Mitochondrial Sirtuins in Parkinson's Disease.

Parkinson's disease (PD), the main risk factor for which is age, is one of the most common neurodegenerative diseases and imposes a substantial burden on affected individuals and the economy. While the aetiology of PD is still largely unclear, substantial evidence indicates that mitochondrial dysfunction, aggregation of α-synuclein (α-syn), oxidative stress, inflammation, and autophagy play major roles in the pathogenesis of PD. Sirtuins are NAD+-dependent protein deacetylases, includeing seven members, i.e., SIRT1-SIRT7. Among these sirtuins, SIRT3, SIRT4 and SIRT5 are located in mitochondria and are called mitochondrial sirtuins. Mitochondrial sirtuins regulate the activity and biological function of mitochondrial proteins through posttranslational modification of substrate proteins. Increasing evidence shows that mitochondrial sirtuins play an important role in degenerative diseases, including PD. Mitochondrial sirtuins exert a beneficial neuroprotective effect in various models of PD. This paper summarizes a large number of studies and discusses the latest research progress on the role of mitochondrial sirtuins in PD, focusing especially on the regulation of the mitochondrial respiratory chain (MRC), oxidative stress, the inflammatory response and autophagy, to provide new insight into the pathogenesis of PD and new targets for the diagnosis and treatment of the disease.

Bone marrow-derived mesenchymal stromal cells promote resistance to tyrosine kinase inhibitors in chronic myeloid leukemia via the IL-7/JAK1/STAT5 pathway.

Chronic myeloid leukemia (CML) is caused by the fusion of the BCR activator of RhoGEF and GTPase activating protein (BCR) and ABL proto-oncogene, the nonreceptor tyrosine kinase (ABL) genes. Although the tyrosine kinase inhibitors (TKIs) imatinib (IM) and nilotinib (NI) have remarkable efficacy in managing CML, the malignancies in some patients become TKI-resistant. Here, we isolated bone marrow (BM)-derived mesenchymal stem cells (MSCs) from several CML patients by Ficoll-Hypaque density-gradient centrifugation for coculture with K562 and BV173 cells with or without TKIs. We used real-time quantitative PCR to assess the level of interleukin 7 (IL-7) expression in the MSCs and employed immunoblotting to monitor protein expression in the BCR/ABL, phosphatidylinositol 3-kinase (PI3K)/AKT, and JAK/STAT signaling pathways. We also used a xenograft tumor model to examine the in vivo effect of different MSCs on CML cells. MSCs from patients with IM-resistant CML protected K562 and BV173 cells against IM- or NI-induced cell death, and this protection was due to increased IL-7 secretion from the MSCs. Moreover, IL-7 levels in the BM of patients with IM-resistant CML were significantly higher than in healthy donors or IM-sensitive CML patients. IL-7 elicited IM and NI resistance via BCR/ABL-independent activation of JAK1/STAT5 signaling, but not of JAK3/STAT5 or PI3K/AKT signaling. IL-7 or JAK1 gene knockdown abrogated IL-7-mediated STAT5 phosphorylation and IM resistance in vitro and in vivo Because high IL-7 levels in the BM mediate TKI resistance via BCR/ABL-independent activation of JAK1/STAT5 signaling, combining TKIs with IL-7/JAK1/STAT5 inhibition may have significant utility for managing CML.

A label-free electrochemical assay for coronavirus IBV H120 strain quantification based on equivalent substitution effect and AuNPs-assisted signal amplification.

