Acupuncture in Multiple Myeloma Peripheral Neuropathy: A Systematic Review.

Background: Peripheral neuropathy (PN) is a prevalent complication of multiple myeloma (MM), due to the disease itself or its treatment. Despite extensive research, the optimal treatment for multiple myeloma peripheral neuropathy (MMPN) remains unclear. Clinical practice has shown the potential efficacy of acupuncture in managing MMPN. This study aimed to conduct a comprehensive analysis of the literature to assess the effectiveness and safety of acupuncture as a treatment for MMPN. Methods: The PubMed, Web of Science, MEDLINE, Cochrane Library, and Embase databases were comprehensively searched from inception to November 1, 2023 to identify relevant studies pertaining to the use of acupuncture to treat MMPN. Results: A total of five studies, encompassing 97 patients diagnosed with drug-related PN, were ultimately included in this analysis. The literature lacks any reports pertaining to the utilization of acupuncture for disease-related PN. ST36, LI4, SP6, and EX-LE-10 were found to be the most frequently chosen acupoints. Following acupuncture treatment, there was a consistent reduction in scores on the Visual Analogue Scale (VAS), Neuropathic Pain Scale (NPS), Brief Pain Inventory-Short Form (BPI-SF), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) among MMPN patients. The results of Nerve Conduction Velocity (NCV) tests yielded conflicting results. No severe adverse effects were reported. Conclusion: The use of acupuncture for disease-related PN has not been studied to date. Acupuncture is safe for drug-related PN and is helpful for relieving pain. But uncertainty exists regarding the efficacy of this approach because there is substantial heterogeneity with respect to acupuncture treatment regimens, and more high-quality studies on this topic are warranted.

Zinc Oxide Nanoparticles Trigger Autophagy in the Human Multiple Myeloma Cell Line RPMI8226: an In Vitro Study.

Multiple myeloma (MM) is a malignant clonal proliferative plasma cell tumor. Zinc oxide nanoparticles (ZnO NPs) are used for antibacterial and antitumor applications in the biomedical field. This study investigated the autophagy-induced effects of ZnO NPs on the MM cell line RPMI8226 and the underlying mechanism. After RPMI8226 cells were exposed to various concentrations of ZnO NPs, the cell survival rate, morphological changes, lactate dehydrogenase (LDH) levels, cell cycle arrest, and autophagic vacuoles were monitored. Moreover, we investigated the expression of Beclin 1 (Becn1), autophagy-related gene 5 (Atg5), and Atg12 at the mRNA and protein levels, as well as the level of light chain 3 (LC3). The results showed that ZnO NPs could effectively inhibit the proliferation and promote the death of RPMI8226 cells in vitro in a dose- and time-dependent manner. ZnO NPs increased LDH levels, enhanced monodansylcadaverine (MDC) fluorescence intensity, and induced cell cycle arrest at the G2/M phases in RPMI8226 cells. Moreover, ZnO NPs significantly increased the expression of Becn1, Atg5, and Atg12 at the mRNA and protein levels and stimulated the production of LC3. We further validated the results using the autophagy inhibitor 3-methyladenine (3­MA). Overall, we observed that ZnO NPs can trigger autophagy signaling in RPMI8226 cells, which may be a potential therapeutic approach for MM.

Zinc oxide nanoparticles induce toxicity in diffuse large B-cell lymphoma cell line U2932 via activating PINK1/Parkin-mediated mitophagy.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. Zinc oxide (ZnO) nanoparticles have excellent anti-tumor properties in the biomedical field. The present study aimed to explore the underlying mechanism by which ZnO nanoparticles induce toxicity in DLBCL cells (U2932) via the PINK1/Parkin-mediated mitophagy pathway. After U2932 cells were exposed to various concentrations of ZnO nanoparticles, the cell survival rate, reactive oxygen species (ROS) generation, cell cycle arrest, and changes in the expression of PINK1, Parkin, P62, and LC3 were monitored. Moreover, we investigated monodansylcadaverine (MDC) fluorescence intensity and autophagosome and further validated the results using the autophagy inhibitor 3-methyladenine (3-MA). The results showed that ZnO nanoparticles could effectively inhibit the proliferation of U2932 cells and induce cell cycle arrest at the G0/G1 phases. Moreover, ZnO nanoparticles significantly increased ROS production, MDC fluorescence intensity, autophagosome formation, and the expression of PINK1, Parkin, and LC3, and decreased the expression of P62 in U2932 cells. In contrast, the autophagy level was reduced after the intervention of the 3-MA. Overall, ZnO nanoparticles can trigger PINK1/Parkin-mediated mitophagy signaling in U2932 cells, which may be a potential therapeutic approach for DLBCL.

