Human brain organoid: trends, evolution, and remaining challenges.

Advanced brain organoids provide promising platforms for deciphering the cellular and molecular processes of human neural development and diseases. Although various studies and reviews have described developments and advancements in brain organoids, few studies have comprehensively summarized and analyzed the global trends in this area of neuroscience. To identify and further facilitate the development of cerebral organoids, we utilized bibliometrics and visualization methods to analyze the global trends and evolution of brain organoids in the last 10 years. First, annual publications, countries/regions, organizations, journals, authors, co-citations, and keywords relating to brain organoids were identified. The hotspots in this field were also systematically identified. Subsequently, current applications for brain organoids in neuroscience, including human neural development, neural disorders, infectious diseases, regenerative medicine, drug discovery, and toxicity assessment studies, are comprehensively discussed. Towards that end, several considerations regarding the current challenges in brain organoid research and future strategies to advance neuroscience will be presented to further promote their application in neurological research.

Engineering the Physical Microenvironment into Neural Organoids for Neurogenesis and Neurodevelopment.

Understanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell-derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting-edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid-based research and neuroscience.

Role of mass effect on neuronal iron deposition after intracerebral hemorrhage.

Mass effect after intracerebral hemorrhage (ICH) not only mechanically induces the brain damage, but also influences the progress of secondary brain damage. However, the influence of mass effect on the iron overload after ICH is still unclear. Here, a fixed volume of ferrous chloride solution and different volumes of poly(N-isopropylacrylamide) (PNIPAM) hydrogel were co-injected into the right basal ganglia of rats to establish the ICH model with certain degree of iron deposition but different degrees of mass effect. We found that mass effect significantly increased the iron deposition on neuronal cells at 6 h after ICH in a volume-dependent manner. Furthermore, the upregulation of Piezo-2, divalent metal transporter 1 (DMT1), transferrin receptor (TfR), and ferroptosis expressions were noted as the increase of mass effect. In addition, the pERK1/2 inhibitor PD98059 treated ICH rats reversed the upregulation of iron uptake protein and ferroptosis. Our findings revealed the relationship between mass effect and the iron uptake and ferroptosis, which are benefit to understand the brain damage process after ICH.

Development trends of human organoid-based COVID-19 research based on bibliometric analysis.

Coronavirus disease 2019 (COVID-19), a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a catastrophic threat to human health worldwide. Human stem cell-derived organoids serve as a promising platform for exploring SARS-CoV-2 infection. Several review articles have summarized the application of human organoids in COVID-19, but the research status and development trend of this field have seldom been systematically and comprehensively studied. In this review, we use bibliometric analysis method to identify the characteristics of organoid-based COVID-19 research. First, an annual trend of publications and citations, the most contributing countries or regions and organizations, co-citation analysis of references and sources and research hotspots are determined. Next, systematical summaries of organoid applications in investigating the pathology of SARS-CoV-2 infection, vaccine development and drug discovery, are provided. Lastly, the current challenges and future considerations of this field are discussed. The present study will provide an objective angle to identify the current trend and give novel insights for directing the future development of human organoid applications in SARS-CoV-2 infection.

Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice.

Human serum albumin (HSA) is a highly water-soluble protein with 67% alpha-helix content and three distinct domains (I, II, and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (rQTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine)-mediated pathways. The designed HSArQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, ii) receptor-mediated cellular transport, iii) tumor cell targeting, and iv) antitumor efficiency compare to denatured HSA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and antitumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.

Plastic or plastic-free life: From formation to removal.

Microplastics (MPs) and nanoplastics (NPs) have caused global environmental concerns due to their ubiquitous existence in our surrounding environment and the potential threats posed to the ecosystem and human health. This review aims to extend current knowledge on the formation and degradation of MPs and NPs. The paper presents the potential sources of MPs and NPs including plastic containers, textiles, cosmetics, personal care products, COVID-19 wastes, and other plastic products. Once in the natural environment, the fragmentation and degradation of plastic wastes are thought to be initiated by physical, chemical, and biological factors. The corresponding degradation mechanism will be presented in the present review. Given the plastic life and environment, humans are inevitably exposed to MPs and NPs through ingestion, inhalation, and dermal contact. The potential risks MPs/NPs pose to humans will be also discussed in our study. Currently, the relevance of MP/NP exposure to human health outcomes is still controversial and not yet fully understood. Deciphering the translocation and degradation of plastics in the human body will be helpful to reveal their potential organotoxicity. In this case, available approaches to alleviate MP/NP pollution and advanced strategies to reduce MP/NP toxicity in humans are recommended to build a plastic-free life.

Unraveling the potential human health risks from used disposable face mask-derived micro/nanoplastics during the COVID-19 pandemic scenario: A critical review.

