradation, while both HCO3- and NO3- exhibited an inhibitory effect on the CAP degradation. The floccules were also analyzed after the reaction by XPS and XRD. Quenching experiments indicated that both sulfate radicals (SO4●-) and hydroxyl radicals (•OH) were responsible for the CAP degradation. In addition, the degradation products were identified by LC/TOF/MS, and the degradation pathways were proposed accordingly. These results indicated that EC/PMS is a promising treatment process for the remediation of water polluted by CAP.

TRPM7 is critical for short-term synaptic depression by regulating synaptic vesicle endocytosis.

Transient receptor potential melastatin 7 (TRPM7) contributes to a variety of physiological and pathological processes in many tissues and cells. With a widespread distribution in the nervous system, TRPM7 is involved in animal behaviors and neuronal death induced by ischemia. However, the physiological role of TRPM7 in central nervous system (CNS) neuron remains unclear. Here, we identify endocytic defects in neuroendocrine cells and neurons from TRPM7 knockout (KO) mice, indicating a role of TRPM7 in synaptic vesicle endocytosis. Our experiments further pinpoint the importance of TRPM7 as an ion channel in synaptic vesicle endocytosis. Ca2+ imaging detects a defect in presynaptic Ca2+ dynamics in TRPM7 KO neuron, suggesting an importance of Ca2+ influx via TRPM7 in synaptic vesicle endocytosis. Moreover, the short-term depression is enhanced in both excitatory and inhibitory synaptic transmissions from TRPM7 KO mice. Taken together, our data suggests that Ca2+ influx via TRPM7 may be critical for short-term plasticity of synaptic strength by regulating synaptic vesicle endocytosis in neurons.

Primary hepatic neuroendocrine tumor - 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings: A case report.

BACKGROUND: Primary hepatic neuroendocrine tumors (PHNETs) are rare hepatic tumors. Their diagnosis, which is based on radiological findings, is difficult. CASE SUMMARY: We present a case of PHNET in a 79-year-old man with no clinical symptoms. Computed tomography (CT) and 2-Deoxy-2-[fluorine-18] fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) were performed for further evaluation. A hypoattenuating mass with rim-like enhancement in segment 6 of the liver was detected on contrast-enhanced CT imaging. Increased uptake was also observed on 18F-FDG PET/CT. Histopathological and immunohistochemical examinations, which revealed a grade 2 neuroendocrine tumor (NET), confirmed the diagnosis. CONCLUSION: Diagnosing PHNET is challenging, and must be distinguished from other liver tumors. Metastatic NETs should be excluded.

MoS2-assisted Fe2+/peroxymonosulfate oxidation for the abatement of phenacetin: efficiency, mechanisms and toxicity evaluation.

In this study, molybdenum disulfide (MoS2) was chosen as a co-catalyst to enhance the removal efficiency of phenacetin (PNT) in water by a ferrous ion-activated peroxymonosulfate (Fe2+/PMS) process. Operating parameters, such as the initial solution pH and chemical dose on PNT degradation efficiency were investigated and optimized. Under an initial pH of 3, an Fe2+ dose of 25 µM, a PMS dose of 125 µM and a MoS2 dose of 0.1 g L-1, the degradation efficiency of PNT reached 94.3%, within 15 min. The presence of common water constituents including Cl-, HCO3 -, SO4 2- and natural organic matter (NOM) will inhibit degradation of PNT in the MoS2/Fe2+/PMS system. Radical quenching tests combined with electron paramagnetic resonance (EPR) results indicated that in addition to free radical species (˙OH, SO4˙- and O2˙-), nonradical reactive species (1O2) were also crucial for PNT degradation. The variations in the composition and crystalline structure of the MoS2 before and after the reaction were characterized by XPS and XRD. Further, the degradation pathways of PNT were proposed according to the combined results of LC/TOF/MS and DFT calculations, and primarily included hydroxylation of the aromatic ring, cleavage of the C-N bond of the acetyl-amino group, and cleavage of the C-O bond of the ethoxy group. Finally, toxicity assessment of PNT and its products was predicted using the ECOSAR program.

Calcitriol enhances pyrazinamide treatment of murine tuberculosis.