High Expression of ACOT2 Predicts Worse Overall Survival and Abnormal Lipid Metabolism: A Potential Target for Acute Myeloid Leukemia.

Acyl-CoA thioesterase (ACOT) plays a considerable role in lipid metabolism, which is closely related to the occurrence and development of cancer, nevertheless, its role has not been fully elucidated in acute myeloid leukemia (AML). To explore the role of ACOT2 in AML and to provide a potential therapeutic target for AML, the expression pattern of ACOT was investigated based on the TNMplot, Gene Expression Profiling Interactive Analysis (GEPIA), and Cancer Cell Line Encyclopedia (CCLE) database, and diagnostic value, prognostic value, and clinical phenotype of ACOT were explored based on data from The Cancer Genome Atlas (TCGA). Functional annotation and enrichment analysis of the common targets between ACOT2 coexpressed and AML-related genes were further performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses. The protein-protein interaction (PPI) network of ACOT2 coexpressed genes and functional ACOT2-related metabolites association network were constructed based on GeneMANIA and Human Metabolome Database. Among ACOTs, ACOT2 was highly expressed in AML compared to normal control subjects according to TNMplot, GEPIA, and CCLE database, which was significantly associated with poor overall survival (OS) in AML (P=0.003). Moreover, ACOT2 exhibited excellent diagnostic efficiency for AML (AUC: 1.000) and related to French-American-British (FAB) classification and cytogenetics. GO, KEGG, and GSEA analyses of 71 common targets between ACOT2 coexpressed and AML-related genes revealed that ACOT2 is closely related to ACOT1, ACOT4, enoyl-acyl carrier protein reductase, mitochondrial (MECR), puromycin-sensitive aminopeptidase (NPEPPS), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and long-chain fatty acid-CoA ligase 1 (ACSL1) in PPI network, and plays a significant role in lipid metabolism, that is, involved in fatty acid elongation and biosynthesis of unsaturated fatty acids. Collectively, the increase of ACOT2 may be an important characteristic of worse OS and abnormal lipid metabolism, suggesting that ACOT2 may become a potential therapeutic target for AML.

Clinical significance and potential mechanism of heat shock factor 1 in acute myeloid leukemia.

BACKGROUND: Heat shock factor 1 (HSF1) is now considered to have the potential to be used as a prognostic biomarker in cancers. However, its clinical significance and potential function in acute myeloid leukemia (AML) remain underexplored. METHODS: In this study, the expression pattern and clinical significance of HSF1 in AML were examined by integrating data from databases including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), Vizome, Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO). Linkedomics was applied to collect HSF1-related genes in AML. GeneMANIA was applied to outline HSF1-related functional networks. CancerSEA analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) were performed to mine the potential mechanism of HSF1 in leukemogenesis. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to explore the correlation between HSF1 and infiltrating immune cells in AML. RESULTS: HSF1 expression was elevated in AML compared to healthy controls and indicate a poor overall survival. HSF1 expression was significantly correlated with patients age, associated with patient survival in subgroup of bone marrow blasts (%) >20. Functional analyses indicated that HSF1 plays a role in the metastatic status of AML, and is involved in inflammation-related pathways and biological processes. HSF1 expression was significantly correlated with the immune infiltration of nature killer cells and T cell population. CONCLUSION: HSF1 plays a vital role in the molecular network of AML pathogenesis, and has the potential to be a biomarker for prognosis prediction.

Realgar (As4S4), a traditional Chinese medicine, induces acute promyelocytic leukemia cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway in vitro.