A label-free electrochemical strategy is proposed combining equivalent substitution effect with AuNPs-assisted signal amplification. According to the differences of S1 protein in various infectious bronchitis virus (IBV) strains, a target DNA sequence that can specifically recognize H120 RNA forming a DNA-RNA hybridized double-strand structure has been designed. Then, the residual single-stranded target DNA is hydrolyzed by S1 nuclease. Therefore, the content of target DNA becomes equal to the content of virus RNA. After equivalent coronavirus, the target DNA is separated from DNA-RNA hybridized double strand by heating, which can partly hybridize with probe 2 modified on the electrode surface and probe 1 on AuNPs' surface. Thus, AuNPs are pulled to the surface of the electrode and the abundant DNA on AuNPs' surface could adsorb a large amount of hexaammineruthenium (III) chloride (RuHex) molecules, which produce a remarkably amplified electrochemical response. The voltammetric signal of RuHex with a peak near - 0.28 V vs. Ag/AgCl is used as the signal output. The proposed method shows a detection range of 1.56e-9 to 1.56e-6 µM with the detection limit of 2.96e-10 µM for IBV H120 strain selective quantification detection, exhibiting good accuracy, stability, and simplicity, which shows a great potential for IBV detection in vaccine research and avian infectious bronchitis diagnosis. Graphical abstract.

Autostereoscopic 3D display with high brightness and low crosstalk.

An autostereoscopic 3D display with high brightness and low crosstalk is proposed. This display consists of a liquid crystal display (LCD) panel, a reflective light source (RLS), and a parallax barrier or lenticular lens. The RLS behind the LCD panel consists of a light source, a light guide plate, and a reflection cavity. The RLS can make light reflect continuously in the reflection cavity and exit from the slits on the cavity surface. The widths of these slits are narrower than those of the subpixels, so they can provide a low aperture ratio, which is helpful in obtaining low crosstalk. Because of the reflection cavity, the optical efficiency is higher than that using a single barrier. The parallax barrier or lenticular lens can project parallax images on the LCD panel into different directions. Then 3D images are formed. A prototype of the proposed 3D display having high brightness 3D images and low crosstalk is developed. The experimental results agree well with the theory.

mTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections.

The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with E. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-ß and less IL-1, IFN-γ, and TNF-α. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.

Preparation of mesoporous silica/hydroxyapatite loaded quercetin nanoparticles and research on its antibacterial properties.

In this study, amino-functionalized mesoporous silica/hydroxyapatite nanoparticles (MSNS/HAP) with the property of acid dissociation have been prepared as a traditional Chinese medicine monomer carriers to improve the drug loading rate and antibacterial properties of antimicrobial quercetin (QUE) in vitro. The experimental results confirm that the drug loading rate of MSNs/HAP is 28.94 %, which is about 3.6 times higher than that of aminated mesoporous sililca nanoparticles (MSNs). The drug release of QUE on MSNs/HAP is pH-sensitive in phosphate buffered saline (pH=4.0-7.4). The above fabricated traditional Chinese medicine monomer modified nanocomposites (QUE@MSNs/HAP) displays concentration-dependent inhibitory effect, which shows better antibacterial effect than free QUE. The minimum inhibitory concentration for two tested bacteria, Staphylococcus aureus (S.aureus) and Escherichia coli (E.coli), is 256 mg·L -1. In summary, QUE@MSNs/HAP have successfully prepared, which not only improves the bio-availability of QUE, but also has acid-sensitive drug release properties. Compared with free QUE, its antibacterial performance significantly enhances, which provides a theoretical basis for the application of Chinese medicine molecules in bacterial treatment.

Correlation of cardiometabolic index and sarcopenia with cardiometabolic multimorbidity in middle-aged and older adult: a prospective study.