BACKGROUND: Tuberculosis is a leading cause of morbidity and mortality in humans worldwide. There is an urgent need for new and effective drugs to treat tuberculosis and shorten the duration of tuberculosis therapy. 1, 25-dihydroxy vitamin D3 (1,25 (OH)2D3) has been reported to have a synergistic effect with pyrazinamide (PZA) in killing tubercle bacilli in vitro. The addition of 1,25 (OH)2D3 to standard tuberculosis treatment should benefit patients if the adjunctive drug has a synergistic effect in vivo. Thus, in this study, calcitriol (bioactive 1,25 (OH)2D3) was administered to mice undergoing treatment for Mycobacterium tuberculosis (M.tb) infection with PZA, a first-line anti-tuberculosis drug, to determine whether vitamin D3 enhances the therapeutic effect. METHODS: C57BL/6 female mice were infected with the M.tb H37Rv strain through aerosol exposure. Calcitriol and PZA, either alone or in combination, were orally administered to the M.tb infected mice. The effect of calcitriol on PZA activity was determined by evaluating the bacterial burden and analyzing the histopathological lesions in the lungs and spleen. To investigate the expression of inflammatory cytokines and anti-microbial peptide genes, we determined the transcriptional levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), mouse ß-defensin-2 (mBD2), and cathelicidin LL-37 through real-time quantitative polymerase chain reaction. The protein levels of IFN-γ were detected by enzyme-linked immunosorbent assay. Differences between groups were analyzed with independent samples t-test or one-way analysis of variance. RESULTS: Calcitriol alone had little effect on tuberculosis infection, whereas PZA, compared with saline control treatment, decreased the bacterial burden (spleens: PZA vs. saline, 4.82 ±â€Š0.22 vs. 5.22 ±â€Š0.40 Log10 colony-forming units [CFU]/gram, t = 2.13, P < 0.05; lungs: PZA vs. saline, 5.55 ±â€Š0.15 vs. 6.83 ±â€Š0.46 Log10 CFU/gram, t = 6.56, P < 0.01) and pathological lesions in the lungs. Simultaneous administration of calcitriol with PZA, compared with PZA alone, decreased the bacterial load (spleen: calcitriol + PZA vs. PZA, 4.37 ±â€Š0.13 vs. 4.82 ±â€Š0.22 Log10 CFU/gram, t = 4.36, P < 0.01; lung: calcitriol + PZA vs. PZA, 5.03 ±â€Š0.32 vs. 5.55 ±â€Š0.15 Log10 CFU/gram, t = 3.58, P < 0.01) and attenuated the lung lesions (gross pathological score: calcitriol + PZA vs. PZA, 3.25 ±â€Š0.50 vs. 2.50 ±â€Š0.58, t = 1.96, P < 0.05; affected area of total lung area: calcitriol + PZA vs. PZA, 30.75% ±â€Š6.50% vs. 21.55% ±â€Š2.99%, t = 2.66, P < 0.05). Further studies demonstrated calcitriol significantly increased the expression of anti-inflammatory cytokine IL-4 but suppressed production of the pro-inflammatory cytokine IFN-γ (IL-4: calcitriol vs. saline, 5.69 ±â€Š0.50 vs. 2.80 ±â€Š0.56 fold of control, t = 6.74, P < 0.01; IFN-γ: calcitriol vs. saline, 1.36 ±â€Š0.11 vs. 4.13 ±â€Š0.83 fold of control, t = 5.77, P < 0.01). In addition, calcitriol alone or in combination with PZA significantly enhanced the transcriptional level of anti-microbial peptides (cathelicidin LL-37: calcitriol vs. saline, 10.59 ±â€Š1.03 vs. 2.80 ±â€Š0.90 fold of control, t = 9.85, P < 0.01; mBD2: calcitriol vs. saline, 7.92 ±â€Š0.62 vs. 1.79 ±â€Š0.45 fold of control, t = 13.82, P < 0.01), whereas PZA exerted a negative effect on anti-microbial peptide gene expression. CONCLUSIONS: Calcitriol as adjunctive treatment can result in beneficial treatment outcomes in M.tb infection by suppressing the inflammatory response and up-regulating the expression of anti-microbial peptides. These results indicate the feasibility of using calcitriol adjunctively with standard chemotherapy for the treatment of M.tb infection.

Mycobacterium tuberculosis Erdman infection of cynomolgus macaques of Chinese origin.

BACKGROUND: Nearly one-third of the population worldwide is estimated to have latent tuberculosis infection (LTBI), which represents a vast reservoir for a constant source of tuberculosis (TB) transmission. It has been suggested that cynomolgus macaques are less susceptible to Mycobacterium tuberculosis (M.tb) infection than rhesus macaques, we examined M.tb infection of Chinese cynomolgus macaques. METHODS: Eight Chinese cynomolgus macaques were infected with M.tb Erdman strain with a small [25 colony forming unit (CFU)] or large dose (500 CFU) via bronchoscopy. The infected animals were monitored for symptoms and examined by chest X-ray, computed tomography (CT), tuberculin skin test (TST), and enzyme-linked immunospot (ELISPOT). RESULTS: Based on TST conversion and the specific immune responses to M.tb antigens, all animals were successfully infected. Half of the animals developed active infection and died within 15 months postinfection. The other four animals were grouped with latent M.tb infection because of positive TST but few clinical signs and pathological changes of TB during the course of this study. Interestingly, a challenge with a large dose of M.tb also induced latent infection. Similar to the changes that occur with human TB patients, the animals with active infection exhibited weight loss, cough and typical TB pathological changes, including caseous granulomas, cavities, consolidation, lipid pneumonia, pleural effusion, lymphadenopathy and bacterial burden in lungs and other organs. CONCLUSIONS: The low dose of M.tb was sufficient to cause both active and latent M.tb infection in cynomolgus macaques of Chinese origin.

