Abstract

Nowadays, it is an established concept that the capability to reach a specialised cell identity via differentiation, as in the case of multi- and pluripotent stem cells, is not only determined by biochemical factors, but that also physical aspects of the microenvironment play a key role; interpreted by the cell through a force-based signalling pathway called mechanotransduction. However, the intricate ties between the elements involved in mechanotransduction, such as the extracellular matrix, the glycocalyx, the cell membrane, Integrin adhesion complexes, Cadherin-mediated cell/cell adhesion, the cytoskeleton, and the nucleus, are still far from being understood in detail. Here we report what is currently known about these elements in general and their specific interplay in the context of multi- and pluripotent stem cells. We furthermore merge this overview to a more comprehensive picture, that aims to cover the whole mechanotransductive pathway from the cell/microenvironment interface to the regulation of the chromatin structure in the nucleus. Ultimately, with this review we outline the current picture of the interplay between mechanotransductive cues and epigenetic regulation and how these processes might contribute to stem cell dynamics and fate.

Introduction

One of the basic principles enabling multicellular life is the differentiation of stem cells (SCs), into specialised cells with a defined identity, shape, and function ( McBeath et al., 2004 ) ( Tewary et al., 2018 ). SCs are defined as cells that are clonogenic, which defines their capability of both, self-renewing and retaining multilineage differentiation potency. In vertebrates, the Zygote represents the earliest stem cell (totipotent) in ontogeny, from which originate the pluripotent stem cells (PSCs) of the inner cell mass of the blastocyst ( Dean et al., 2003 , Smith, 2017 ). Soon thereafter, PSCs continue to expand during embryo development becoming progressively committed in their cell fate and acquiring a more restricted potency ( Dean et al., 2003 , Osorno et al., 2012 , Smith, 2017 ). Even at the end of embryogenesis, when the organism is fully formed, and its organs are composed of functionally mature cells, some SCs are still present. These cells, which possess a more limited differentiating potential (multipotent), in turn, give rise to a progeny of precursor cells and, finally, to functionally mature cells. Some examples are represented by the hematopoietic SCs in the bone marrow, the intestinal SCs in the gut’s crypts, the epithelial SCs in the epidermis or the mesenchymal stem cells (MSCs) which play an important role in the maintenance and regeneration of bones and cartilage ( Barker, 2014 , Evans et al., 2013 , Guan et al., 2012 , Tewary et al., 2018 , Watt, 2002 , Weissman, 2000 ).

The inherent high level of plasticity characterising SCs is at the base of their capability to respond precisely to appropriate stimuli with differentiative behaviour. Understanding this essential principle of multicellular life; i.e., the regulation of cell identity and fate, is one of the most important fields of research in modern cell biology, primarily due to its impact on the development of new therapeutic approaches in regenerative medicine. Such knowledge can directly benefit stem cell bioengineering by leveraging the SC plasticity and control over SC behaviour for the application in tissue engineering, patient-specific disease modelling and cell therapies ( Tewary et al., 2018 ).

Conclusions

In recent years there has been a fascinating expansion of our knowledge about the interplay between mechanotransductive signalling and chromatin regulation, and how this impacts on multi- and pluripotent stem cell dynamics, which we try to highlight in this review.

However, what shapes the life of a cell and its identity, from the outside (biophysical and structural cues of the cellular microenvironment) and from the inside (nuclear and chromatin organisation) and how it is connected (mechanotransduction and epigenetics) are highly relevant biological issues that are yet far from being understood in detail. Starting from the stem cell/microenvironment interface, a much more detailed understanding of the nanoscale events in this interface is necessary to unravel 1) what the SC perceives of the biophysical nature and the 3D adhesion site configuration and 2) how the immanent nanoscale information is interpreted and converted, through force-based actions, into a remodelling at the level of the IACs, cell/cell adhesions, cytoskeleton and nucleus.

Abstract

Cancer vaccines based on tumor cell components have shown promising results in animal and clinical studies. The vaccine system contains abundant tumor antigen components, which can activate the immune system by antigens. However, their efficacy has been limited by the inability of antigens delivery, which are the core components of vaccines, further fail to be presented and activation of effective cells. Nanotechnology offers a novel platform to enhance the immunogenicity of tumor-associated antigens and deliver them to antigen-presenting cells (APCs) more efficiently. In addition, nanotreatment of tumor cells derivate active ingredients could also help improve the effectiveness of cancer vaccines. In this review, we summarize recent advances in the development of cancer vaccines by the combination of nanotechnology and tumor-based ingredients, including liposomes, polymeric nanoparticles, metallic nanoparticles, virus-like particles and tumor cells membrane, tumor lysate, and specific tumor antigens. These nanovaccines have been designed to increase antigen uptake, prolong antigen presentation, and modulate immune responses through codelivery of immunostimulatory agents. We also further discuss challenges and opportunities in the clinical translation of these nanovaccines.

Introduction

Cancer immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and attack cancer cells [1–3]. Among various immunotherapeutic approaches, cancer vaccines have attracted significant attention due to their potential to induce long-lasting and specific immune responses against tumor cells [4–7]. By comparison with surgery, it hardly produce large wounds, nor does it cause higher toxicity in normal tissues and drug tolerance like chemotherapy in the treatment of tumor. However, the clinical efficacy of cancer vaccines based on tumor cell components, such as peptides and proteins, is limited by their poor immunogenicity and inefficient delivery to antigen presentation cells (APCs). Although, many cancer vaccines were applied with the immune-stimulatory agents, such as the programmed cell death protein 1 (PD-1), CpG oligonucleotide, etc. The clinical response rates remain low, especially in the hypoimmunogenic tumors. As we all know, pancreatic cancer is a more difficult type for immunotherapy as a low immunogenic tumor. Therefore, there are few effective cancer vaccines that can actively promote the pancreatic cancer treatment. Meanwhile, limited by the specific tumor antigens, the development of cancer vaccines was extremely difficult.