Background: Research has demonstrated that sarcopenia and visceral obesity are significant risk factors for chronic disease in middle-aged and older adults. However, the relationship between sarcopenia, the cardiac metabolic index (CMI), a novel measure of visceral obesity, and cardiometabolic multimorbidity (CMM) remains unclear. In this study, data from the China Longitudinal Study of Health and Retirement (CHARLS) were analyzed to investigate the association between sarcopenia and CMI with CMM in the middle-aged and older adult population. Methods: The study included 4,959 participants aged 45 and over. Sarcopenia was defined using the criteria of the Asian Sarcopenia Working Group 2019. CMM is defined as having two or more of the following conditions: physician-diagnosed heart disease, diabetes, stroke, and/or hypertension. CMI was calculated using the formula: CMI = (TG/HDL-C) × WHtR. To explore the association between CMI and sarcopenia and CMM, cox proportional risk regression models were used. Results: The median age of all participants was 57 years, with 47.1% being male. Over the 8-year follow-up, 1,362 individuals developed CMM. The incidence of CMM was 8.7/1,000 person-years in the group without sarcopenia or high CMI, 17.37/1,000 person-years in those with high CMI, 14.22/1,000 person-years in the sarcopenia group, and 22.34/1,000 person-years in the group with both conditions. After adjusting for covariates, the group with both sarcopenia and high CMI had a significantly increased risk of CMM (HR 2.48, 95% CI 1.12-5.51) and heart disease (HR 2.04, 95% CI 1.05-3.98). Among those over 65 years, sarcopenia was discovered to be associated with an increased risk of CMM [HR (95% CI: 4.83 (1.22, 19.06)]. The risk of CMM was further increased to 7.31-fold (95% CI:1.72, 31.15) when combined with high CMI. Conclusions: The combination of sarcopenia and high CMI is associated with an increased risk of developing CMM. Early identification and intervention of sarcopenia and CMI not only enable the development of targeted therapeutic strategies but also provide potential opportunities to reduce the morbidity and mortality of CMM.

[Recent Advance of Newly Therapy for Chronic Myeloid Leukemia with BCR-ABLT315I Mutation--Review].

BCR-ABLT315I mutation is the main mechanism of resistance to the first and second generation tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML). Ponatinib as the third generation TKI has been found that can significantly improve the prognosis of CML patients with T315I mutation. However, the latest report has discovered that the T315I compound mutant is even resistant to ponatinib, which aroused the enthusiasm of research on the mechanism of CML resistance and targeted therapy once again. Previous studies have shown that TKI combined with other targeted drugs is effective to CML patients with drug resistance or relapse due to T315I mutation. The latest research has found that the allosteric inhibitor asciminib combined with TKI therapy is equally effective to CML patients with T315I compound mutant, but the specific mechanism is not yet clarified. This review will focus on the latest research progress of therapy for CML with BCR-ABLT315I mutation, hoping to provide reference for researching new drugs and improve therapy for treating CML with T315I mutation.

A universal biosensor utilizing bacteria-initiated in situ growth of electroactive polymers for bacteria-related hazards detection.

Here, an ultrasensitive and highly selective electrochemical biosensor is engineered by integrating bacteria-initiated click chemistry with in situ growth of electroactive polymers. Leveraging the unique copper-binding redox pathway of bacteria to reduce CuII to CuI, CuI-catalyzed click chemistry is initiated and high-density electroactive ferrocenyl polymers are subsequently generated and efficiently grafted on biosensing interface by potentiostatic electrochemical atom transfer radical polymerization that greatly enhances the sensitivity of electro-analytical performance. A good linearity between electrochemical signal and the logarithm of Staphylococcus aureus and Escherichia coli concentration over the range from 102 to 107 CFU/mL is obtained with detection limits down to 4 and 6 CFU/mL, respectively. In order to further expand the applicability and universality of the sensor, bacterial magnetic separation section is supplemented into the system. With the help of aptamer-based magnetic preseparation section, selective detection of target bacteria with great anti-interference is achieved in complex real samples. Moreover, this biosensor can be applied in convenient antibiotics residue detection and rapid drug resistance analysis by merely substitution of recognition element or preincubation of bacteria with different anti-bacteria drugs. Thus, after further expansion of bacterial magnetic separation section or simple replacement of the originally identification element, a universal biosensor including bacteria analysis system and antibiotics detection system with excellent analytical performance is constructed. It provides new insight into the aspects of bacteria-related hazards detection that could not only reduce the detriment caused by bacterial contamination, but also guide antibiotic rational usage and help to control the emergence of multidrug-resistant bacteria.

The Predictive Value of Neutrophil-Lymphocyte Ratio in Patients with Polycythemia Vera at the Time of Initial Diagnosis for Thrombotic Events.

