Manganese Associated with Non-Wilsonian Hepatolenticular Degeneration as a Rare Cause of Encephalopathy: Case Report

Aim: To describe the clinical picture, diagnosis, and treatment of a patient with encephalopathy as a manifestation of manganese-induced non-Wilsonian hepatolenticular degeneration (NWHD) in a high-complexity care center in a Latin American country. Case description: A 55-year-old male patient from the United States with a history of liver disease associated with alcohol consumption was admitted to the emergency department due to diarrhea, hematemesis, and psychomotor agitation. During his stay, his state of consciousness deteriorated, requiring orotracheal intubation. In his diagnostic study, cerebrospinal fluid tests were negative for infectious etiologies; the endoscopic examinations showed no marks of portal hypertension bleeding, while ammonium and tests for metabolic causes were normal. However, areas of hyperintensity in the basal ganglia were documented on brain MRI, with normal ceruloplasmin serum and urine copper levels, which ruled out Wilson's disease and determined the diagnosis of manganese-induced NWHD. Conclusion: NWHD is a rare cause of chronic encephalopathy with clinical manifestations of extrapyramidal symptoms secondary to basal ganglia dysfunction due to severe liver disease. Its diagnosis becomes a challenge, given that manganese deposits produce it, and no biomarkers can establish the level of exposure to this metal. Brain MRI is indispensable in reflecting these deposits in the basal ganglia.

Objetivo: Describir la presentación clínica, el diagnóstico y el tratamiento de un paciente con encefalopatía como manifestación de degeneración hepatolenticular no wilsoniana producida por manganeso, en un centro de alta complejidad de un país latinoamericano. Descripción del caso: Paciente masculino de 55 años, procedente de Estados Unidos, con antecedente de enfermedad hepática asociada con consumo de alcohol, quien ingresó al servicio de urgencias por un cuadro de diarrea, hematemesis y agitación psicomotora. Durante la estancia presentó deterioro en el estado de consciencia, por lo que requirió intubación orotraqueal. En su estudio diagnóstico, las pruebas de líquido cefalorraquídeo fueron negativas para etiologías infecciosas, en los estudios endoscópicos no tenía estigmas de sangrado portal hipertensivo y el amonio y los estudios para causas metabólicas fueron normales. Sin embargo, se documentaron áreas de hiperintensidad en los ganglios de la base en la resonancia magnética cerebral, con niveles de ceruloplasmina sérica y cobre urinario normales, lo que descartó enfermedad de Wilson y definió el diagnóstico de degeneración hepatolenticular no wilsoniana por depósitos de manganeso. Conclusión: La degeneración hepatolenticular no wilsoniana es una causa infrecuente de encefalopatía crónica con manifestaciones clínicas de extrapiramidalismo, secundaria a disfunción de los ganglios de la base por enfermedad hepática grave. Su diagnóstico se convierte en un reto, dado que se produce por depósitos de manganeso y no existen biomarcadores que puedan establecer el nivel de exposición a este metal. La resonancia magnética cerebral juega, por tanto, un papel indispensable al reflejar esos depósitos en los ganglios de la base.

Anti-cisplatin-induced Renal-injury Effect of Human Manganese Superoxide Dismutase with Leader Peptide / 肿瘤防治研究

Objective To investigate the effect of the fusion of leader peptide on the structure of human manganese superoxide dismutase (SOD2) and anti-cisplatin (DDP)-induced renal injury. Methods The effect of mitochondrion targeting sequence (MTS) on the structure and activity of SOD2 was analyzed by structure prediction and superoxide dismutase (SOD) specific-activity determination. The DDP injury model of Kunming (KM) mice was established, and amifostine (AMFT) was set as a positive control. Indicators such as kidney index, renal function, kidney antioxidant capacity, and appearance and pathology changes of mice kidney were used to evaluate the effect of MTS-SOD2 against DDP-induced kidney injury. Results The MTS leader peptide seemed to change the secondary and tertiary structures of SOD2 to some extent, but it also increased the specific activity of the MTS-SOD2 protein. Pre-administration of a medium dose of MTS-SOD2 (0.84 mg/kg) before the use of DDP significantly reduced the level of renal malondialdehyde and increased the SOD activity and total antioxidant capacity (T-AOC) in the kidney, thereby reducing the renal pathological damage and consequently maintaining renal function. The overall protective effect of MTS-SOD2 was comparable to or even better than that of 200 mg/kg AMFT. Conclusion The MTS leader peptide enhances the activity of SOD2 and confers it with an excellent anti-DDP-induced renal-injury effect because of its transmembrane function.