The field of cancer vaccines has seen significant advancements in recent years, with numerous studies focusing on different aspects of vaccine development and application [8–12]. These advances have been facilitated by the exploration of various types of cancer vaccines, including those targeting viral antigens, neoantigens, and other tumor-specific antigens [13–16]. One approach in cancer vaccine research involves targeting shared antigens from viral infections linked to certain cancer types, such as Epstein–Barr virus and HPV. Studies have shown promising results with vaccines targeting viral antigens like Epstein–Barr nuclear antigen 1 and latent membrane proteins, as well as HPV-related antigens, demonstrating favorable antitumor efficacy and the potential to establish durable T cell memory in rapidly progressing HPV-positive tumors [17]. Another significant area of research is neoantigen cancer vaccines. Neoantigens, derived from nonsynonymous cell variants, are only expressed in tumor cells and can bypass thymus-negative selection, leading to robust neoantigen-specific T cell responses [14]. Advances in genomic and transcriptional profiling have made identifying putative neoantigens possible, although challenges remain in predicting which neoantigens can effectively induce neoantigen-specific T cell responses [18–20]. Cancer vaccines are being developed to stimulate antitumor immunity with tumor antigens delivered in various forms, such as cells, peptides, viruses, and nucleic acids [21–24]. These vaccines aim to overcome tumor heterogeneity and reverse the immunosuppressive microenvironment. Challenges in the field include single antigen targeting, weak immunogenicity, off-target effects, and impaired immune response [25–27]. Current research and reviews provide insights into the principle of action, components, classification, delivery methods, and progress of cancer vaccines, offering a broader perspective for future vaccine design.

Recent studies have shown that tumor antigens can be used for the design of cancer vaccines without the necessity to identify, parse, and reconstruct certain antigens [28–31]. A novel concept has been proposed that the whole antigen vaccine systems derived from tumor cells could be designed to conquer cancer treatments [32–34]. The tumor cells themselves are a huge antigen pool with countless tumor antigen epitopes, which can be used to activate antitumor immune response. Among them, more studies have focused on the application of tumor cell membrane as tumor antigens to stimulate APCs and further activate the antitumor immune response of T cells. In addition, the activation of T cells in immune response requires the involvement of costimulatory molecules. Some studies are based on this theoretical foundation, using genetic engineering to modify tumor cell membranes. By retaining antigen on the cell membrane and inducing the expression of costimulatory molecule CD80, T cells can be directly activated, thereby achieving antitumor immune response [35] (Figure 1). Of course, many studies combine tumor cell membranes that retain tumor antigens with other functional molecules to directly activate dendritic cells (DCs) for antigen presentation, leading to the activation of T cell immune response. These are two different approaches aimed at achieving the same goal [36–38]. A series of nanovaccines developed on this basis have been widely used in the treatment of different tumor cells and preclinical experiments.

Abstract

Liver fibrosis is an intrahepatic chronic damage repair response caused by various reasons such as alcoholic liver, fatty liver, viral hepatitis, autoimmune diseases, etc., and is closely related to the progression of liver disease. Currently, the mechanisms of liver fibrosis and its treatment are hot research topics in the field of liver disease remedy. Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential, which can ameliorate fibrosis through hepatic-directed differentiation, paracrine effects, and immunomodulation. However, the low inner-liver colonization rate, low survival rate, and short duration of intervention after stem cell transplantation have limited their wide clinical application. With the intensive research on liver fibrosis worldwide, it has been found that MSCs and MSCs-derived exosomes combined with drugs have shown better intervention efficiency than utilization of MSCs alone in many animal models of liver fibrosis. In this paper, we review the interventional effects and mechanisms of mesenchymal stem cells and their exosomes combined with drugs to alleviate hepatic fibrosis in vivo in animal models in recent years, which will provide new ideas to improve the efficacy of mesenchymal stem cells and their exosomes in treating hepatic fibrosis in the clinic.

Introduction

The liver is mainly composed of hepatocytes, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs) that perform a comprehensive range of hepatic functions, such as detoxification, bile acid synthesis, and participation in various metabolic processes. However, a variety of stimuli, such as alcohol, drugs, inflammation, or cholestasis, often cause damage to hepatocytes resulting in abnormal liver function and a series of pathophysiologic changes [1] . Liver fibrosis is a common intermediate pathological process of various chronic liver diseases, which is mainly manifested by diffuse excessive deposition of extracellular matrix, leading to abnormal changes in liver tissue structure and affecting the normal physiological functions of liver severely [2] . Clinically, if liver fibrosis is not effectively reversed or curbed, it will progress to irreversible cirrhosis, hepatocellular carcinoma, and other end-stage liver diseases, eventually, leading to the death of patients [3] . Therefore, finding effective therapeutic strategies to ameliorate liver fibrosis in patients is of great importance in preventing the development of end-stage liver diseases.

