Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer\'s disease (AD), Parkinson\'s disease (PD), Huntington\'s disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.
神经退行性疾病 (Neurodegenerative diseases，ND) 是一类主要影响老年人群的神经疾病，包括阿尔茨海默病 (Alzheimer’s disease，AD)、帕金森病 (Parkinson’s disease，PD)、亨廷顿病 (Huntington’s disease，HD) 和肌萎缩侧索硬化症 (Amyotrophic lateral sclerosis，ALS)。目前，临床上尚无可以延迟、阻止或逆转 ND 病理进展的疗法。随着人口老龄化，ND 给公共卫生系统和患者家庭带来巨大负担。动物模型是临床前研究了解疾病发病机制和测试潜在治疗方法的重要工具。虽然已经开发出许多神经退行性疾病的啮齿类动物模型，并极大地增强了我们对疾病机制的理解，但动物模型的研究结果临床转化效果低下，这表明仍然需要弥合临床前研究和临床研究之间的差距。旧大陆非人类灵长类动物（non-human primates，NHPs），如恒河猴、食蟹猴和黑长尾猴，在系统发育、生理、生化和行为上，特别是在中枢神经系统结构和功能方面与人类最为接近，这使得它们对神经科学的研究具有重要作用。最近，已经有几种神经退行性疾病的转基因 NHP 模型报道，它们复刻了关键病理学指征并揭示了新的分子机制。在这篇综述中，我们描述了 NHP 模拟 ND 的能力以及来自这些 NHP 模型的新病理学见解。我们还讨论了模型制备及后续研究中面临的挑战。.

Acute myeloid leukemia (AML) is a fatal blood malignancy. With the development of immunotherapy, particularly chimeric antigen receptor T cells (CAR-T), the treatment of AML has undergone a significant change. Despite its advantages, CAR-T still faces a number of limitations and challenges while treating AML. Finding novel targets, altering the structure of CAR to increase efficacy while lowering side effects, and using double-target CAR and logic circuits are typical examples of key to answer these problems. With the advancement of gene editing technology, gene editing of tumor cells or normal cells to create therapeutic effects has grown in popularity. Additionally, the combination of multiple drugs is routinely used to address some of the obstacles and difficulties associated with CAR-T therapy. The review\'s primary goal was to summarize recent strategies and developments of CAR-T therapy for AML.

BACKGROUND: The emergence of SARS-CoV-2 becomes life-threatening for the older and immunocompromised individuals, whereas limited treatment is available on these populations. Mesenchymal stromal cells (MSCs) have been reported to be useful in SARS-CoV-2 treatment and reduce SARS-CoV-2-related sequelae.
RESULTS: In this study, we developed an autonomous cellular machine to secret neutralizing antibody in vivo constantly based on the clinical-grade MSCs, to combat SARS-CoV-2 infections. First, various modified recombinant plasmids were constructed and transfected into clinical-grade MSCs by electroporation, for assembly and expression of neutralizing anti-SARS-CoV-2 antibodies. Second, the stable antibody secreting MSCs clones were screened through pseudovirus neutralization assay. Finally, we investigated the pharmacokinetics and biodistribution of neutralizing antibody secreted by engineered MSCs in vivo. The stable clinical-grade MSCs clones, expressing XGv347-10 and LY-CoV1404-5 neutralizing antibodies, exhibited their feasibility and protective efficacy against SARS-CoV-2 infection. Transplanted engineered clinical-grade MSCs effectively delivered the SARS-CoV-2 antibodies to the lung, and the immune hyperresponsiveness caused by COVID-19 was coordinated by MSC clones through inhibiting the differentiation of CD4 + T cells into Th1 and Th17 subpopulations.
CONCLUSIONS: Our data suggested that engineered clinical-grade MSCs secreting effective neutralizing antibodies as cellular production machines had the potential to combat SARS-CoV-2 infection, which provided a new avenue for effectively treating the older and immunocompromised COVID-19 patients.

Cell spheroids offer cell-to-cell interactions and show advantages in survival rate and paracrine effect to solve clinical and biomedical inquiries ranging from tissue engineering and regenerative medicine to disease pathophysiology. Therefore, cell spheroids are ideal vehicles for gene delivery. Genetically modified spheroids can enhance specific gene expression to promote tissue regeneration. Gene deliveries to cell spheroids are via viral vectors or non-viral vectors. Some new technologies like CRISPR/Cas9 also have been used in genetically modified methods to deliver exogenous gene to the host chromosome. It has been shown that genetically modified cell spheroids had the potential to differentiate into bone, cartilage, vascular, nerve, cardiomyocytes, skin, and skeletal muscle as well as organs like the liver to replace the diseased organ in the animal and pre-clinical trials. This article reviews the recent articles about genetically modified spheroid cells and explains the fabrication, applications, development timeline, limitations, and future directions of genetically modified cell spheroid.