Acute promyelocytic leukemia (APL) is a specific subtype of acute myelogenous leukemia (AML) characterized by the proliferation of abnormal promyelocytes. Realgar, a Chinese medicine containing arsenic, can be taken orally. Traditional Chinese medicine physicians have employed realgar to treat APL for over a thousand years. Therefore, realgar may be a promising candidate for the treatment of APL. Nevertheless, the underlying mechanism behind realgar therapy is largely unclear. The present study aimed to investigate the effect of realgar on cell death in the APL cell line (NB4) in vitro and to elucidate the underlying mechanism. In this study, after APL cells were treated with different concentrations of realgar, the cell survival rate, apoptotic assay, morphological changes, ATP levels and cell cycle arrest were assessed. The expression of Bcl-2, Bax, Cytochrome C (Cyt-C) and apoptosis-inducing factor (AIF) at the mRNA and protein levels were also measured by immunofluorescence, quantitative PCR (qPCR) and Western blotting. We found that realgar could significantly inhibit APL cell proliferation and cell death in a time- and dose-dependent manner. Realgar effectively decreased the ATP levels in APL cells. Realgar also induced APL cell cycle arrest at the S and G2/M phases. Following realgar treatment, the mRNA and protein levels of Bcl-2 were significantly downregulated, whereas the levels of Bax, Cyt-C, and AIF were significantly upregulated. In summary, realgar can induce APL cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway, suggesting that realgar may be an effective therapeutic for APL.

Induced effect of zinc oxide nanoparticles on human acute myeloid leukemia cell apoptosis by regulating mitochondrial division.

Zinc oxide nanoparticles (ZnO NPs) have exhibited excellent anti-tumor properties; the present study aimed to elucidate the underlying mechanism of ZnO NPs induced apoptosis in acute myeloid leukemia (AML) cells by regulating mitochondrial division. THP-1 cells, an AML cell line, were first incubated with different concentrations of ZnO NPs for 24 hr. Next, the expression of Drp-1, Bcl-2, Bax mRNA, and protein was detected, and the effects of ZnO NPs on the levels of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), apoptosis, and ATP generation in THP-1 cells were measured. Moreover, the effect of Drp-1 inhibitor Mdivi-1 and ZnO NPs on THP-1 cells was also detected. The results showed that the THP-1 cells survival rate decreased with the increment of ZnO NPs concentration and incubation time in a dose- and time-dependent manner. ZnO NPs can reduce the cell Δψm and ATP levels, induce ROS production, and increase the levels of mitochondrial division and apoptosis. In contrast, the apoptotic level was significantly reduced after intervention of Drp-1 inhibitor, suggesting that ZnO NPs can induce the apoptosis of THP-1 cells by regulating mitochondrial division. Overall, ZnO NPs may provide a new basis and idea for treating human acute myeloid leukemia in clinical practice.

Zinc oxide nanoparticle-triggered oxidative stress and autophagy activation in human tenon fibroblasts.

Glaucoma is a leading cause of irreversible blindness worldwide due to elevated intraocular pressure, and filtering surgery can efficiently control intraocular pressure of glaucoma patients. However, failure of filtering surgery commonly results from scarring formation at the surgical site, in which fibroblast proliferation plays an essential role in the scarring process. Our previous study has demonstrated that zinc oxide (ZnO) nanoparticles could efficiently inhibit human tenon fibroblasts (HTFs) proliferation. The present study aimed to explore the underlying mechanism involved in oxidative stress and autophagy signaling in zinc oxide (ZnO) nanoparticles-induced inhibition of HTFs proliferation. In this study, we investigated the effect of ZnO nanoparticles on HTFs proliferation, mitochondrial function, ATP production and nuclear morphology. Moreover, we also explored the interactions between ZnO nanoparticles and HTFs, investigated the influence of ZnO nanoparticles on the autophagosome formation, the expression of autophagy-related 5 (Atg5), Atg12 and Becn1 (Beclin 1), and the level of light chain 3 (LC3). The results suggested that ZnO nanoparticles can efficiently inhibit HTFs proliferation, disrupt the mitochondrial function, attenuate the adenosine triphosphate (ATP) generation, and damage the nuclear morphology of HTFs. Exposure of HTFs to ZnO nanoparticles can also induce the shifted peak, elevate the expression of Atg5, Atg12 and Becn1, enhance the autophagosome formation, and promote the LC3 expression, and thus activate autophagy signaling. Overall, ZnO nanoparticles can apparently trigger oxidative stress and activate autophagy signaling in HTFs, and thus inhibit HTFs proliferation and mediate HTFs apoptosis.

Efficacy and safety of chemotherapy combined with different doses of IL-2 maintenance therapies for acute myeloid leukemia: A protocol for a Bayesian network meta-analysis.

