TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

Nonlinear chaotic dynamics in nonlocal plasmonic core-shell nanoparticle dimer.

Plasmonic nanoparticles can be employed as a promising integrated platform for lumped optical nanoelements with unprecedentedly high integration capacity and efficient nanoscale ultrafast nonlinear functionality. Further minimizing the size of plasmonic nanoelements will lead to a rich variety of nonlocal optical effects due to the nonlocal nature of electrons in plasmonic materials. In this work, we theoretically investigate the nonlinear chaotic dynamics of the plasmonic core-shell nanoparticle dimer consisting of a nonlocal plasmonic core and a Kerr-type nonlinear shell at nanometer scale. This kind of optical nanoantennae could provide novel switching functionality: tristable, astable multivibrators, and chaos generator. We give a qualitative analysis on the influence of nonlocality and aspect ratio of core-shell nanoparticles on the chaos regime as well as on the nonlinear dynamical processing. It is demonstrated that considering nonlocality is very important in the design of such nonlinear functional photonic nanoelements with ultra-small size. Compared to solid nanoparticles, core-shell nanoparticles provide an additional freedom to adjust their plasmonic property hence tuning the chaotic dynamic regime in the geometric parameter space. This kind of nanoscale nonlinear system could be the candidate for a nonlinear nanophotonic device with a tunable nonlinear dynamical response.

Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies.

In cell transplantation therapy, mesenchymal stem cells(MSCs)are ideal seed cells due to their easy acquisition and cultivation, strong regenerative capacity, multi-directional differentiation abilities, and immunomodulatory effects. Autologous MSCs are better applicable compared with allogeneic MSCs in clinical practice. The elderly are the main population for cell transplantation therapy, but as donor aging, MSCs in the tissue show aging-related changes. When the number of generations of in vitro expansion is increased, MSCs will also exhibit replicative senescence. The quantity and quality of MSCs decline during aging, which limits the efficacy of autologous MSCs transplantation therapy. In this review, we examine the changes in MSC senescence as a result of aging, discuss the progress of research on mechanisms and signalling pathways of MSC senescence, and discuss possible rejuvenation strategies of aged MSCs to combat senescence and enhance the health and therapeutic potential of MSCs.

Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.

The role of AGEs in pathogenesis of cartilage destruction in osteoarthritis.

Osteoarthritis (OA) is a degenerative disease resulting from progressive joint destruction caused by many factors. Its pathogenesis is complex and has not been elucidated to date. Advanced glycation end products (AGEs) are a series of irreversible and stable macromolecular complexes formed by reducing sugar with protein, lipid, and nucleic acid through a non-enzymatic glycosylation reaction (Maillard reaction). They are an important indicator of the degree of ageing. Currently, it is considered that AGEs accumulation in vivo is a molecular basis of age-induced OA, and AGEs production and accumulation in vivo is one of the important reasons for the induction and acceleration of the pathological changes of OA. In recent years, it has been found that AGEs are involved in a variety of pathological processes of OA, including extracellular matrix degradation, chondrocyte apoptosis, and autophagy. Clearly, AGEs play an important role in regulating the expression of OA-related genes and maintaining the chondrocyte phenotype and the stability of the intra-articular environment. This article reviews the latest research results of AGEs in a variety of pathological processes of OA, to provide a new direction for the study of OA pathogenesis and a new target for prevention and treatment. Cite this article: Bone Joint Res 2022;11(5):292-300.

Identification and evolutionary analysis of the metal-tolerance protein family in eight Cucurbitaceae species.