Research progress of manganese exposure on abnormal GnRH release in hypothalamus affecting reproductive function / 环境与职业医学

Manganese plays an important physiological role in the organism, and excessive manganese exposure can cause impairment of neurological and reproductive functions. Gonadotropin-releasing hormone secreted by the hypothalamus acts as an initiator to regulate reproductive functions, such as gonadal development, onset of puberty, and gonadal hormone release. But the mechanism by which manganese damages the hypothalamus leading to abnormal gonadotropin-releasing hormone release is still unclear yet. Kisspeptin, prostaglandin E2, and nitric oxide may act as stimulators to increase the release of gonadotropin-releasing hormone, while the stimulatory or inhibitory effect of γ-aminobutyric acid on the release of gonadotropin-releasing hormone is controversial. Based on current research, manganese has been less studied with Kisspeptin, and studies with prostaglandin E2, nitric oxide, and γ-aminobutyric acid mainly focused on inflammation, oxidative stress, and neurotransmitter transmission. Therefore, taking Kisspeptin, prostaglandin E2, γ-aminobutyric acid, and nitric oxide as the breakthrough points, this paper introduced the mechanism of manganese affecting the release of gonadotropin-releasing hormone in the hypothalamus through the above four pathways, and proposed that the abnormal release of gonadotropin-releasing hormone in the hypothalamus may be one of the mechanisms by which manganese regulates reproductive function, providing a new direction for the prevention and treatment of manganese-induced reproductive damage in the future.

Relationship between trace elements in synovial fluid and cartilage and severity of knee osteoarthritis / 中国修复重建外科杂志

OBJECTIVE@#To investigate the relationship between trace elements in synovial fluid and cartilage and severity of knee osteoarthritis (KOA).@*METHODS@#Patients with KOA who underwent knee arthrocentesis or total knee arthroplasty (TKA) were recruited based on inclusion criteria between June 2021 and December 2021. Synovial fluid samples were obtained during knee arthrocentesis and TKA, and participants were divided into the mild group (grading Ⅰ/Ⅱ) and the severe group (grading Ⅲ/Ⅳ) according to the Kellgren-Lawrence grading (K-L grading). Cartilage samples with different degrees of wear were collected during the TKA from the same patient and were divided into mild wear (0-1 point) and severe wear (2-4 points) groups based on the Pelletier score. The contents of copper (Cu), zinc (Zn), and manganese (Mn) in synovial fluid and cartilage were evaluated by inductively coupled plasma mass spectrometry, and the differences between groups were compared.@*RESULTS@#A total of 33 synovial fluid samples were collected, including 19 specimens from 14 patients who underwent knee arthrocentesis of mild group, with 5 bilateral sides knee arthrocentesis in them, and 14 specimens from 14 TKA patients of severe group. The patients were significantly younger in the mild group than in the severe group ( P<0.05), but there was no significant difference in gender or body mass index between the two groups ( P>0.05). Nineteen pairs of cartilage samples with mild and severe wear were collected from severe KOA patients (K-L grading Ⅲ and Ⅳ), including 9 males and 10 females, with an average age of 70.4 years (range, 58-80 years). The body mass index ranged from 21.2 to 30.7 kg/m 2, with an average of 25.6 kg/m 2. The content of Zn in synovial fluid and cartilage from KOA patients was the highest, followed by Cu, and Mn was the lowest. The Cu content in synovial fluid was significantly higher in the severe group than in the mild group ( P<0.05), and in the severe wear group than in the mild wear group ( P<0.05). There was no significant difference in Zn and Mn content between the two groups ( P>0.05).@*CONCLUSION@#The Cu content increases with the severity of cartilage wear in patients with KOA.