BACKGROUND: Acute myeloid leukemia (AML) is the most common malignant tumor of the hematopoietic system, which seriously threatens the lives of patients. Most AML patients have acute onset, severe condition, and poor prognosis. The present study aimed to comprehensively evaluate the effectiveness and safety of chemotherapy combined with different doses of interleukin-2 (IL-2) maintenance treatments in AML by Bayesian network meta-analysis (NMA). METHODS: From its inception until October 2021, we will search PubMed, Cochrane Library, CNKI, Embase, and other databases to comprehensively collect randomized controlled trials (RCTs) of chemotherapy combined with different doses of IL-2 maintenance therapies for AML. Two independent researchers will complete the literature screening and data extraction according to the inclusion and exclusion criteria, and then independently conduct a bias risk assessment of all the evidence. Bayesian NMA was used to evaluate all the evidence comprehensively. Use STATA16.0 and WinBUGS1.4.3 software to process and analyze all data, and classify the quality of evidence in NMA according to grading of recommendations assessment, development, and evaluation . RESULTS: The study will evaluate the efficacy and safety of chemotherapy combined with different doses of IL-2 maintenance therapies for AML. CONCLUSION: The study will provide a basis for the efficacy and safety of chemotherapy combined with different doses of IL-2 maintenance therapies for AML. We hope that this study can provide meaningful support for clinicians and patients. PROTOCOL REGISTRATION NUMBER: INPLASY202140106. ETHICAL APPROVAL: Since the study is based on published or registered RCTs, ethical approval and patient informed consent are abandoned.

A drug-biomarker interaction model to predict the key targets of Scutellaria barbata D. Don in adverse-risk acute myeloid leukaemia.

A poor prognosis, relapse and resistance are burning issues during adverse-risk acute myeloid leukaemia (AML) treatment. As a natural medicine, Scutellaria barbata D. Don (SBD) has shown impressive antitumour activity in various cancers. Thus, SBD may become a potential drug in adverse-risk AML treatment. This study aimed to screen the key targets of SBD in adverse-risk AML using the drug-biomarker interaction model through bioinformatics and network pharmacology methods. First, the adverse-risk AML-related critical biomarkers and targets of SBD active ingredient were obtained from The Cancer Genome Atlas database and several pharmacophore matching databases. Next, the protein-protein interaction network was constructed, and topological analysis and pathway enrichment were used to screen key targets and main pathways of intervention of SBD in adverse-risk AML. Finally, molecular docking was implemented for key target verification. The results suggest that luteolin and quercetin are the main active components of SBD against adverse-risk AML, and affected drug resistance, apoptosis, immune regulation and angiogenesis through the core targets AKT1, MAPK1, IL6, EGFR, SRC, VEGFA and TP53. We hope the proposed drug-biomarker interaction model provides an effective strategy for the research and development of antitumour drugs.

Structural and Functional Reorganization Within Cognitive Control Network Associated With Protection of Executive Function in Patients With Unilateral Frontal Gliomas.

Background: The cognitive control network (CCN) is widely considered to be a frontoparietal circuit that is involved in executive function. This study aimed to investigate the structural and functional plasticity within the CCN in unilateral frontal gliomas, which are associated with the protection of executive functions. Methods: To detect structural and functional changes within the CCN, we measured gray matter (GM) volume, regional homogeneity, the amplitude of low-frequency fluctuation (ALFF), degree centrality, and functional connectivity within the CCN in 37 patients with gliomas invading the left frontal lobe (n = 16) or the right frontal lobe (n = 21) and 40 healthy controls (CNs). Partial correlation analysis was performed to assess the association between the altered structural and functional indices and executive function. Results: When the tumor invaded the left frontal lobe, the patients showed reduced ALFF in the dorsal medial prefrontal cortex (dmPFC) within the CCN and increased ALFF in the right superior parietal cortex (rSP) within the CCN compared to the CNs. When the tumor invaded the right frontal lobe, the patients showed significantly increased GM volume and ALFF in the left superior parietal cortex (lSP) within the CCN compared to the CNs. Furthermore, the patients showed significantly increased functional connectivities between the lSP and the dmPFC and between the lSP and the rSP within the CCN compared to the CNs. Increased ALFF in the lSP within the CCN was positively correlated with executive function. Conclusions: Tumors invading the frontal lobe induced contralesional structural and functional reorganization within the posterior CCN in patients with unilateral frontal gliomas. This further suggests that the contralesional superior parietal cortex acts as a functional compensation hub within the CCN, which may protect it against the detrimental effects of tumor invasion on executive functions.