Objective: To investigate and discuss the predictive value of the neutrophil-to-lymphocyte ratio (NLR) in patients with polycythemia vera (PV) at the time of initial diagnosis, as well as its clinical significance in predicting the occurrence of thrombotic events and the progression of future thrombotic events during follow-ups, with the goal of providing a reference for the early identification of high-risk PV patients and the early intervention necessary to improve the prognosis of PV patients. Method: A total of 170 patients diagnosed with PV for the first time were enrolled in this study. The risk factors affecting the occurrence and development of thrombotic events in these patients were statistically analyzed. Results: NLR (P = 0.030), WBC count (P = 0.045), and history of previous thrombosis (P < 0.001) were independent risk factors for thrombotic events at the time of initial diagnosis. Age ≥ 60 years (P = 0.004), NLR (P = 0.025), history of previous thrombosis (P < 0.001), and fibrinogen (P = 0.042) were independent risk factors for the progression of future thrombotic events during follow-ups. The receiver operating characteristic curve (ROC curves) showed that NLR was more effective in predicting the progression of future thrombotic events than age ≥ 60 years, history of previous thrombosis, and fibrinogen. Kaplan-Meier survival analysis showed progression-free survival time of thrombotic events in the high NLR value group (NLR ≥ 4.713) (median survival time 22.033 months, 95% CI: 4.226-35.840), which was significantly lower compared to the low NLR value group (NLR < 4.713) (median overall survival time 66.000 months, 95% CI: 50.670-81.330); the observed difference was statistically significant (P < 0.001). The 60-month progression-free survival in the low NLR value group was 58.8%, while it was 32.8% in the high NLR value group. Conclusion: Peripheral blood NLR levels in patients with PV resulted as an independent risk factor for the occurrence of thrombotic events at the time of initial diagnosis and for the progression of future thrombotic events during follow-ups. Peripheral blood NLR levels at the time of initial diagnosis and treatment had better diagnostic and predictive value for the progression of future thrombotic events in patients with PV than age ≥ 60 years, history of previous thrombosis, and fibrinogen.

Chitosan functionalized graphene oxide nanocomposites for fluorescence imaging of apoptotic processes and targeted anti-inflammation study.

This work reports novel chitosan functionalized graphene oxide (GO) nanocomposites combined fluorescence imaging and therapeutic functions in one agent, which can serve as a promising alternative to alleviate related diseases caused hyperinflammation. Briefly, GO was designed to be conjugated with chitosan, fluorescein-labeled peptide, toll-like receptor 4 antibody and hydroxycamptothecin/aloe emodin. We have demonstrated that such nanocomposites could effectively achieve active targeted delivery of pro-apoptotic and anti-inflammatory drugs into inflammatory cells and cause cells apoptosis by acid-responsive drug release. Moreover, confocal fluorescence imaging confirms that the drug-induced inflammatory cells apoptosis could be visualized the light-up fluorescence of fluorescein activated by caspase-3. Meanwhile, inflammatory-related biomarkers have down-regulated after the nanocomposites' treatment in both vitro and vivo experiments consistent with the results in histological sections. In summary, the bifunctional nanocomposites that possess anti-inflammation and fluorescence imaging could serve as a promising therapeutic agent for reducing hyperinflammation caused by numerous diseases.

Exosomes from Bone Marrow Microenvironment-Derived Mesenchymal Stem Cells Affect CML Cells Growth and Promote Drug Resistance to Tyrosine Kinase Inhibitors.