Effects of Munc13-1 and Munc18-1 on dopamine secretion dysfunction in manganese-exposed SH-SY5Y cells / 环境与职业医学

Background Neurotransmitter secretion disorder induced by chronic manganese poisoning has always been one of the important causes of body injury, but the mechanism of neurotransmitter secretion disorder caused by manganese is not clear at present. Objective To investigate the effects of presynaptic membrane intracellular protein 13-1 (Munc13-1) and synapse fusion protein binding protein 18-1 (Munc18-1) on dopamine secretion dysfunction induced by manganese chloride (MnCl2) in human neuroblastoma (SH-SY5Y) cells. Methods A SH-SY5Y cell model induced by MnCl2 was established. Cell viability was measured by MTT assay. Four experimental groups were set up: control group and low-, medium-, and high-dose manganese groups (0, 100, 200, and 400 μmol·L−1 MnCl2). They were treated with corresponding doses of MnCl2 for 24 h. The secretion of dopamine was measured by enzyme-linked immunosorbent assay. The mRNA expression of Syntaxin-1 was detected by real-time quantitaive PCR. Total cell proteins were extracted, and the protein expression levels of Munc13-1, Munc18-1, and Syntaxin-1 were detected by Western blotting. The correlations of MnCl2 exposure and dopamine secretion with the protein expressions of Munc13-1 and Munc18-1 were also analyzed by Pearson correlation. Results Compared with the control group, the cell viability rate decreased gradually with the increase of manganese exposure concentration, and the difference between the medium- and the high-dose manganese groups was statistically significant (P<0.05). The concentration of dopamine in cell culture medium of all manganese exposure groups decreased with the increase of manganese concentration, and compared with the control group and the low-dose manganese group, the medium- and the high-dose manganese groups were statistically significant (P<0.05). The expression of Syntaxin-1 at mRNA or protein level did not change significantly among groups (P>0.05). Compared with the control group, the protein expression of Munc13-1 decreased and that of Munc18-1 increased with the increase of manganese concentration (P<0.05). Compared with the low-dose manganese group, the changes of Munc13-1 protein in the high-dose manganese group and Munc18-1 protein in the medium- and high-dose manganese groups had statistical significance (P<0.05). Compared with the medium-dose manganese group, the protein changes of Munc18-1 in the high-dose manganese group were statistically significant (P<0.05). The correlation analysis showed that MnCl2 dose was negatively correlated with Munc13-1 protein expression (r=−0.898, P<0.05), and positively correlated with Munc18-1 protein expression (r=0.678, P<0.05). Dopamine secretion was positively correlated with Munc13-1 protein expression (r=0.932, P<0.05), and negatively correlated with Munc18-1 protein expression (r=−0.817, P<0.05). Conclusion The inhibition of dopamine secretion in SH-SY5Y cells induced by manganese exposure is related to up-regulation of Munc18-1 and down-regulation of Munc13-1 expression levels, which may be one of the reasons for nerve injury caused by manganese.

Evaluation of anti-tumor effect of a novel manganese adjuvant collaborated with tumor antigens / 中国生物制品学杂志

@#ObjectiveTo investigate the anti-tumor effect of agonist MnCl_2of a novel cyclic guanosine monophosphate-adenosine monophosphate synthase(c GAS)/stimulator of interferon genes(STING)pathway collaborated with tumor cell lysate(Lysate)and the neo-antigen 10K-Adpgk of mouse colon cancer MC38 cell line.MethodsBone marrow-derived dendritic cells(BMDCs)were extracted from mouse bone marrow and divided into three groups:PBS,1 μmol/L MnCl_2and 10 μmol/L MnCl_2,which were analyzed for the maturation by flow cytometry,determined for the concentration of IL-6 in supernatant by ELISA,and detected for the transcription levels of IL-6,IFN-α,IFN β and CXCL9 genes by q PCR.Mouse tumor model was established by using MC38 cell line.When the tumor volume reached 100 mm3,the mice were randomly divided into two groups for administration,PBS,Lysate,MnCl_2,10K-Adpgk,Lysate + MnCl_2group and Lysate +10K-Adpgk + MnCl_2combined treatment group,which were administered subcutaneously through the tail for 3 times,with each interval of 1 week,and measured for the tumor volume every 2 days.One week after the last dose,serum samples were collected and determined for the concentrations of IFNγ and TNFα by ELISA.The tumor and spleen were isolated.The proportions of tumor infiltrating T cells and T cells in peripheral blood mononuclear cells(PBMCs)and the ratio of T cells to memory T cells in spleen were detected by flow cytometry,and the proportion of antigen specific T cells in spleen was detected by ELISPOT.Results10 μmol/L MnCl_2stimulated the maturation of BMDCs and activated the subsequent immune process.The tumor volumes of mice in the combined treatment group were considerably smaller than those in PBS group,the contents of IFNγ and TNF-α in serum were higher than those in other groups,and the proportions of tumor infiltrating T cells,T cells in PBMCs and ratio of T cells to memory T cells in spleen were also significantly higher than those in PBS group.Combined therapy caused strong antigen-specific T cell immune response.ConclusionThe addition of the novel adjuvant MnCl_2significantly enhanced the treatment effect of tumor cell lysate and neo-antigen,which provided an experimental basis for the development of the combination tumor treatment method based on MnCl_2and tumor antigens.