Alterations of white matter integrity associated with cognitive deficits in patients with glioma.

OBJECTIVE: This study aimed to investigate the characteristic of brain structural connections in glioma patients and further evaluate the relationship between changes in the white matter tracts and cognitive decline. METHODS: This retrospective study included a total of 35 subjects with glioma and 14 demographically matched healthy controls, who underwent diffusion tensor imaging scans and formal neuropsychological assessment tests. Fractional anisotropy (FA) values of white matter tracts were derived from atlas-based analysis to compare group differences. Furthermore, subgroup-level analysis was performed to differentiate the effects of tumor location on white matter tracts. Partial correlation analysis was used to examine the associations between neurocognitive assessments and the integrity of tracts. Region of interest-based network analysis was performed to validate the alteration of structural brain network in subjects with glioma. RESULTS: Compared with controls, subjects with glioma exhibited reduced FA values in the right uncinate fasciculus. Besides, subjects with glioma exhibited worse performance in several cognitive assessments. Partial correlation analysis indicated that the FA value in the right superior longitudinal fasciculus temporal part was significantly positively correlated with scores of visual-spatial abilities in subjects with glioma in the right temporal lobe (r = .932, p = .002). Region of interest-based network analysis revealed that subjects with glioma exhibited reduced FA, fiber length (FL), and fiber number (FN) between specific brain regions compared with controls. CONCLUSION: The present study demonstrated the reduced integrity of white matter tracts and altered structural connectivity in brain networks in patients with glioma. Notably, white matter tracts in the right hemisphere might be vulnerable to the effects of a frontal or temporal lesion and might be associated with deficient cognitive function.

Altered Rich-Club Organization and Regional Topology Are Associated With Cognitive Decline in Patients With Frontal and Temporal Gliomas.

OBJECTIVES: Gliomas are widely considered to be related to the altered topological organization of functional networks before operations. Tumors are usually thought to cause multimodal cognitive impairments. The structure is thought to form the basics of function, and the aim of this study was to reveal the rich-club organization and topological patterns of white matter (WM) structural networks associated with cognitive impairments in patients with frontal and temporal gliomas. METHODS: Graph theory approaches were utilized to reveal the global and regional topological organization and rich-club organization of WM structural networks of 14 controls (CN), 13 frontal tumors (FTumor), and 18 temporal tumors (TTumor). Linear regression was used to assess the relationship between cognitive performances and altered topological parameters. RESULTS: When compared with CN, both FTumor and TTumor showed no alterations in small-world properties and global network efficiency, but instead showed altered local network efficiency. Second, FTumor and TTumor patients showed similar deficits in the nodal shortest path in the left rolandic operculum and degree centrality (DC) of the right dorsolateral and medial superior frontal gyrus (SFGmed). Third, compared to FTumor patients, TTumor patients showed a significantly higher DC in the right dorsolateral and SFGmed, a higher level of betweenness in the right SFGmed, and higher nodal efficiency in the left middle frontal gyrus and right SFGmed. Finally, rich-club organization was disrupted, with increased structural connectivity among rich-club nodes and reduced structural connectivity among peripheral nodes in FTumor and TTumor patients. Altered local efficiency in TTumor correlated with memory function, while altered local efficiency in FTumor correlated with the information processing speed. CONCLUSION: Both FTumor and TTumor presented an intact global topology and altered regional topology related to cognitive impairment and may also share the convergent and divergent regional topological organization of WM structural networks. This suggested that a compensatory mechanism plays a key role in global topology formation in both FTumor and TTumor patients, and as such, development of a structural connectome for patients with brain tumors would be an invaluable medical resource and allow clinicians to make comprehensive preoperative planning.

Altered cerebral blood flow in patients with anti-NMDAR encephalitis.