In the clinical setting, liver transplantation is mostly used for the treatment of end-stage liver diseases, but liver transplantation cannot be widely used due to the defects of extremely rare donors, high cost, rejection, etc [4] . Currently, mesenchymal stem cells for the treatment of liver disease have become a hot spot in the field of biomedicine. As the intermediate pathological process of end-stage liver disease, mesenchymal stem cells can effectively ameliorate hepatic fibrosis through hepatogenic differentiation, immunomodulation, paracrine effects, and other mechanisms [5] . However, it has been reported that MSCs transplanted in the body may have some disadvantages such as low inner-liver colonization and short duration of intervention, which affect their therapeutic efficacy [6] . Nowadays, an increasing number of researchers have demonstrated in animal models of liver fibrosis that the combination of MSCs with drugs can boost the therapeutic effect of MSCs in the treatment of liver fibrosis by promoting the homing of MSCs, differentiating them into functional hepatocyte-like cells, improving the microenvironment, inhibiting the activation of HSCs, and modulating the signaling pathway, and so on. In addition, MSCs-derived extracellular vesicles with the advantages of higher penetrability and lower carcinogenicity also effectively ameliorate liver fibrosis with ultimate safety. What’s more, nanoscale intracellular vesicles can also be used as carriers of natural drugs for drug delivery. This provides new ideas to solve the poor efficiency of MSCs in the treatment of liver fibrosis in the clinic.

Discussion and outlook

Liver fibrosis, as an intermediate pathological process from chronic liver disease to cirrhosis and hepatocellular carcinoma, has become a research hotspot for the treatment of liver diseases due to its reversible properties. However, there is no very effective means to treat liver fibrosis in clinical practice. MSCs, as a kind of pluripotent stem cells, have no ethical issues and wide sources compared with liver transplantation and hepatocyte transplantation, which have attracted much attention in animal experiments and clinical studies of cell transplantation for the treatment of liver fibrosis. Unfortunately, MSCs confront with the challenges such as in vivo microenvironment inadaptation and attenuation of inflammatory response ability after isolation and culture in vitro [45] , which ultimately leads to a low colonization rate and short duration of intervention after transplantation of MSCs into the liver [6] . Therefore, it has not been widely used in clinical practice.

Abstract

Oral cavity stem cells (OCSCs) have been the focus of intense scientific efforts due to their accessibility and stem cell properties. The present work aims to compare the different characteristics of 6 types of dental stem cells derived from the oral cavity: dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), bone marrow mesenchymal stem cells (BMSC), and gingival mesenchymal stem cells (GMSC). Using immunofluorescence and real-time polymerase chain reaction techniques, we analysed the cells for stem cell, differentiation, adhesion, and extracellular matrix markers; the ability to proliferate in vitro; and multilineage differentiation potential. Markers such as vimentin, CD44, alkaline phosphatase, CD146, CD271, CD49f, Oct 3/4, Sox 9, FGF7, nestin, and BMP4 showed significant differences in expression levels, highlighting the heterogeneity and unique characteristics of each cell type. At the same time, we confirmed that all cell types successfully differentiated into osteogenic, chondrogenic, or adipose lineages, with different readiness. In conclusion, our study reveals the distinct properties and potential applications of various dental-derived stem cells. These findings contribute to a deeper understanding of OCSCs and their significance in future clinical applications.

Introduction

Bone marrow mesenchymal stem cells (BMSCs) exhibit high proliferation ability and multilineage differentiation potential. They were the first mesenchymal stem cells (MSCs) to be described, isolated from adults’ bone marrow aspirate.1 They have been extensively researched in human and animal model systems using in vivo and in vitro cell cultures. Further, they have bridged the divide and are integrated into various trials for clinical applications, with mixed success.2,3 BMSCs are not easily accessible, and an invasive procedure is required. Therefore, further research in the field, aiming at identifying alternative stem cell sources, has led to the discovery of oral cavity stem cells (OCSCs).

Currently, several different types of OCSCs are well known, including dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), dental follicle stem cells (DFSC), and gingival mesenchymal stem cells (GMSC).

Conclusions

This analysis of oral cavity–derived stem cells has exposed distinct and specific expression patterns of surface markers, ECM components, ECM remodelling enzymes, collagen genes, integrins, and differentiation potential. These findings may provide insights into the functional properties of these cell populations. Оur study aims to uncover the nuanced characteristics specific to each distinct cell type. Through experimentation and analysis, we anticipate to not only understand their individual functionalities but also gain deeper insights into their collective behaviour. Understanding both their shared characteristics and distinct attributes is an important step in using their regenerative potential in various tissue repair and regeneration contexts, thereby advancing the field of regenerative medicine and tissue engineering. By contributing meaningfully to the advancement of knowledge in regenerative medicine and tissue engineering, we aspire to pave the way for transformative breakthroughs in health care.

Abstract

Stress can lead to various health problems. Exposure to stress is linked to several diseases including cancer, hypertension, diabetes, mental disorders, and heart attacks. Stress stimulates several pathways that produce free radicals, which increases oxidative stress. This results in functional and structural damage to organs, such as the brain, which is highly sensitive to oxidative stress Vitamin E is a naturally occurring potent antioxidant used for various purposes. The main purpose of the current study was to evaluate how vitamin E protects the brain and to what extent it affects antioxidant levels in rats subjected to two hours per day of immobilization stress, the form of stress with the strongest effect. The rats were immobilized by folding their limbs in and wrapping them in netting to prevent movement, while allowing their tails to be extended. The rats were then hung upside down. The effect of vitamin E was tested by intraperitoneally injecting rats with 40 mg/kg of vitamin E daily. Oxidative stress parameters were determined at the completion of the experiment. A dramatic decrease in malondialdehyde (MDA) levels and an increase in catalase (CAT), including glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), has been shown by vitamin E in the brain. The effects of vitamin E were significantly higher in the acute and chronic stress groups than in the control group. Vitamin E can decrease oxidative stress in stressed rats, indicating that it exerts therapeutic and protective effects owing to its antioxidant properties.