Effects of lead and manganese combined exposure on neurodevelopmental toxicity and JNK expression in zebrafish / 环境与职业医学

Background Lead and manganese are heavy metal pollutants widely existing in the environment, which can accumulate in the human body through the food chain, exert neurotoxicity, and cause neurodegenerative disorders. Especially in early childhood, the developing blood-brain barrier and nervous system are highly susceptible to environmental chemical pollutants. Most of the previous studies focused on the toxic effects of single heavy metal such as lead or manganese, while the studies on combined toxic effect are still scarce, and involved mechanisms are still unclear. c-Jun N-terminal kinase (JNK) is involved in neuronal development and regeneration, and some studies have found that JNK is involved in lead or manganese induced neurotoxicity. Its role in the toxicity of combined lead and manganese is unknown. Objective To understand the neurodevelopmental toxicity mechanism and to observe changes of JNK expression in zebrafish induced by combined lead and manganese exposure at environmentlly low concentrations. Methods Zebrafish embryos within 2 h post fertilization (hpf) were divided into four groups: control group, lead exposure group (0.1 mg·L−1 lead acetate), manganese exposure group (0.3 mg·L−1 manganous chloride), and lead-manganese combined exposure group (0.1 mg·L−1 lead acetate +0.3 mg·L−1 manganous chloride) and exposed to lead or/and manganese at designed levels for 7 d. Spontaneous movements and motor locomotion were observed, and mortality rate were calculated. The changes of JNK mRNA expression in zebrafish were evaluated. Results The experimental results showed that no significant effect of lead or/and manganese on spontaneous movements and mortality rate was found in zebrafish compared with the control group (P＞0.05). The results of locomotion analysis showed that compared with the control group, the activity counts and activity distance of zebrafish in the manganese exposure group were slightly increased (P＜0.01); the activity counts and activity distance of zebrafish in the lead exposure group were reduced by 50% and those in the lead-manganese exposure group were reduced by 80% (P＜0.01). Compared with the lead exposure group, the activity counts and activity distance of zebrafish in the lead-manganese combined exposure group decreased significantly by 60% (P＜0.05). The real-time quantitative PCR results showed that the JNK mRNA expression level was significantly increased in the lead-manganese combined exposure group compared with the control group(P＜0.01). Conclusion Lead exposure combined with manganese exposure at environmentlly low concentration can induce neurodevelopmental toxicity to zebrafish. JNK may be involved in neurodevelopmental toxicity induced by the combined exposure to lead and manganese.

Research progress on metal ion-induced Parkinson's disease / 环境与职业医学

Parkinson's disease (PD) is one of the hotspots in the research field of neurodegenerative diseases, and its pathogenesis is still controversial. Trace metal elements play an important role in normal growth and development of the human body. Metal ions can cross the blood-brain barrier and enter the brain, leading to α-synapnuclein aggregation, mitochondrial dysfunction, and degeneration of dopaminergic neurons, and then inducing the occurrence of PD. This article mainly reviewed the potential mechanisms of metal elements in PD, discussed the role of metabolic imbalance of common trace metals (copper, iron, manganese, and zinc) in PD, and put forward new insights into the treatment of PD.

Actividades ligninolíticas y producción de basidiomas de Ganoderma lucidum en cultivo sólido suplementado con manganeso / Ligninolytic activities and production of Ganoderma lucidum basidiomes in solid culture supplemented with manganese