OBJECTIVE: This study aimed to identify to resting-state cerebral blood flow (CBF) connectivity alterations in patients with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. METHODS: Three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 23 patients with anti-NMDAR encephalitis at the peak stage of the disease and 32 healthy subjects. CBF was normalized to reduce variations among subjects. CBF was compared between the groups, and the correlations between the CBF alterations and clinical parameters were assessed. Differences in CBF connectivity in specific brain regions were also compared between groups. RESULTS: Compared with the healthy subjects, the patients with anti-NMDAR encephalitis exhibited increased CBF in the left insula (L_insula), left superior temporal lobe (L_STL), L_hippocampus, L_pallidum, bilateral putamen (Bi_putamen), and Bi_caudate, and decreased CBF in the bilateral precuneus (Bi_Pc) and bilateral occipital lobe (Bi_OL) (P < 0.05, FEW corrected). Compared with healthy subjects, the patients with anti-NMDAR encephalitis exhibited increased negative CBF connectivity between the Bi_Pc, Bi_OL and L_TL, L_insula (P < 0.05, FEW corrected). Anti-NMDAR encephalitis patients with behavioral changes exhibited higher CBF in the L_insula and lower CBF in the R_Pc, Bi_calcarine, Bi_cuneus, and Bi_lingual than patients without behavioral changes and health controls. The ROC curve shows changed CBF in the L_insula, and R_Pc, Bi_calcarine, Bi_cuneus, and Bi_lingual served as a predictor of behavioral changes in patients with anti-NMDAR encephalitis. CONCLUSIONS: Our results suggest that patients with anti-NMDAR encephalitis may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of anti-NMDAR encephalitis.

Zinc oxide nanoparticles induce human multiple myeloma cell death via reactive oxygen species and Cyt-C/Apaf-1/Caspase-9/Caspase-3 signaling pathway in vitro.

BACKGROUND: Human multiple myeloma (MM) is a malignant and incurable B cell tumor. Zinc oxide nanoparticles (ZnO NPs) have been widely used in biomedical fields including anti-bacterial and anti-tumor. However, the influence of ZnO NPs on MM cells is still unclear. The present study aimed to investigate the effect of ZnO NPs on MM cell (a human myeloma-derived RPMI8226 cell line) death in vitro and the underlying mechanism. METHODS: The morphology of ZnO NPs was characterized by transmission electron microscopy (TEM), and the inhibitory and apoptotic effect of ZnO NPs on human MM cells was monitored by a CCK-8 method and an Annexin V-FITC/PI assay. Meanwhile, the morphological change in the cells after exposure to ZnO NPs was observed by a light field microscope. Moreover, the effects of ZnO NPs on the ATP level, reactive oxygen species (ROS) generation, and apoptosis were separately explored by the DCFH-DA fluorescent probe, flow cytometry, and ATP bioluminescence assay. Moreover, the expression of cytochrome C (Cyt-C), Apaf-1, Caspase-9 and Caspase-3 at mRNA and protein levels was further determined by using quantitative PCR (Q-PCR) and western blotting. In the present study, the human peripheral blood mononuclear cells (PBMCs) were used as normal control samples for the relevant experiment. RESULTS: The results indicated that ZnO NPs could significantly inhibit human MM cell proliferation and cell death in a time- and dose-dependent manner in vitro, and this outcome can be confirmed by cell morphology and apoptosis assay. Meanwhile, the results also showed that ZnO NPs could effectively increase ROS production and decrease ATP levels in human MM cells. ZnO NPs could also significantly elevate the expression of Cyt-C, Apaf-1, Caspase-9 and Caspase-3 at mRNA and protein levels, leading to cell death. By contrast, ZnO NPs showed little cytotoxic influence on PBMCs. CONCLUSION: ZnO NPs can significantly induce human MM cell death in a time- and dose-dependent manner in vitro, decrease the ATP production and enhance the ROS generation. ZnO NPs can also increase Cyt-C, Apaf-1, Caspase-9 and Caspase-3 expression at mRNA and protein levels in human MM cells, and initiate MM cell apoptosis, indicating that Cyt-C, Apaf-1, Caspase-9 and Caspase-3 play crucial roles in ZnO NPs-induced, mitochondria-mediated apoptosis in human MM cells. Overall, ZnO NPs may be a potential agent in treating human multiple myeloma in clinical practice.

Potential Intra- or Cross-Network Functional Reorganization of the Triple Unifying Networks in Patients with Frontal Glioma.