Introduction

Stress is a normal factor in everyday vernacular and a fundamental aspect of the human condition. Millions of missed working days are attributed to stress, which is acknowledged globally as the main contributor to chronic illnesses (e.g., Am. Psychol. Assoc. 2019, UK Health Saf. Executive 2019). It has been reported that stress affects every aspect of life. Furthermore, stress is known to have both direct and indirect negative effects on health via changes in neuroendocrine and autonomic functions (O’Connor et al., 2021).

Activation of the HPA axis, which causes an increase in corticosterone levels in the brain, is a key mechanism linked to stress-induced behavioral problems. Rapid depolarization caused by elevated corticosterone levels causes glutamate to be released into limbic and cortical areas. An increase in metabolic rate and mitochondrial dysfunction may result from glutamate overproduction. An increase in the metabolic rate results in a conflict between the generation of ROS and antioxidant system activity, which causes the generation of more free radicals. Nucleic acids, proteins, and lipids are just a few cellular components that oxidatively damage these free radical species oxidatively damage (Samarghandian et al., 2017).

Free radicals are associated with oxidative stress. Free radicals are highly reactive with unpaired electrons and atoms. An increase in the levels of antioxidants and free radicals can lead to oxidative stress.

Conclusion

Levels of the antioxidants GSH, SOD, and CAT in the brain were significantly higher in the vitamin E group than in the acute and chronic stress groups (controls). Vitamin E also significantly reduced MDA levels and oxidative stress in stressed rats. These findings suggest that vitamin E can prevent and relieve stress.

Abstract

Bacteria extracellular vesicles (BEVs), characterized as the lipid bilayer membrane-surrounded nanoparticles filled with molecular cargo from parent cells, play fundamental roles in the bacteria growth and pathogenesis, as well as facilitating essential interaction between bacteria and host systems. Notably, benefiting from their unique biological functions, BEVs hold great promise as novel nanopharmaceuticals for diverse biomedical potential, attracting significant interest from both industry and academia. Typically, BEVs are evaluated as promising drug delivery platforms, on account of their intrinsic cell-targeting capability, ease of versatile cargo engineering, and capability to penetrate physiological barriers. Moreover, attributing to considerable intrinsic immunogenicity, BEVs are able to interact with the host immune system to boost immunotherapy as the novel nanovaccine against a wide range of diseases. Towards these significant directions, in this review, we elucidate the nature of BEVs and their role in activating host immune response for a better understanding of BEV-based nanopharmaceuticals’ development. Additionally, we also systematically summarize recent advances in BEVs for achieving the target delivery of genetic material, therapeutic agents, and functional materials. Furthermore, vaccination strategies using BEVs are carefully covered, illustrating their flexible therapeutic potential in combating bacterial infections, viral infections, and cancer. Finally, the current hurdles and further outlook of these BEV-based nanopharmaceuticals will also be provided.

Introduction

Vesiculation is a crucial and fundamental process across all kinds of species to produce the extracellular vesicles that serve as essential mediators of basic physiological events [1]. These nanovesicles are filled with molecular patterns originated from parent cells, including metabolites, nucleic acids, proteins, and signaling molecules, to maintain cell growth and homeostasis [2, 3]. Biological regulation by extracellular vesicles is widespread across both prokaryotes and eukaryotes [4]. Notably, bacteria, as one of the major inhabitants in the human body, establish intricate relationships with host health and disease, wherein bacterial extracellular vesicles (BEVs) are indispensably involved in these processes [5, 6]. With the increasing and deep understanding of their biological function, BEVs are found to influence various cellular behaviors, including the transport of genetic information, phage infection, mediation of metabolism, as well as interaction between bacteria-bacteria and bacteria-host [7, 8].

Particularly, BEVs are characterized as nanosized nanoparticles, surrounded by lipid-bilayer membranes, ranging from 20 to 400 nm in diameter [7]. In account of the diversity of bacterial types and biogenesis mechanisms, the BEVs could carry versatile cargos inherited from mother cells, such as lipopolysaccharides (LPS), endotoxins, genetic information, cytosolic and membrane proteins [9]. By thanking the unique structure and intrinsic properties of BEVs, these naturally occurring nanovesicles attract the research interest to be developed as novel nanopharmaceuticals, prompting further exploration of their biomedical applications [10, 11]. Generally, BEVs are widely evaluated as biotherapeutics in different forms. Firstly, these nanovesicles with hollow structures could serve as novel drug delivery platforms, facilitating the transport of diverse bioactive molecules and therapeutic cargo to the recipient cells at the lesion site [12]. Thanks to the stability of naturally-occurring membrane structure, the BEVs-based drug delivery platform could carry the therapeutic genetic tools (e.g. siRNA, CRISPR-Cas9, etc.), protecting them from enzymatic degradation or hydrolysis in the complex physiological environment [13, 14]. Besides, benefiting from the ease of modification, BEVs-based drug delivery platforms could efficiently load the small molecular therapeutics [14], or directly produce the synthetic cargo (e.g. antigens, enzymes, therapeutic proteins, etc.) on the BEVs by editing the desired gene in parent bacteria. The BEVs-based drug carriers are also featured in their capability for targeting delivery toward the disease area to enhance drug accumulation and availability [15]. Moreover, the BEVs drug delivery platform can integrate with functional materials, to facilitate combinational therapy (e.g. photodynamic therapy, photothermal therapy, etc.) and maximize the synergistic therapeutic efficiency [16].