RESUMEN Ganoderma lucidum es un basidiomiceto de pudrición blanca estudiado especialmente por sus atributos medicinales. No obstante, la información sobre la suplementación de los medios de cultivo con metales como Zn, Li, Mn, Cu es escasa aun conociendo que la presencia de metales en los sustratos mejora las características de los basidiomas obtenidos e incrementa su productividad. El objetivo fue evaluar las actividades enzimáticas lacasa (Lc) y manganeso peroxidasa (MnP), la fructificación y eficiencia biológica (EB) de G. lucidum en cultivos sólidos formulados con residuos agroindustriales (aserrín de roble, cascarilla de café, salvado de maíz) suplementados con dos niveles de sal de manganeso II (0,05 % y 0,1 % p/p) y una formulación sin adición de la sal de manganeso. Las actividades enzimáticas se determinaron durante 98 días del ciclo productivo, con toma de muestras semanales. El tratamiento uno (0,05 % p/p de MnSO4H2O) suministró la mayor EB del cultivo con 25,90 ± 2,12 % y los mayores títulos de actividades ligninolíticas en el tiempo con 0,7299 UE/g s.s. de MnP a los 35 días de fermentación y 4,1 760 UE/g s.s para la actividad de Lc a los 42 días de proceso con relación a los tratamientos dos y control. Asimismo, hubo una disminución del ciclo de cultivo del hongo para los tratamientos uno (83 días) y dos (95 días) en comparación con el tratamiento control (117 días). Los resultados de este trabajo son promisorios para cultivadores industriales de G. lucidum, ya que la suplementación de los sustratos con Mn incrementa la productividad de los cultivos.

ABSTRACT Ganoderma lucidum is a white rot basidiomycete specially studied for its medicinal attributes. However, the information on the supplementation of the substrate with metals such as Zn, Li, Mn, Cu and others is scarce. Even knowing that the presence of metals in the substrates improves the characteristics of the basidiomes produced and increases their productivity. The objective was to evaluate the enzymatic activities laccase (Lc) and manganese peroxidase (MnP). The fructification and biological efficiency (BE) of G. lucidum in solid culture formulated with agroindustrial residues, (oak sawdust, coffee husk, bran corn) supplemented with two levels of manganese II salt, (0.05 % and 0.1 % w/ w) and a formulation without addition of manganese II salt. Enzymatic activities were determined during 98 days of the production cycle, with weekly sampling. Treatment one (0.05 % w/w MnSO4.H2O) provided the highest BE of the culture with 25.90 ± 0.54% and the highest titers of ligninolytic activities, in the time with 0.7299 EU/g d.s for MnP at 35 days of fermentation and 4.1760 EU/g d.s for Lc activity at 42 days of process, in relation to treatments two and control. Likewise, there was a decrease in the fungus culture cycle for treatments one (83 days) and two (95 days) compared to the control treatment (117 days). The results of this work are promising for industrial growers of G. lucidum, since the supplementation of the substrates with Mn increase the productivity of the cultures.

Comparative Study of Iron, Manganese and Nickel Contamination Potential of Disc and Hammer Milling Equipment and their Toxic Effect on Rat Kidney

Aim: To investigate the effect of hammer and disc milling equipment on the levels of Iron (Fe), Manganese (Mn) and Nickel (Ni) contents in maize (Zea mays) flour and the consequent impact on the kidney of albino rats. Study Design: The rats were randomly divided into groups of five rats per group. Six of the groups were fed with maize flour milled with a hammer mill, while the other six groups were fed with maize flour milled with a disc mill, and the thirteenth group was fed with crushed flour in a mortar and pestle as a control. The rats were sacrificed by decapitation under anesthesia on the 14th and 28th days. Place and Duration of Study: Departments of Biochemistry and Histology laboratories of the University of Jos, Nigeria, between, January to June, 2021. Methodology: For six days, a portion of the maize grains was milled with a hammer mill, another with a disc mill, and a third fraction was crushed into flour with a wooden mortar. The inductive coupled plasma mass spectrophotometric method was used to determine the levels of Fe, Mn, and Ni in maize flour. To avoid lysing the blood, blood samples were carefully collected by allowing it to run down the test tube's wall. The blood was allowed to coagulate at room temperature before being centrifuged and the serum collected and frozen until it was time for biochemical analysis. The kidneys of the rats were excised, cleaned, and preserved in chloroform until histological examinations were required. Results: The results show that Fe (325.16 ± 30.00 mg/kg and 205.05 ± 30.20 mg/kg) and Ni (20.92 ± 5.92 mg/kg and 18.00 ± 2.70 mg/kg) levels were extremely high in both disc and hammer milling machines. The Fe and Mn values in disc milled maize flour were higher than those in hammer milled maize flour. Rats in all groups had significantly higher serum urea, creatinine, K+, Na+, and Cl- levels than the control group. The kidney tissues of all the rats in the control and hammer-milled flour groups were normal, except for group 1 of the disc mill, which showed mild damage, according to the histopathological analysis. Conclusion: The Day 1 group fed with disc-milled flour showed a dense cast, atrophy, and nuclei loss in their kidney tissue. According to the results of the study, hammer milled maize flour is less harmful than disc milled maize flour, as shown by kidney histopathology.