Metal-tolerance proteins (MTPs) are divalent cation transporters and play fundamental roles in plant metal tolerance and ion homeostasis. Despite that, a systematic investigation of MTPs in Cucurbitacea is still lacking. In this study, 142 MTPs were identified from 11 released genomes of 8 Cucurbitaceae species. They were phylogenetically separated into three clusters (Zn-cation diffusion facilitator proteins [CDFs], Fe/Zn-CDFs, and Mn-CDFs) and further subdivided into seven groups (G1, G5, G6, G7, G8, G9, and G12). Characterization analysis revealed that most MTPs were plasma membrane-located hydrophobic proteins. Motif and exon/intron analysis showed that members in the same group contained similar conserved motifs and gene structures. Moreover, 98 pairs of segmental-like duplication events were found. The nonsynonymous/synonymous substitution ratios between each pair were less than 1, implying that Cucurbitaceae MTPs were under purification selection. Expression profiling suggested that several MTP genes, such as CsCLMTP1, CmeMTP3, LsMTP3, and Cl97103MTP3, were constitutively expressed in corresponding Cucurbitaceae species, and their expression levels were not significantly altered by NaCl, drought, or pathogen infection. The expression patterns of cucumber MTP genes under Zn2+ , Cu2+ , Mn2+ , and Cd2+ stress were studied by quantitative real-time polymerase chain reaction and the results showed that these MTPs were induced by at least one metal ion, suggesting their involvement in metal tolerance or transportation. The identification and comprehensive investigation of MTP family members will provide a basis for the analysis of ion transport functions and ion tolerance mechanisms of Cucurbitaceae MTPs.

Silicon confers cucumber resistance to salinity stress through regulation of proline and cytokinins.

Salt stress is a continuous threat to global crop production. Here, we studied the alleviation role of exogenous silicon (Si) in NaCl-stressed cucumber, with special emphasis on plant growth, proline (Pro) and hormone metabolisms. The results showed that Si supplementation ameliorated the adverse effects of NaCl on plants growth, biomass, and oxidative stress. Salt stress greatly increased the content of Pro throughout the experiment, while Si regulated Pro content in two distinct ways. Si promoted the salt-induced Pro levels after 3 and 6 days of treatment, but decreased it after 9 and 12 days of treatment. Moreover, P5CS and ProDH activities and P5CS gene play important roles in Si and salt-regulated Pro levels in different stress phase. Under stress condition, Si addition tend to revert the content of ABA, IAA, cytokinin and SA to the control levels in most cases. Further correlation analysis revealed a negative correlation between the root cytokinin and Pro content after 3 days of treatment, suggesting the interaction between cytokinin and Pro metabolism. Exogenous application of Pro and ProDH competitive inhibitor D-Lactate confirmed the possible interplay between Pro and cytokinin metabolism. Further study identified several CKX (Csa4G647490 and Csa1G589070) and IPT (Csa7G392940 and Csa3G150100) genes that may be responsible for the regulation of cytokinin accumulation by Si and/or Pro after short-term of treatment. The results suggested that Pro is a key factor in Si-induced salt tolerance, and Si-increased Pro content may participate in the regulation of cytokinin metabolism under short-term of salt stress.

Genome-wide characterization of the C2H2 zinc-finger genes in Cucumis sativus and functional analyses of four CsZFPs in response to stresses.

BACKGROUNDS: C2H2-type zinc finger protein (ZFPs) form a relatively large family of transcriptional regulators in plants, and play many roles in plant growth, development, and stress response. However, the comprehensive analysis of C2H2 ZFPs in cucumber (CsZFPs) and their regulation function in cucumber are still lacking. RESULTS: In the current study, the whole genome identification and characterization of CsZFPs, including the gene structure, genome localization, phylogenetic relationship, and gene expression were performed. Functional analysis of 4 selected genes by transient transformation were also conducted. A total of 129 full-length CsZFPs were identified, which could be classified into four groups according to the phylogenetic analysis. The 129 CsZFPs unequally distributed on 7 chromosomes. Promoter cis-element analysis showed that the CsZFPs might involve in the regulation of phytohormone and/or abiotic stress response, and 93 CsZFPs were predicted to be targeted by one to 20 miRNAs. Moreover, the subcellular localization analysis indicated that 10 tested CsZFPs located in the nucleus and the transcriptome profiling analysis of CsZFPs demonstrated that these genes are involved in root and floral development, pollination and fruit spine. Furthermore, the transient overexpression of Csa1G085390 and Csa7G071440 into Nicotiana benthamiana plants revealed that they could decrease and induce leave necrosis in response to pathogen attack, respectively, and they could enhance salt and drought stresses through the initial induction of H2O2. In addition, Csa4G642460 and Csa6G303740 could induce cell death after 5 days transformation. CONCLUSIONS: The identification and function analysis of CsZFPs demonstrated that some key individual CsZFPs might play essential roles in response to biotic and abiotic stresses. These results could lay the foundation for understanding the role of CsZFPs in cucumber development for future genetic engineering studies.