Conclusion and further perspective

In this review, we comprehensively summarize the development of BEV-based nanopharmaceuticals to facilitate disparate biomedical applications in recent years. Amongst the unique advantages and functions of BEVs, we demonstrated the tremendous potential of applying these naturally occurring nanovesicles to establish a myriad of innovative therapeutic strategies for new-generation pharmaceuticals evolution, especially in the versatile bioactive cargo delivery and powerful vaccination approaches.

Taking the unique merits of nanovesicles, the structural stability, ease of cargo loading, promising penetration across physiological barriers, and specific targeting capabilities endow the BEVs application to be beneficial in delivery for a wide range of therapeutics. Particularly, the naturally occurring membrane structure of BEVs enables targeting delivery of therapeutic genetic tools (e.g., siRNA, DNA, CRISPR-Cas9, etc.) in the physiological, preserving stability and bioactivity, thus enhancing gene therapy. Leveraging the ease of genetic modification in parent bacteria, protein cargo, such as enzymes and antigens, can also be directly expressed within BEVs, optimizing loading efficiency compared to conventional delivery platforms. Furthermore, advancements in nanotechnology and material science have witnessed the integration of functional materials with BEV delivery platforms to achieve combinational therapy, thereby further improving the synergistic therapeutic efficacy.

Introduction

Tumor microenvironment (TME) is a complex network of cancer cells and various other cellular and noncellular components. Microorganisms such as bacteria, viruses, fungi, phages, and protozoa naturally occur in the TME, modulating the metabolic composition and promoting or inhibiting tumorigenesis. In the last decades, a growing interest has emerged in microorganisms in the TME and their potential applications for cancer therapy 1, 2.

Bacterial and viral infections have been long associated with cancer development and have been used in cancer therapy decades ago. Bacteria have various effects on cancer cells through different modes of action, for instance, depending on the strain, tissue, and environment 1, 2. Viruses also naturally occur in the TME, and some strains promote cancer growth, such as the human papillomavirus (HPV) [3], while others have oncolytic activity, such as the influenza A virus (IAV) [4]. The different mechanisms through which bacteria and viruses affect tumor proliferation and metastasis include altering immune responses 5, 6, 7•, secreting cytotoxic molecules such as formate or colibactine 8••, 9, and alterations of metabolic and signaling pathways 8••, 10. The natural abilities of microorganisms to colonize and alter the TME can also be used for cancer detection and therapy with the help of engineered bacteria and viruses 2, 11, 12. However, the metabolic interactions among viruses, bacteria, cancer cells, and TME are not well understood. Metabolites function as signaling molecules, and we are just beginning to understand the functional role of small molecules within the TME 13, 14, 15. For instance, the immunometabolite itaconate has antimicrobial properties but may also affect tumor progression by altering cancer cell metabolism or the composition of the TME 16, 17•, 18, 19. Thus, further research is needed to identify the key players within the TME that affect immune responses and tumor progression.

Approaches in virotherapy

Virotherapy aims to transform the ‘cold’ immunosuppressive TME, characterized by high levels of TAMs, T-regulatory cells (Tregs), MDSCs, and activated M2-like macrophages, into a ‘hot’ immunoreactive TME (Figure 3). This transformation involves the recruitment of, for instance, NKs, DCs, and M1-like macrophages (Figure 3). OV administration targets different approaches in cancer therapies, such as making the virus dependent on specific genes within the cancer host cell to enable selective replication in malignant cells, followed by direct lysis. Furthermore, it is applied to deliver specific antibodies to inhibit tumor growth [45]. For instance, the recombinant human type-5 adenovirus (Ad5) selectively replicates in tumor cells with p53-defective influencing cancer cell growth [46]. OVs may also indirectly affect the TME and tumor growth by inducing the release of cytokines, such as interferon (IFN), damage-associated molecular patterns (DAMPs), high mobility group box 1 protein (HMGB1), or pathogen-associated molecular patterns (PAMPs) 41, 47, leading to further recruiting and activation of the innate and adaptive immune system, including DCs (Figure 3). DCs play an elementary role in connecting both immune systems and are infrequently present in the cold TME. These findings highlight various targets that can be used to modulate the immune response in the TME through OVs, aiming to constrain tumor growth and increase patient outcomes.

Conclusion

Bacterial and viral infections play a vital role in altering the composition of the TME, thus influencing its potential as pro- or anti-tumorigenic. Many bacteria and viruses influence TME, for instance, by secreting signal molecules, altering specific immune responses, causing DNA damage, or inducing metabolic rewiring. While promising approaches utilizing bacteria and viruses for cancer detection and therapy exist, how infections influence metabolism to promote either pro- or antitumor properties is still not well understood. Engineered bacteria and viruses could be optimized to work effectively against cancer with potentially less off-target effects compared with conventional therapies. For example, altering levels of cytokines or metabolites such as itaconate or arginine in the TME may promote an anticancer immune response, either alone or in combination with existing treatments. Expanding our current knowledge of the complex interaction of microorganisms and cancer cells will provide us with effective ways to develop new treatment strategies.