Bioinformatics study on role of IL-17 signaling in manganese poisoning and manganese-related neurodegenerative diseases / 环境与职业医学

Background Manganese (Mn) is one of the environmental factors of Parkinson's disease (PD), and long-term exposure to Mn can cause nerve damage. It is important to explore the common mechanism of neurotoxic effects of Mn and neurodegenerative diseases (NDD), especially PD, for early diagnosis of the disease. Objective To comprehensively analyze the core messenger RNA (mRNA)-microRNAs (miRNAs) co-expressed in frontal cortex of NDD patients and neuronal cells exposed to Mn via bioinformatics, and to reveal the potential common mechanism between Mn-induced neurotoxicity and NDD, especially PD. Methods Difference of the mRNAs from frontal cortex of NDD patients (GSE150696) and human neuroblastoma (SH-SY5Y) cells exposed to Mn were analyzed by R software; Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed on the overlapping differentially expressed genes (DEGs). The miRNAs were predicted using the miRNet database, mRNA-miRNA interactions were identified by the starBase and miRTarBase databases, and mRNA-miRNA regulatory networks were constructed with Cytoscape software. The core miRNAs associated with PD (GSE77667) were incorporated into Weighted Gene Co-Expression Network Analysis (WGCNA) and the mRNA-miRNA regulatory network was comparatively analyzed. Results A total of 34 overlapping DEGs were identified in the frontal cortical of NDD patients and the neuronal cells exposed to Mn, mainly enriched in interleukin-17 (IL-17) signaling pathway, cyclic adenosine monophosphate (cAMP) signaling pathway, and primary immunodeficiency. Based on the results of database prediction, 52 miRNAs with 71 pairs of interaction relationships were finally included to construct the miRNA-mRNA regulatory network. Six core miRNAs were screened by WGCNA: hsa-let-7i-5p, hsa-mir-155-5p, hsa-mir-219-2-3p, hsa-mir-221-3p, hsa-mir-485-3p, and hsa-mir-509-3-5p, among which hsa-let-7i-5p interacted with the target gene FBXW2 and hsa-mir-155-5p interacted with the target gene CCL2. The results of the KEGG analysis indicated that CCL2 was closely related to the IL-17 signaling pathway. Conclusion There are similar molecular regulatory mechanisms involved in the neurotoxicity of Mn and NDD, and the IL-17 signaling pathway may play a role in Mn-related NDD through CCL2 and hsa-mir-155-5p.

The mechanism of microbial removal of Mn(Ⅱ) and its influencing factors: a review / 生物工程学报

Manganese is an element essential for living organisms. Development of industrial technologies and exploitation of mineral resources have led to the release of large amount of Mn(Ⅱ) into the environment, posing a serious threat to human health. Bioremediation can remove the Mn(Ⅱ) from the environment rapidly and effectively without generating secondary pollution, thus received increasing attention. This review summarized the diversity and distribution of Mn(Ⅱ) removal microorganisms and the associated mechanisms, followed by discussing the effect of environmental factors on microbial Mn(Ⅱ) removal. Finally, the challenges and prospects for bioremediation of Mn(Ⅱ) polluted wastewater were proposed.

Tetrahedral DNA nanostructures synergize with MnO2 to enhance antitumor immunity via promoting STING activation and M1 polarization

Stimulator of interferon genes (STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here, we showed that tetrahedral DNA nanostructures (TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn2+ to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn2+, we constructed a TDN-MnO2 complex and found that it displayed a much higher efficacy than TDN plus Mn2+ to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO2. These findings provide new therapeutic opportunities for cancer therapy.