Phosphatase and tensin homolog protein may be linked to lymph node metastasis and tumor node metastasis staging in nonsmall cell lung cancer.

BACKGROUND: This study aims to investigate the correlations of positive rate of phosphatase and tensin homolog (PTEN) protein with lymph node metastasis (LNM) and tumor node metastasis (TNM) staging of nonsmall cell lung cancer (NSCLC) patients by conducted a meta-analysis. MATERIALS AND METHODS: Covering several electronic databases (Embase, Cochrane Library, China BioMedicine, China National Knowledge Infrastructure, PubMed, and Web of Science), published papers eligible for enrollment in the current meta-analysis had to fulfill our predefined selection criteria. Odds ratios (ORs) with their 95% confidence interval (95%CI) were aggregated utilizing comprehensive meta-analysis 2.0 software (Biostatic Inc., Englewood, New Jersey, USA). RESULTS: Twelve cohort studies with a total of 419 NSCLC patients were incorporated into the current meta-analysis. A decreased positive rate of PTEN protein was detected in NSCLC patients with TNM stage III-IV rather than those patients with TNM stage I-II (OR = 0.454, 95%CI = 0.338-0.610, P < 0.001). PTEN in NSCLC patients without LNM expressed higher than that in the patients with LNM (OR = 0.532, 95%CI: 0.299-0.948, P = 0.032). Ethnicity-stratified analysis demonstrated a negative relationship between positive rate of PTEN protein and TNM staging of NSCLC among both Asians and Caucasians (both P < 0.05). However, we found no significant association between positive rate of PTEN protein and LNM among Asians and Caucasians (both P > 0.05). CONCLUSION: Our findings indicate that decreased positive rate of PTEN protein may be linked to TNM staging and LNM in NSCLC, and it could be an important diagnostic biomarker of NSCLC.

Serum containing Gengnianchun formula suppresses amyloid ß­induced inflammatory cytokines in BV­2 microglial cells by inhibiting the NF­κB and JNK signaling pathways.

As the resident macrophages of the brain's innate immune system, microglial cells are key modulators in the neurodegenerative disease Alzheimer's disease (AD). In particular, the activation and accumulation of microglial cells around amyloid plaques is considered to result in chronic neuroinflammation. Although the pathologic mechanism remains to be fully elucidated, inflammation has been shown to be critical in the pathogenesis of AD. The Gengnianchun (GNC) formula has long been used to treat perimenopausal syndrome clinically, and is particularly effective in improving learning ability and memory. Our previous study demonstrated that GNC formula had an anti­inflammatory effect and offered neuroprotection in animal experiments. In the present study, the anti­inflammatory properties of GNC and its underlying mechanism of action were examined in BV­2 microglial cells. Amyloid­ß peptide (Aß)­stimulated microglial cells were examined for the production of proinflammatory cytokines and the underlying signaling pathways. Compared with the normal control group, the protein expression levels of IL­1ß and TNF­α were significantly increased following treatment with Aß (P<0.01), but medicated rat serum containing GNC formula (MRS) could significantly attenuated the Aß­induced secretion of these pro­inflammatory cytokines. It was identified by CCK­8 assay that the viability of the BV­2 cells was not reduced following treatment with various concentrations of MRS. The phosphorylation of factor­κB (NF­κB) and c­Jun N­terminal kinase (JNK) was markedly increased following treatment with Aß, compared with the normal control group (P<0.01). However, treatment with MRS resulted in a significant reduction in the phosphorylation of NF­κB (P<0.05). These results suggested that MRS suppressed the Aß­induced inflammatory response of microglial cells by inhibiting the NF­κB and JNK signaling pathways. These novel findings provide insights into the development of GNC formula as a therapeutic agent for the treatment of neurodegenerative disorders.

A Promising Listeria-Vectored Vaccine Induces Th1-Type Immune Responses and Confers Protection Against Tuberculosis.