Abstract

Several microRNAs (miRNAs), including miR-23 and miR-27a have been reportedly involved in regulating myelination in the central nervous system. Although miR-23 and miR-27a form clusters in vivo and the clustered miRNAs are known to perform complementary functions, the role of these miRNA clusters in myelination has not been studied. To investigate the role of miR-23-27-24 clusters in myelination, we generated miR-23-27-24 cluster knockout mice and evaluated myelination in the brain and spinal cord. Our results showed that 10-week-old knockout mice had reduced motor function in the hanging wire test compared to the wild-type mice. At 4 weeks, 10 weeks, and 12 months of age, knockout mice showed reduced myelination compared to wild-type mice. The expression levels of myelin basic protein and myelin proteolipid protein were also significantly lower in the knockout mice compared to the wild-type mice. Although differentiation of oligodendrocyte progenitor cells to oligodendrocytes was not inhibited in the knockout mice, the percentage of oligodendrocytes expressing myelin basic protein was significantly lower in 4-week-old knockout mice than that in wild-type mice. Proteome analysis and western blotting showed increased expression of leucine-zipper-like transcription regulator 1 (LZTR1) and decreased expression of R-RAS and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) in the knockout mice. In summary, loss of miR-23-27-24 clusters reduces myelination and compromises motor functions in mice. Further, LZTR1, which regulates R-RAS upstream of the ERK1/2 pathway, a signal that promotes myelination, has been identified as a novel target of the miR-23-27-24 cluster in this study.

Introduction

In the central nervous system (CNS), myelin, produced by oligodendrocytes, supports axonal metabolism and allows for rapid transmission of action potentials along axons [1–3]. In demyelinating conditions such as multiple sclerosis or spinal cord injury, myelin is lost and axons degenerate, resulting in permanent loss of function. Remyelination in these demyelinating conditions remains a challenge. Developmental myelination and remyelination have the common goal of attaching myelin sheaths to axons [4]. In addition, there is a common mechanism underlying developmental myelination and remyelination, and remyelination is considered as “rerunning” of myelination [4]. Therefore, understanding the mechanism underlying myelination will help in developing novel strategies for remyelination in various disease conditions. Normal myelination is a multistep process in which oligodendrocyte differentiation and initiation of myelination are tightly regulated [5]. Previous studies have shown that several genes, transcription factors, and pathways are involved in oligodendrocyte progenitor cell (OPC) proliferation and oligodendrocyte differentiation, maturation, and myelination [6–8]. Furthermore, recent studies have shown that microribonucleic acids (miRNAs) play important roles in regulating myelination [9–15].

Results

3.1. Expression of the miR-23-27-24 Cluster in the CNS
KO mice were slightly smaller than wild-type mice but were born and grew without morphological abnormalities (Figure 1(a)). Compared to 10-week-old wild-type mice, the expression of all miRNAs in the miR-23-27-24 cluster was significantly lower in the KO mice, both in the spinal cord and brain () (Figures 1(b) and 1(c) and Table 1).

Next, we compared the expression of the miR-23-27-24 cluster in the spinal cord of mice at different ages (4 weeks, 10 weeks, and 12 months of age). For all miRNAs in the miR-23-27-24 cluster, the expression levels in 10- and 12- week-old wild-type mice were significantly higher than those in 4-week-old wild-type mice (p < 0:001) (Figure 2). The expression of miR-23a in 12-month-old wild-type mice was significantly lower than that in 10-week-old wild-type mice (p < 0:001) (Figure 2(a)), but there were no significant differences in the expression of other miRNAs (Figures 2(b)–2(e)). The expression of all miRNAs in KO mice was significantly lower than that in wild-type mice at all ages (Table 2).

Abstract

Objective. Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Method. Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. Result. The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Conclusion. Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.

Introduction

Huntington disease (HD) is a neurodegenerative disorder of the central nervous system resulting from a dominantly inherited CAG trinucleotide repeat expansion in exon 1 of the huntingtin (HTT) gene that encodes the Huntingtin protein [1]. Pathological changes are characterized by a general shrinkage of the brain and distinct degeneration of the striatum (caudate nucleus and putamen) [2]. Although HD prevalence is only 4-10 individuals per 100,000, it seriously affects the life quality of the patients in many ways, including movement, cognition, and psychological condition, as well as other functional disabilities [3]. Motor defects typically include chorea and loss of coordination. Psychiatric symptoms, such as depression, psychosis, and obsessive-compulsive disorder, are common in HD [4]. Death typically occurs about 20 years after symptom onset [1].

Current therapies for HD are directed at symptom relief, as there are no any disease-modifying therapies. Therapeutic attempts based on pathogenic mechanisms including gene silencing [5], antiapoptosis/caspase inhibition [6], transglutaminase inhibition [7], antioxidative stress [8], upregulating autophagy [9], and physical exercise [10] have been investigated; unfortunately, none of these have met the criteria for clinical translation. For instance, silencing the expression of the mutant HTT gene is attractive; however, allele specificity and off-target effects are not fully resolved. Treatment of mouse models with antioxidants was considered to be beneficial [8], whereas trials of creatine for symptomatic patients were disappointing [11].

Conclusion

This meta-analysis reveals MSC therapy attenuates morphological changes and improves motor function in HD models, but cognition was not influenced. Furthermore, the weight of male, but not female, HD rodents may be benefited from MSC treatment. These results support MSC-based strategies becoming an alternative treatment for HD; however, before MSC therapies can be translated into clinical practice, their safety, efficacy, and mechanism must be established with more preclinical and clinical studies.