BACKGROUND: Patients with frontal glioma might experience cognition alterations together with potential dysfunction of resting-state networks (RSNs). To understand the altered patterns of the intrinsic activity and underlying network interactions between the cognitive-related RSNs is of great importance. OBJECTIVE: This study aimed to investigate the characteristics of the altered RSNs, including default mode network, executive control network, and salience network and further elucidate the possible functional reorganization of RSNs in patients with frontal glioma. METHODS: Thirteen patients with frontal glioma and 10 healthy controls (HCs) were enrolled in this study. Independent component analysis was performed to identify the characteristics of the selected RSNs activity. Further, functional connectivity analysis was applied to investigate the relationship between the altered regions. Subsequently, partial correlation analysis was performed to examine associations between the neural activity of RSNs and neurocognitive characteristics. RESULTS: Compared with the HCs group, the patient group exhibited significant differences in functional connectivity among default mode network, executive control network, and salience network. In addition, the number of the significant functional connectivities between the paired seeds observed in the patients was greater than that in HCs and significantly increased functional connectivity was detected between left posterior cingulate cortex and right angular gyrus. Furthermore, altered neural activities in the RSNs of patients with frontal glioma were positively associated with certain aspects of cognitive function. CONCLUSIONS: Our results suggested underlying network functional reorganization of the triple unifying RSNs in patients with frontal glioma, providing novel insights for improving understanding of brain function.

Temporal Proteomic Analysis of Pancreatic ß-Cells in Response to Lipotoxicity and Glucolipotoxicity.

Chronic hyperlipidemia causes the dysfunction of pancreatic ß-cells, such as apoptosis and impaired insulin secretion, which are aggravated in the presence of hyperglycemia. The underlying mechanisms, such as endoplasmic reticulum (ER) stress, oxidative stress and metabolic disorders, have been reported before; however, the time sequence of these molecular events is not fully understood. Here, using isobaric labeling-based mass spectrometry, we investigated the dynamic proteomes of INS-1 cells exposed to high palmitate in the absence and presence of high glucose. Using bioinformatics analysis of differentially expressed proteins, including the time-course expression pattern, protein-protein interaction, gene set enrichment and KEGG pathway analysis, we analyzed the dynamic features of previously reported and newly identified lipotoxicity- and glucolipotoxicity-related molecular events in more detail. Our temporal data highlight cholesterol metabolism occurring at 4 h, earlier than fatty acid metabolism that started at 8 h and likely acting as an early toxic event highly associated with ER stress induced by palmitate. Interestingly, we found that the proliferation of INS-1 cells was significantly increased at 48 h by combined treatment of palmitate and glucose. Moreover, benefit from the time-course quantitative data, we identified and validated two new molecular targets: Setd8 for cell replication and Rhob for apoptosis, demonstrating that our temporal dataset serves as a valuable resource to identify potential candidates for mechanistic studies of lipotoxicity and glucolipotoxicity in pancreatic ß-cells.

Structural elucidation and antioxidant activity of a water-soluble polysaccharide from the fruit bodies of Bulgaria inquinans (Fries).

The non-lichenized ascomycete Bulgaria inquinans (Fries), growing in the Changbai Mountain of China, has been used as medicinal diet for many years. In a previous study, we have reported that a heteropolysaccharide BIWS-4b from the fruit bodies of B. inquinans (Fries) exhibited markedly antimalarial and immunostimulating activities. In this paper, the structural features and antioxidant activity of BIWS-4b were investigated. The results showed that BIWS-4b contains an α-(1→2), (1→6)-mannan core to which the glucogalactan chains are attached. The glucogalactan chains were composed of (1→6)-, (1→5)- and (1→5,6)-linked ß-Galf, (1→4)-linked and non-reducing terminal ß-Glcp units, and might be attached to the mannan core at the O-2 positions of α-Manp units. The antioxidant assays showed that BIWS-4b exhibited good activities, including free radicals scavenging effects, ferrous ion-chelating ability and reducing power. Thus, BIWS-4b could be used as a natural antioxidant agent for food and pharmaceutical industries.

Preparation of a novel glucuronomannan from Auricularia auricala and its immunological activity.

A glucuronomannan (AA-4-H, Mw around 4 KDa) was prepared from the fruit bodies of Auricularia auricala by extraction with hot water, deproteination by Sevag reagent, stepwise precipitation with ethanol and partial acid hydrolysis. Monosaccharides analysis revealed that AA-4-H consisted of 91% mannose (Man) and 9% glucuronic acid (GlcA). FT-IR, NMR and methylation analyses indicated that AA-4-H is a branched glucuronomannan. Its main chains are composed of 1, 3-linked alpha-Manp, side chains are single a-Manp or alpha-GlcA residues attached to the O-2 and O-6 of Man residues of the main chains. Bioassay indicated that AA-4-H remarkably enhanced B lymphocyte proliferation and increased the production of nitric oxide of macrophages in vitro. Thus, glucuronomannan AA-4-H could be explored as a potential immunostimulation agent.