Deaths associated with tuberculosis (TB) is rising and accounted for 1.4 million deaths in 2015 many of which were due to drug-resistant bacteria. Vaccines represent an important medical intervention, but the current Bacilli Calmette-Guerin (BCG) vaccine is not ideal for the protection of teenagers and adults. Therefore, a safe and effective vaccine is urgently needed. In this study, we designed a novel vaccine using an attenuated Listeria monocytogenes strain carrying fusion antigen FbpB-ESAT-6 (rLM) and characterized its safety and protective efficacy against Mycobacterium tuberculosis (M.tb) infection in mice. Compared to the wild type strain yzuLM4 and parental strain LMΔactA/plcB (LM1-2), the virulence of rLM was significantly reduced as judged by its infectious kinetics and LD50 dose. Further characterization of intravenous immunization showed that prime-boost vaccination significantly increased the levels of Th1 cytokines (IFN-γ, IL-17, and IL-6), and enhanced cytotoxic T lymphocyte (CTL) CTLs activity, suggesting that rLM could elicit potent Th1/Th17 responses. More importantly, rLM significantly conferred the protection against M.tb H37Rv challenge. Collectively, our findings indicated that rLM is a novel and useful tool to prevent M.tb infection, and can be potentially be used to boost BCG-primed immunity.

A novel truncation mutation in CRYBB1 associated with autosomal dominant congenital cataract with nystagmus.

PURPOSE: To identify the potential candidate genes for a large Chinese family with autosomal dominant congenital cataract (ADCC) and nystagmus, and investigate the possible molecular mechanism underlying the role of the candidate genes in cataractogenesis. METHODS: We combined the linkage analysis and direct sequencing for the candidate genes in the linkage regions to identify the causative mutation. The molecular and bio-functional properties of the proteins encoded by the candidate genes was further explored with biophysical and biochemical studies of the recombinant wild-type and mutant proteins. RESULTS: We identified a c. C749T (p.Q227X) transversion in exon 6 of CRYBB1, a cataract-causative gene. This nonsense mutation changes a phylogenetically conserved glutamine to a stop codon and is predicted to truncate the C-terminus of the wild-type protein by 26 amino acids. Comparison of the biophysical and biochemical properties of the recombinant full-length and truncated ßB1-crystallins revealed that the mutation led to the insolubility and the phase separation phenomenon of the truncated protein with a changed conformation. Meanwhile, the thermal stability of the truncated ßB1-crystallin was significantly decreased, and the mutation diminished the chaperoning ability of αA-crystallin with the mutant under heating stress. CONCLUSIONS: Our findings highlight the importance of the C-terminus in ßB1-crystallin in maintaining the crystalline function and stability, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human autosomal dominant congenital cataract.

9-cis-Neoxanthin in Light Harvesting Complexes of Photosystem II Regulates the Binding of Violaxanthin and Xanthophyll Cycle.

The light-harvesting chlorophyll a/b complex of photosystem II (LHCII) is able to switch to multiple functions under different light conditions (i.e. harvesting solar energy for photosynthesis and dissipating excess excitation energy for photoprotection). The role of the different carotenoids bound to LHCII in regulating the structure and function of the complex is a long-lasting question in photosynthesis research. 9-cis-Neoxanthin (Nx) is one of the important carotenoids, which can only be found in the LHCIIs. High-resolution structural analysis of LHCII shows that Nx is located between different monomeric LHCIIs, with one side protruding into the lipid membrane. In this study, the various functional significances of this unique feature of Nx binding in LHCII are studied with the in vitro reconstituted LHCIIs both with and without Nx and the native complexes isolated either from wild-type Arabidopsis (Arabidopsis thaliana) or from its mutant aba4-3 lacking Nx Our results reveal that the binding of Nx affects the binding affinity of violaxanthin (Vx) to LHCII significantly. In the absence of Nx, Vx has a much higher binding affinity to trimeric LHCII. The strong coordination between Nx and Vx at the interfaces of adjacent monomers of LHCII plays an important role both in operating the xanthophyll cycle and in the transient modulation of nonphotochemical quenching.

Evaluation of Immunogenicity and Protective Efficacy Elicited by Mycobacterium bovis BCG Overexpressing Ag85A Protein against Mycobacterium tuberculosis Aerosol Infection.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is currently the only vaccine available for preventing tuberculosis (TB), however, BCG has varying success in preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A) strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. Our results indicated that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, and the Ag85A peptide-MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG::Ag85A were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ) responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that rBCG::Ag85A can enhance protection against Mycobacterium tuberculosis (M. tuberculosis) H37Rv infection compared to the BCG vaccine alone. Our results demonstrate the potential of rBCG::Ag85A as a candidate vaccine against TB.