SUMMARY

The coordination of chloroplast and nuclear genome status is critical for plant cell function. Here, we report that Arabidopsis CHLOROPLAST AND NUCLEUS DUAL-LOCALIZED PROTEIN 1 (CND1) maintains genome stability in the chloroplast and the nucleus. CND1 localizes to both compartments, and complete loss of CND1 results in embryo lethality. Partial loss of CND1 disturbs nuclear cell-cycle progression and photosynthetic activity. CND1 binds to nuclear pre-replication complexes and DNA replication origins and regulates nuclear genome stability. In chloroplasts, CND1 interacts with and facilitates binding of the regulator of chloroplast genome stability WHY1 to chloroplast DNA. The defects in nuclear cell-cycle progression and photosynthesis of cnd1 mutants are respectively rescued by compartment-restricted CND1 localization. Light promotes the association of CND1 with HSP90 and its import into chloroplasts. This study provides a paradigm of the convergence of genome status across organelles to coordinately regulate cell cycle to control plant growth and development.

INTRODUCTION

Chloroplasts in plants and algae have an endosymbiotic origin: over 2 billion years ago, a photosynthetic cyanobacterium-like organism was stably engulfed by a heterotrophic unicellular eukaryote.1 This initial event was followed over the course of evolution by massive gene transfer from the green prokaryote genome to the host-cell nucleus, leading to the complete dependency of the endosymbiont on its surrounding cells and the generation of a novel type of organism, photosynthetic eukaryotes.2 The development of higher plants requires the tight coordination of chloroplast development from undifferentiated proplastids in meristematic cells or from etioplasts, which differentiate from proplastids when seeds germinate in darkness. In addition to being the site of photosynthesis in leaf mesophyll cells, chloroplasts house essential metabolic pathways and contribute to storage and pigmentation in specialized cells.3

Eukaryote genomes are organized into multiple chromosomes whose replication initiates from numerous origins and is strictly regulated.4 To maintain genome integrity and stability, genomic DNA must be replicated completely and accurately, but also only once during the S phase of the cell cycle. The formation of a pre-replication complex (pre-RC) is required for the subsequent ordered assembly of replication factors such as the Origin Recognition Complex (Orc), Cell Division Cycle6 (Cdc6) in budding yeast (Saccharomyces cerevisiae) or its ortholog CDC18 in fission yeast (Schizosaccharomyces pombe), chromatin licensing and DNA replication factor 1 (CDT1), and Mini Chromosome Maintenance (MCM) proteins (MCM2–7).5 MCM proteins are essential replication initiation factors that were originally identified as proteins required for minichromosome maintenance, plasmid replication, or cell-cycle progression in yeast.6 Indeed, cell-cycle checkpoints are crucial for genome integrity, as they stop cell-cycle progression upon DNA damage until repairs have been completed. Such mechanisms are particularly important in plants, which endure daily exposure to DNA-damaging agents such as light and reactive oxygen species (ROS).7

RESULTS

CND1 is a nucleus and chloroplast dual-localized protein
To understand the functional coordination between the chloroplast and nucleus, we systematically screened proteins with predicted chloroplast and nucleus dual localization by combining bioinformatics and proteomics analyses. We focus here on one such putative chloroplast and nucleus dual-localized protein, encoded by the nuclear gene At1g32730 that we named CHLOROPLAST AND NUCLEUS DUAL-LOCALIZED PROTEIN 1 (CND1). CND1 contains four predicted functional domains: two targeting domains, consisting of an N-terminal chloroplast transit peptide (cTP) (amino acids [aa] 1–65) based on TargetP prediction27 and a nuclear localization sequence (NLS) containing the amino acid motif KRKK28; a zinc finger domain (ZF); and the domain of unknown function DUF702 (Figure 1A ).

Summary

β-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-β-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in β-arrestin interactions with both receptors and the lipid bilayer. Unexpectedly, our results reveal that β-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, they indicate that, following receptor interaction, the plasma membrane stabilizes β-arrestin in a longer-lived, membrane-bound state, allowing it to diffuse to clathrin-coated pits separately from the activating receptor. These results expand our current understanding of β-arrestin function at the plasma membrane, revealing a critical role for β-arrestin preassociation with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.

Introduction

G protein-coupled receptors (GPCRs) are implicated in virtually every physiological process and are major drug targets.1,2 Following agonist-mediated GPCR activation and phosphorylation by G protein-coupled-receptor kinases (GRKs), β-arrestins translocate from the cytosol to bind agonist-occupied, phosphorylated receptors on the plasma membrane. There are four arrestins—two visual arrestins (also known as arrestin 1 and 4), β-arrestin 1 (βArr1) (arrestin 2), and β-arrestin 2 (βArr2) (arrestin 3).

By interacting with the receptor core, β-arrestins mediate rapid signal desensitization.3 In addition, β-arrestins trigger receptor internalization via interaction with the adaptor protein 2 (AP2) and clathrin heavy chain.4 Moreover, β-arrestins have been proposed to mediate “non-classical” G protein-independent effects,5 providing a mechanism for “biased” signaling.6 This diversity of functions has been linked to multiple conformations in receptor-arrestin complexes revealed by structural and biophysical studies with purified proteins.7,8,9,10,11,12,13,14,15,16,17 Furthermore, recent findings of prolonged β-arrestin activation18,19,20 suggest that β-arrestin signaling might be more complex than previously thought. However, how this complexity operates on the plasma membrane of living cells remains largely unknown.

Here, we combined an innovative multicolor single-molecule microscopy approach21,22 with molecular dynamics (MD) simulations to dissect the sequence of events in receptor-β-arrestin interactions at the plasma membrane of living cells with ∼20 nm spatial and 30 ms temporal resolution.21,22 Our results reveal that β-arrestin binds directly to the lipid bilayer, allowing it to transiently interact with receptors via lateral diffusion, and reaches clathrin-coated pits (CCPs) separately from the activating receptor.