Radiotherapy (RT) is an effective treatment option for multiple thoracic malignant tumors, including lung cancers, thymic cancers, and tracheal cancers. Radiation-induced lung injury (RILI) is a serious complication of radiotherapy. Radiation causes damage to the pulmonary cells and tissues. Multiple factors contribute to the progression of Radiation-induced lung injury, including genetic alterations, oxidative stress, and inflammatory responses. Especially, radiation sources contribute to oxidative stress occurrence by direct excitation and ionization of water molecules, which leads to the decomposition of water molecules and the generation of reactive oxygen species (ROS), reactive nitrogen species (RNS). Subsequently, reactive oxygen species and reactive nitrogen species overproduction can induce oxidative DNA damage. Immune cells and multiple signaling molecules play a major role in the entire process. Mesenchymal stem cells (MSCs) are pluripotent stem cells with multiple differentiation potentials, which are under investigation to treat radiation-induced lung injury. Mesenchymal stem cells can protect normal pulmonary cells from injury by targeting multiple signaling molecules to regulate immune cells and to control balance between antioxidants and prooxidants, thereby inhibiting inflammation and fibrosis. Genetically modified mesenchymal stem cells can improve the natural function of mesenchymal stem cells, including cellular survival, tissue regeneration, and homing. These reprogrammed mesenchymal stem cells can produce the desired products, including cytokines, receptors, and enzymes, which can contribute to further advances in the therapeutic application of mesenchymal stem cells. Here, we review the molecular mechanisms of radiation-induced lung injury and discuss the potential of Mesenchymal stem cells for the prevention and treatment of radiation-induced lung injury. Clarification of these key issues will make mesenchymal stem cells a more fantastic novel therapeutic strategy for radiation-induced lung injury in clinics, and the readers can have a comprehensive understanding in this fields.

Sulforaphane (SFN) was generated by the hydrolysis of glucoraphanin under the action of myrosinase. However, due to the instability of SFN, the bioavailability of SFN was limited. Meanwhile, the gut flora obtained the ability to synthesize myrosinase and glucoraphanin, which could be converted into SFN in the intestine. However, the ability of microorganisms to synthesize myrosinase in the gut was limited. Therefore, microorganisms with myrosinase synthesis ability need to be supplemented. With the development of research, microorganisms with high levels of myrosinase synthesis could be obtained by artificial selection and gene modification. Researchers found the SFN production rate of the transformed microorganisms could be significantly improved. However, despite applying transformation technology and regulating nutrients to microorganisms, it still could not provide the best efficiency during generating SFN and could not accomplish colonization in the intestine. Due to the great effect of microencapsulation on improving the colonization ability of microorganisms, microencapsulation is currently an important way to deliver microorganisms into the gut. This article mainly analyzed the possibility of obtaining SFN-producing microorganisms through gene modification and delivering them to the gut via microencapsulation to improve the utilization rate of SFN. It could provide a theoretical basis for expanding the application scope of SFN.

In this study, Clostridium sp. strain WK-AN1 carrying both genes of agarase (Aga0283) and neoagarobiose hydrolase (NH2780) were successfully constructed to convert agar polysaccharide directly into butanol, contributing to overcome the lack of algal hydrolases in solventogenic clostridia. Through the optimization by the Plackett-Burman design (PBD) and response surface methodology (RSM), a maximal butanol production of 6.42 g/L was achieved from 17.86 g/L agar. Further application of utilizing the butyric acid pretreated Gelidium amansii hydrolysate demonstrated the modified strain obtained the butanol production of 7.83 g/L by 1.63-fold improvement over the wild-type one. This work for the first time establishes a novel route to utilize red algal polysaccharides for butanol fermentation by constructing a solventogenic clostridia-specific secretory expression system for heterologous agarases, which will provide insights for future development of the sustainable third-generation biomass energy.