Although major advances have been achieved in the treatment of chronic myeloid leukemia (CML) by using tyrosine kinase inhibitors, patients relapse after withdrawal and need long-term medication. This reflects the CML clones have not been eliminated completely. The precise mechanisms for the maintenance of CML cells are not yet fully understood. The bone marrow microenvironment constitutes the sanctuary for leukemic cells. Mesenchymal stem cells (MSC) are an important component of the bone marrow microenvironment (BM). It plays an important role in the development and drug resistance of CML. Accumulating evidence indicates that exosomes play a vital role in cell-to-cell communication. We successfully isolated and purified exosomes from human bone marrow microenvironment-derived mesenchymal stem cells (hBMMSC-Exo) by serial centrifugation. In the present study, we investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells. The results demonstrated that hBMMSC-Exo had the ability to inhibit the proliferation of CML cells in vitro via miR-15a and arrest cell cycle in the G0/G1 phase. However, the results obtained from BALB/c nu/nu mice studies apparently contradicted the in vitro results. In fact, hBMMSC-Exo increased tumor incidence and promoted tumor growth in vivo. Further study showed the antiapoptotic protein Bcl-2 expression increased, whereas the Caspase3 expression decreased. Moreover, the in vivo study in the xenograft tumor model showed that hBMMSC-Exo promoted the proliferation and decreased the sensitivity of CML cells to tyrosine kinase inhibitors, resulting in drug resistance. These results demonstrated that hBMMSC-Exo supported the maintenance of CML cells and drug resistance in BM by cell-extrinsic protective mechanisms. They also suggested that hBMMSC-Exo might be a potential target to overcome the microenvironment-mediated drug resistance.

[Research Advances on the Biological Characteristics of Hematological Malignant Cells Immunologically Regulated by Exosome--Review].

Abstract　　The minimal residual disease (MRD) is the origin element that caused the relapse and drug resistance of hematological malignancies, the immune cells play a great role to clear MRD. A variety of immune cells have anti-tumor effects. However, tumor cells antagonize anti-tumor effects by reprogramming of constituents associated with tumor environment. Many different cell types, including immune cells, mesenchymal cells and tumor cells in tumor microenvironment release exosomes. The latest researches indicate that "cargo" and surface ligands carried by exosomes secreted by hematological malignant cells not only can affect the function of natural killer cell (migration, activation, proliferation, secretion and NKG2D expression), macrophage (migration and secretion) and dendritic cell (maturation and presentation), but also regulate the expression of PD-L1 and CCR2, CCL2 secretion and transformation of monocytes. The altered function of immune cells will eventually have effect on the progression of hematological malignancies.

Design of gradient nanopores in phenolics for ultrafast water permeation.

Membrane technology is playing a pivotal role in providing potable water to our thirsty planet. However, the strong demand for highly permeable and durable membranes with affordable costs remains. Such membranes are synthesized herein by designing gradient nanopores in low-cost phenolics. The gradient nanopores are achieved by spontaneous assembly of phenolic nanoparticles with gradually enlarged sizes. These particles nucleate and grow as a result of ZnCl2-accelerated thermopolymerization of resol in the progressive downward gelating polymer. Subsequent removal of the gelated polymer and ZnCl2 exposes the gradient nanopores. The gradient nanopores endow the phenolic structures with unprecedented permselectivity when used in membrane separation, totally rejecting fine particulates down to 5 nm dispersed in water or aggressive solvents while allowing water to permeate up to two orders of magnitude faster than other membranes with similar rejections. Our work opens up an avenue for the rational design and affordable synthesis of ultrafast membranes.

[MSC Senescence-related Signaling Pathway - Review].

The replicative senescence of mesenchymal stem cells(MSC) during the in vitro expansion limits their use in the research and treatment of many disease. Also, MSC senescence may promote the individual senility, hypofunction of tissue and organ, and tumorigenesis. Thus, in order to better understand the senescent mechanism and delay the senescence, even reverse MSC senescence, the roles of signaling pathway, such as Wnt/ß-catenin, MAPK/ERK, PI3K/AKT and ROS-related signaling pathway during the MSC senescence all were reviewed, so as to can deepen the under-standing of MSC senescence and provide a new thinkings for delaying, even reversing the MSC senescence.

[Role of Exosomal miRNA in Multiple Myeloma Progression and Its Possible Mechanism -Review].