Results

Single-molecule imaging reveals spontaneous membrane translocation and lateral diffusion of βArr2
As a main model, we chose βArr2 and the β2-adrenergic receptor (β2AR), a prototypical family-A GPCR that regulates numerous physiological processes.23,24 To investigate the behavior of individual βArr2 and β2AR molecules on the plasma membrane of living cells, we labeled them with two distinct organic fluorophores via fusion of Halo25 and SNAP26 tags to their C and N termini, respectively (Figure 1A). Both constructs were transiently expressed at low physiological levels in Chinese hamster ovary (CHO) cells, which have no detectable β1AR/β2AR.27 Both βArr2-Halo and SNAP-β2AR constructs are functional; βArr2-Halo binds receptors and mediates receptor internalization to a similar extent as wild-type (WT) βArr2, and co-localizes with internalized receptors in endosomes (Figures S1A–S1D; see STAR Methods for details). CHO cells were then labeled with saturating concentrations of both organic fluorophores (Figure S1E) and were simultaneously imaged by fast multicolor total internal reflection fluorescence (TIRF) microscopy combined with single-particle tracking22 (Figure 1B; Videos S1 and S2); unspecific labeling was <1% (Figure S1F). We additionally visualized CCPs by co-transfection of GFP-labeled clathrin light chain. Data were acquired both under basal conditions and after early (2–7 min) and late (8–15 min) stimulation with the β-adrenergic full agonist isoproterenol (Iso). An excess of 5.8 million individual molecular trajectories were acquired and analyzed in this study. Numbers of trajectories and particle densities in the analyzed groups are given in Table S1.

Abstract

Introduction

Wastewater in area of focus

Nanotechnology in water purifcation

Nano‑adsorption

Microbial agent

Nanocomposites

Types of nanocomposites

Synthesis modes for nanocomposites

Graphene oxide‑based composites as a disinfectant

Zinc oxide nanocomposites as disinfectant

Copper oxide nanocomposites

Silver/silver oxide nanocomposites

Titanium oxide nanocomposites

Discussion

Conclusion

References

Abstract

     Water is crucial for the existence of life. The world, however, is facing a global water crisis. There are variety of microorganisms, gases and other toxins responsible for water contamination. Various types of nanomaterials exist that have enormous potential to treat contaminated water (water containing metal toxins or specific organic or inorganic impurities) due to their unique properties such as a high surface area and their ability to work effectively even at low concentrations. In recent years, scientists have been giving considerable attention to the application of nanocomposites for water purification, wastewater treatment, microorganism elimination, chemical contaminants, heavy metals removal and so forth. The incorporation of different nanofillers such as carbon nanotubes, graphene oxide, 2D materials, zinc oxide, titanium dioxide, copper and silver nanoparticles into polymeric materials has facilitated important advances, such as suppressing the accumulation of pollutants and foulants, improving the hydrophilicity, increasing the efficiency and improving the mechanical properties. This review discusses leading advances in the development of nanocomposites for antimicrobial and wastewater treatment with the aim of providing an improved understanding of nanocomposites and their applications in antimicrobial and wastewater treatment.

Introduction

     Water is a basic requirement for human life. However, we are far from meeting global requirements for clean water, and this issue will continue to grow over the time (Hillie and Hlophe 2007; Elwakeel et al. 2020b). The demand of clean drinking water is rising as a result of the deterioration of water quality, global climate change and population growth (Tchobanoglous et al. 1991; Elwakeel et al. 2020d). Emissions of organic dyes and heavy metal ions from the paper, leather and textile industries are a serious problem, as they are potentially mutagenic and carcinogenic. To meet environmental requirements, wastewater contaminated with these organic and inorganic species need to be treated before being discharged (Santhosh et al. 2016; Elwakeel et al. 2021). Heavy metals are widely used in various industries for many purposes, including mining and pigment production. Synthetic dyes are also an important type of pollutant, and their sources for water contamination include the textile, pulp and paper, tinting, printing, painting and tanning industries. The removal of dye from such wastewater is a challenging task, as pigments and synthetic dyes are biodegradation-resistant and remain in the environment for a long time. The destruction and handling of organic dyes is therefore an important issue, and a cost-efective method for removing dye substances from wastewater has been developed (Santhosh et al. 2016; Elwakeel et al. 2018).

Conclusion

     This paper explores the existing nanocomposites used to extract heavy metal ions and dyes from wastewater as efective adsorbents. This article addressed recent developments in nanomaterials as economical and environmentally sustainable water purifcation adsorbents. This review highlights fve commonly used nanomaterials/nanoparticles that are used in most existing nanocomposites. In this review, we concluded that TiO2-based nanocomposites have been used for photodegradation activity by most of the researchers in the literature. Silver-based nanocomposites are mostly used for antimicrobial activity. Silver and GO-based nanocomposites were used for the removal of green dye, anionic dye and Cu(II). Copper-based nanocomposites are mostly used for adsorption and photodegradation activity. Zinc oxide nanocomposites are used for adsorption, antimicrobial and photodegradation activity. Finally, we concluded that GO also greatly contributes to the improvement of other materials’ efciency. Further, much needs to be done to control the two-dimensional GO sheets for advanced technologies in the future. There are many challenges and obstacles associated with handling wastewater, and many precautions are required to prevent environmental and health problems. Therefore, new modern wastewater treatment equipment should be versatile, low-cost and commercially efective.