The transplantation of adipose-derived stem cells (ASCs) is a most promising treatment for diabetic erectile dysfunction (DMED). However, the effect of high glucose on the post-transplantation survival of stem cells limits the efficacy of ASCs transplantation. Prolonging the survival time of ASCs in vivo after transplantation is a key issue in the utilization of ASCs for DMED. Herein, we aimed to investigate the therapeutic effect of ASCs by downregulating NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) as well as its mechanism of action in DMED.
ASCs were obtained by isolating subcutaneous fat from SD rats and were identified using lipogenic and osteogenic differentiation assays, as well as flow cytometric analysis. The shNLRP3 lentivirus with the best downregulating effect was screened, and shNLRP3 lentivirus (LV-shNLRP3) was transfected into ASCs (ASCsshNLRP3) to detect apoptosis and the reactive oxygen species (ROS) levels in each group under high glucose conditions. In DMED rats, ASCsLV-shNLRP3, ASCsLV-control, or phosphate buffered saline (PBS) were administrated via intra-cavernous injection, and normal rats served as normal controls. One week post-injection, animal imaging was performed to track the ASCs. Four weeks post-injection, erectile function was evaluated by measuring the intra-cavernosal pressure and mean arterial pressure. Corpus cavernosum pyroptosis and endothelial function were examined by western blotting and immunofluorescence.
NLRP3-mediated pyroptosis might be a pathogenic mechanism of ED and DMED. ASCs were isolated successfully. Thereafter, the LV-shNLRP3 with the highest transfection efficiency was selected and used to modify ASCs successfully. LV-shNLRP3 could protect ASCs paracrine function under hyperglycemia through anti-apoptosis and anti-ROS deposition mechanisms. Furthermore, ASCsLV-shNLRP3 showed an advantage in the suppression of pyroptosis compared to ASCsLV-control. The ASCsLV-shNLRP3 group had improved cavernous endothelial function and smooth muscle injury, thus reversing erectile function, and was superior to the ASCsLV-control group.
NLRP3 Inflammasome-mediated pyroptosis might be involved in DMED formation. Intra-cavernous injection of ASCsLV-shNLRP3 could suppress cavernosal pyroptosis, contributing to improved erectile function in DMED rats.

BACKGROUND: Therapy with genetically modified mesenchymal stem cells (MSCs) has clinical translation promise. Optimizing the targeting migratory ability of MSCs relies on accurate imaging of the distribution and extravasation kinetics of MSCs, and the corresponding imaging results could be used to predict therapeutic outcomes and guide the optimization of the treatment program. Among the different imaging modalities, second near-infrared (NIR-II) optical-resolution photoacoustic microscopy (OR-PAM) has merits, including a fine resolution, a deep penetration, a high sensitivity, and a large signal-to-background ratio. It would be an ideal candidate for precise monitoring of MSCs, although it has not been tested for this purpose so far.
RESULTS: Penetrating peptide-decorated conjugated polymer nanoparticles (TAT-CPNPs) with strong NIR-II absorbance were used to label chemokine-receptor genetically modified MSCs, which were subsequently evaluated under intravital NIR-II OR-PAM regarding their targeting migratory ability. Based on the upregulation of chemokine (C-X-C motif) ligand 10 in the inflamed ears of contact hypersensitivity mice, MSCs with overexpression of corresponding receptor, chemokine (C-X-C motif) receptor 3 (Cxcr3) were successfully generated (MSCCxcr3). TAT-CPNPs labeling enabled NIR-II photoacoustic imaging to discern MSCCxcr3 covered by 1.2 cm of chicken breast tissue. Longitudinal OR-PAM imaging revealed enhanced inflammation-targeting migration of MSCCxcr3 over time attributed to Cxcr3 gene modification, which was further validated by histological analysis.
CONCLUSIONS: TAT-CPNPs-assisted NIR-II PA imaging is promising for monitoring distribution and extravasation kinetics of MSCs, which would greatly facilitate optimizing MSC-based therapy.

Obesity is a chronic process and could activate various inflammatory responses, which in turn aggravates obesity and related metabolic syndrome. Here we explored whether long-term inhibition of inflammation could successfully alleviate high-fat diet (HFD)-induced obesity.
We constructed stable overexpressing interleukin 10 (IL10) human umbilical cord-derived mesenchymal stromal cells (HUCMSCs) which repeatedly were applied to obesity mice with HFD feeding to obtain a long-term anti-inflammation based on the prominent anti-inflammation effects of IL10 and immunomodulatery effects of HUCMSCs. Then we monitored the features of obesity including body weight, serum ALT, AST, and lipids. In addition, glucose homeostasis was determined by glucose tolerance and insulin sensitivity tests. The infiltrated macrophages in adipose tissues and hepatic lipid accumulation were detected, and the expressions of adipogenesis and inflammatory genes in adipose tissues were examined by real-time (RT) PCR and western blot analysis.
Compared with HUCMSCs, IL10-HUCMSCs treatment had much better anti-obesity effects including body weight reduction, less hepatic lipids accumulation, lower amount and size of adipocyte, greater glucose tolerance, less systemic insulin resistance, and less adipose tissue inflammation in HFD feeding mice. Finally, IL10-HUCMSCs could decrease the activation of MAPK JNK of adipose tissue induced by HFD. The inhibition of MAPK JNK signal pathway by a small chemical molecule SP600125 in 3T3-L1 cells, a preadipocyte line, reduced the differentiation of adipocytes and lipid droplet accumulation.
A lasting anti-inflammation based on gene modified stem cell therapy is an effective strategy in preventing diet-induced obesity and obesity-related metabolic syndrome.