Multiple myeloma (MM)is a kind of plasma tumor originated from B cell line. Its incidence ranks in second place of hematopoietic malignancies. Although continued progress was made in treatment of MM,the survival rate and prognosis of MM patients are still not satisfactory. Further understanding of the pathogenesis of MM may provide information to develop new treatment strategies, so as to improve survival rate and ameliorate its prognosis. Many researches have demonstrated that bone marrow microenvironment plays an important role in MM pathogenesis, which regulates the biological properties of MM cells, including migration and proliferation, through miRNA, mRNA and protein contained in the exosomes released from the cells in the tumor microenvironment. Recently, as the tumor suppressor genes and oncogenes, exosomal microRNA become a hot spot in research. Compared with those of the normal ones, exosomes in MM have less miR-15a and/or more miR-135b and miR-21. These differences will accelerate the progression of MM via PI3K/Akt/eNOS/VEGF pathway, FIH-HIF pathway, MAPK/ERK/Ras pathway and so on, that are expected to become the new targets for the treatment of MM. This review summarizes the role and the possible mechanism of exosomes in the progression of MM.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Roles in Tumor Growth, Progression, and Drug Resistance.

Mesenchymal stem cells (MSCs) are ubiquitously present in many tissues. Due to their unique advantages, MSCs have been widely employed in clinical studies. Emerging evidences indicate that MSCs can also migrate to the tumor surrounding stroma and exert complex effects on tumor growth and progression. However, the effect of MSCs on tumor growth is still a matter of debate. Several studies have shown that MSCs could favor tumor growth. On the contrary, other groups have demonstrated that MSCs suppressed tumor progression. Extracellular vesicles have emerged as a new mechanism of cell-to-cell communication in the development of tumor diseases. MSCs-derived extracellular vesicles (MSC-EVs) could mimic the effects of the mesenchymal stem cells from which they originate. Different studies have reported that MSC-EVs may exert various effects on the growth, metastasis, and drug response of different tumor cells by transferring proteins, messenger RNA, and microRNA to recipient cells. In the present review, we summarize the components of MSC-EVs and discuss the roles of MSC-EVs in different malignant diseases, including the related mechanisms that may account for their therapeutic potential. MSC-EVs open up a promising opportunity in the treatment of cancer with increased efficacy.

[Role of Exosomes in the Cross-Talk between Leukemia Cells and Mesenchymal Stem Cells -Review].

More and more studies have demonstrated that bone marrow microenvironment, the fundament of the multiplication and differentiation of hematopoietic stem cells, plays a crucial role in leukemia progression and resistance to treatment. It provides a permissive environment for minimal residual disease and contributes to relapse and multidrug resistance. Mesenchymal stem cells are a kind of important stromal cells in bone marrow niche. In recent researches, MSC have been shown to be one of the major factors modulating the biological features of leukemia cells. The cross-talk between MSC and leukemia cells can take place not only by direct contact, but also by exosome exchange. Exosomes are nano-sized vesicles released by a variety of cells, which contain protein, RNA and mRNA. They are effective tools for transportation between cells, and play an important role in many physiological and pathological processes. Exosome is a new topic in the research of leukemia and microenvironment. The exosome research will help elucidate the mechanism of leukemia, thus providing new ideas for the treatment.

High IL-7 levels in the bone marrow microenvironment mediate imatinib resistance and predict disease progression in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a three-stage myeloproliferative disease caused by translocation between chromosomes 9 and 22. Although tyrosine kinase inhibitors (TKI) are highly effective in the treatment of CML, numerous clinical trials have shown that many patients become refractory or drug resistance, especially those in the blastic crisis of CML. The molecular mechanisms underlying CML, however, remain poorly understood. In the present study, we used a coculture model to address possible mechanisms underlying the involvement of bone marrow microenvironment in the drug resistance of CML. Our data show that interleukin-7(IL-7) levels in the bone marrow of CML patients in blastic crisis are significantly higher than those of both healthy persons and CML patients in chronic and accelerated phases. The increased IL-7 was secreted by mesenchymal stem cells (MSC) in the bone marrow, which may protect leukemic cells from apoptosis induced by imatinib through JAK1/STAT5 signaling pathway. Our findings suggest that therapeutic strategies IL-7 signaling pathway may represent a promising approach for improving CML therapy, especially for patients in blastic crisis.