Perfluorooctyl bromide nanoemulsions holding MnO2 nanoparticles with dual-modality imaging and glutathione depletion enhanced HIFU-eliciting tumor immunogenic cell death

Tumor-targeted immunotherapy is a remarkable breakthrough, offering the inimitable advantage of specific tumoricidal effects with reduced immune-associated cytotoxicity. However, existing platforms suffer from low efficacy, inability to induce strong immunogenic cell death (ICD), and restrained capacity of transforming immune-deserted tumors into immune-cultivated ones. Here, an innovative platform, perfluorooctyl bromide (PFOB) nanoemulsions holding MnO2 nanoparticles (MBP), was developed to orchestrate cancer immunotherapy, serving as a theranostic nanoagent for MRI/CT dual-modality imaging and advanced ICD. By simultaneously depleting the GSH and eliciting the ICD effect via high-intensity focused ultrasound (HIFU) therapy, the MBP nanomedicine can regulate the tumor immune microenvironment by inducing maturation of dendritic cells (DCs) and facilitating the activation of CD8+ and CD4+ T cells. The synergistic GSH depletion and HIFU ablation also amplify the inhibition of tumor growth and lung metastasis. Together, these findings inaugurate a new strategy of tumor-targeted immunotherapy, realizing a novel therapeutics paradigm with great clinical significance.

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Metallic insignia in primary teeth A biomarker for Autism Spectrum Disorders

Background: Lead accumulations have been found in teeth and related to behavior deficits in children, but there is a dearth of studies in exploring the role of zinc and manganese dysregulations in autism spectrum disorders (ASD) using the primary tooth as biomarker. Aims: The objectives of the study were to evaluate and compare the concentrations of zinc and manganese in the primary teeth serving as biomarker, in typically developing children and children with ASD. Settings and Design: Twelve primary incisors indicated for extraction were collected from children between the age group 6 and 9 years, for the study. Six primary incisors were obtained from children who had been diagnosed with ASD (study group). The other six teeth were obtained from typically developing children, in the similar age group. Methods: The primary incisors obtained were analyzed for metal concentrations using the technique Inductively Coupled Plasma Optical Emission Spectrometry. Statistical Analysis: This study was statistically analyzed by student's t-test. Results: It was observed that there are significant differences in metal concentrations found between tooth samples of ASD children and typically developing children. Zinc concentrations were double and manganese concentrations were three times, in teeth of ASD children group as compared to the children in the control group. Conclusions: Results of the current study indicate that there are considerable differences in concentrations of zinc and manganese between the two groups and support the contention that there might be an association between metal exposures of a pregnant mother and child during early years of childhood and incidence of ASD.

Analysis of Heavy Metals (Cadmium, Chromium, Lead, Manganese, and Zinc) in Well Water in East Java Province, Indonesia

@#Introduction: Indonesia is one of the countries whose inhabitants use well water for drinking and cooking purposes. In East Java, 48.90% of the population uses well water for their daily needs. Well water contained heavy metals had bad effects on health such as cancer, damage of liver, kidneys, and others. The objective of this study was to evaluate the concentration of heavy metals in well water and relate them to a potential health outcomes. Methods: The method used in this study was analytical descriptive. Data used was secondary from East Java Environmental Office. A total of 101 samples were collected from 33 locations. There were 5 heavy metals analyzed, namely cadmium, chromium, lead, manganese, and zinc. Equipment using ICPMS and AAS. Data analyzed with descriptive statistics by SPSS. Data obtained were compared to the WHO Standard for Drinking Water Quality. Results: Concentration for cadmium was 0.002 mg/l, followed by manganese at 1.80 mg/l and zinc at 0.020 mg/l. Besides, all water samples had levels of chromium and lead below the detection limit. Conclusion: All heavy metals had concentrations below the maximum allowable standard, except for five water samples from three locations with levels of manganese which was above the maximum standard. Long term effects of manganese include neurological problems, intelligence, and low birth weight. Further studies need to be done to determine the source of manganese contamination. It is recommended that bottled water is used for drinking purposes in an area where heavy metal concentration is above the allowable limit.

Analysis of proficiency test for determination of manganese in drinking water in Shaanxi Province / 公共卫生与预防医学

Objective To understand and improve the laboratory detection capacity of water manganese in testing organizations of Shaanxi Province． Methods The self-made manganese capacity testing samples were used as the reference in this proficiency testing program. The homogeneity of the samples was tested by single factor analysis of variance. The t-test method was used to evaluate the stability of the samples. The results of manganese in water provided by participant laboratories were analyzed by the robust statistical technique Z-score. Results A total of 136 laboratories participated in the proficiency testing program throughout the province. Among them, 129 laboratories (including retest laboratory) or 94.85% of total participating laboratories obtained satisfactory results. Conclusion The water quality monitoring agencies of our province had shown a strong detection capability for the determination of metal elements in drinking water, which ensures to provide safe water supply to the residents in Shaanxi Province.

Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ1-42 / 中国实验方剂学杂志

Objective:To explore the possible mechanism of Kaixinsan in improving cognitive impairment in Alzheimer's disease （AD） model rats based on the epichlorohydrin associated protein-1 （Keap-1）/nuclear factor E2 related factor （Nrf2）/manganese superoxide dismutase （MnSOD） signaling pathway. Method:The AD model was established by injecting Amyloid <italic>β</italic>_1-42 （A<italic>β</italic>_1-42， 5 μL） into the lateral ventricle. After modeling， the experimental rats were randomly divided into model group， donepezil group， and Kaixinsan low dose， medium dose and high dose groups. Another normal control group was also established. The donepezil group received donepezil tablets （1.8 g·kg^-1·d^-1）， Kaixinsan low dose， medium dose and high dose groups received corresponding doses of Kaixinsan （10， 20， 40 g·kg^-1·d^-1， respectively）， and the normal control group and model group were given with equal volume of pure water. Morris water maze was used to test the learning and memory ability of rats. The pathological morphology of hippocampal CA3 area was observed by Nissl staining. The expression levels of myeloperoxidase （MPO）， inducible nitric oxide synthase （iNOS） and superoxide dismutase （SOD） in serum were detected by colorimetry， and the protein expression levels of Keap-1， Nrf2 and MnSOD in hippocampus were detected by immunohistochemistry （IHC） and Western bolt. Result:Compared with the normal control group， the escape latency， total swimming distance and first arrival time of the plateau in the model group increased （<italic>P</italic><0.01）， while the times of crossing the plateau and the time in target quadrant decreased （<italic>P</italic><0.01）. Compared with the model group， the rats in donepezil group and Kaixinsan groups showed less latency， lower total swimming distance and first arrival time on the platform （<italic>P</italic><0.05， <italic>P</italic><0.01）， while the times of crossing the platform and time in target quadrant increased （<italic>P</italic><0.05， <italic>P</italic><0.01）. Compared with the normal control group， the expression levels of MPO and iNOS in serum of the model group increased （<italic>P</italic><0.01）， while the expression levels of SOD decreased （<italic>P</italic><0.01）. Compared with model group， the expression of MPO and iNOS in serum of donepezil group and Kaixinsan groups decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）， while the expression of SOD increased （<italic>P</italic><0.05， <italic>P</italic><0.01）. In the normal control group， the neurons in the hippocampal CA3 of the rats were arranged neatly， without obvious Nissl body shrinkage. The neurons in the CA3 of the hippocampus of the model group were not arranged neatly， with obvious neuron loss and pyknosis of Nissl body. The neurons in the CA3 of the hippocampus of the rats in the donepezil group and Kaixinsan groups were arranged neatly， with increased number of neurons and decreased Nissl body shrinkage. Compared with the normal control group， the integrated optical density （<italic>IA</italic>） and protein level of Keap-1 in the hippocampus of the model group decreased（<italic>P</italic><0.01）， while the <italic>IA</italic> and protein level of Nrf2 and MnSOD increased （<italic>P</italic><0.01）. Compared with model group， <italic>IA</italic> and protein levels of Keap-1 and MnSOD in hippocampus of rats in donepezil group and Kaixinsan groups increased （<italic>P</italic><0.05， <italic>P</italic><0.01）， while <italic>IA</italic> and protein levels of Nrf2 decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）. Conclusion:Kaixinsan could alleviate memory impairment in AD rats， and its mechanism may be related to its regulation of Keap-1/Nrf2/MnSOD signaling pathway.

Risk assessment of manganese in lip cosmetics / 上海预防医学

Objective:To determine the level of manganese and assess potential health risks of lip cosmetics. Methods:Assessment on manganese of lip cosmetics was performed using high-end exposure analysis mode based on the daily dosage. Results:In a total of 264 lip cosmetics samples， manganese was detected in the 249 sample， with a detection rate of 94.3%. Daily exposure was determined to be 3.88×10-5 mg/kg. Safety margin was 3 608 and safety limit was 45 mg/kg. Conclusion:Level of manganese in lip cosmetics remains safe. Health risk is low when appropriately used according to the daily usage. However， it is noted that level of manganese exceeds the limits in approximately 10% of the samples， posing a potential health threat.