With the global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), disposable face masks (DFMs) have caused negative environmental impacts. DFMs will release microplastics (MPs) and nanoplastics (NPs) during environmental degradation. However, few studies reveal the release process of MPs/NPs from masks in the natural environment. This review presents the current knowledge on the abiotic and biotic degradation of DFMs. Though MPs and NPs have raised serious concerns about their potentially detrimental effects on human health, little attention was paid to their impacts on human health from DFM-derived MPs and NPs. The potential toxicity of mask-derived MPs/NPs, such as gastrointestinal toxicity, pneumotoxicity, neurotoxicity, hepatotoxicity, reproductive and transgenerational toxicity, and the underlying mechanism will be discussed in the present study. MPs/NPs serve as carriers of toxic chemicals and pathogens, leading to their bioaccumulation and adverse effects of biomagnification by food chains. Given human experiments are facing ethical issues and animal studies cannot completely reveal human characteristics, advanced human organoids will provide promising models for MP/NP risk assessment. Moreover, in-depth investigations are required to identify the release of MPs/NPs from discarded face masks and characterize their transportation through the food chains. More importantly, innovative approaches and eco-friendly strategies are urgently demanded to reduce DFM-derived MP/NP pollution.

Rational Design of High-Performance Keratin-Based Hemostatic Agents.

Keratins are considered ideal candidates as hemostatic agents, but the development lags far behind their potentials due to the poorly understood hemostatic mechanism and structure-function relations, owing to the composition complexity in protein extracts. Here, it is shown that by using a recombinant synthesis approach, individual types of keratins can be expressed and used for mechanism investigation and further high-performance keratin hemostatic agent design. In the comparative evaluation of full-length, rod-domain, and helical segment keratins, the α-helical contents in the sequences are identified to be directly proportional to keratins' hemostatic activities, and Tyr, Phe, and Gln residues at the N-termini of α-helices in keratins are crucial in fibrinopeptide release and fibrin polymerization. A feasible route to significantly enhance the hemostatic efficiency of helical keratins by mutating Cys to Ser in the sequences for enhanced water wettability through soluble expression is then further presented. These results provide a rational strategy to design high-efficiency keratin hemostatic agents with superior performance over clinically used gelatin sponge in multiple animal models.

Distinct accumulation of nanoplastics in human intestinal organoids.

Plastic particles, especially nanoplastics, represent an emerging concern of threat to human health, oral uptake is an important pathway for the plastic particles ingestion by human. While their fate and adverse effects in animal gastrointestinal tract are increasingly investigated, knowledge about their uptake and toxicity in human intestine is still limited. Here, by exposing human intestinal organoids to polystyrene nanoplastics (PS-NPs, ~50 nm in size) with concentrations of 10 and 100 µg/mL, we present evidence of their distinct accumulation in various type cells in intestinal organoids, then causing the cell apoptosis and inflammatory response. Our results further revealed that the effective inhibition of PS-NPs accumulation in secretive cells through co-exposure to a clathrin-mediated endocytosis inhibitor (chlorpromazine), and proved the essential role of active endocytosis in the PS-NPs uptaking into enterocyte cells. Our work not only elucidated the potential uptake and toxicity of PS-NPs in human intestinal cells and the underlying mechanism, but also provide a potential therapeutic approach to relieve the toxicity of PS-NPs to human through the endocytosis inhibition.

Role of mass effect and trehalose on early erythrolysis after experimental intracerebral hemorrhage.

The mechanisms of brain injury after intracerebral hemorrhage (ICH) involve mass effect-induced primary injury and secondary injury caused by a pathologic response to the hematoma. Considerable attentions have recently been paid to the mechanisms and therapeutic strategy for secondary brain injury due to no overall benefit from early surgery compared with initial conservative treatment. However, it is unclear whether there is a causal relationship between mass effect and secondary brain injury. Here, the role of mass effect on early erythrolysis after experimental ICH was investigated based on the poly(N-isopropylacrylamide) (PNIPAM) ICH model. Autologous blood and PNIPAM hydrogel were co-injected into the right basal ganglia of rats to induce different degrees of mass effect, but with a constant hematoma. The influences of different mass effect and time courses on erythrolysis and brain damages after ICH were investigated. Furthermore, the protective effect of trehalose against erythrolysis after ICH was evaluated. The results showed that mass effect caused erythrocyte morphological change at 24 hr after ICH. The released hemoglobin was quantitatively evaluated by a polynomial concerning with the mass effect, the volume of hematoma, and the time of ICH. An obvious increase in heme oxygenase-1 (HO-1) and ionized calcium binding adaptor molecule-1 (Iba-1) expression, iron deposition, cell death, and neurological deficits was observed with increasing mass effect. Moreover, trehalose alleviated brain injury by inhibiting erythrolysis after ICH. These data demonstrated that mass effect accelerated the erythrolysis and brain damages after ICH, which could be relieved through trehalose therapy.

Hypolipidemic and antioxidant activities of Trichosanthes kirilowii maxim seed oil and flavonoids in mice fed with a high-fat diet.

Trichosanlhes kirilowii Maxim seed oil (TSO) is rich in conjugated linolenic acids, and the flavonoids (FLA) combined with n-3 fatty acids can effectively change the plasma antioxidant capacity. Hyperlipidemia and oxidative stress are one of the most important risk factors for cardiovascular disease. This study aims to evaluate the effect of the TSO, FLA, and TSO combined with FLA (TSOFLA) intake on hyperlipemia mice. TSO and TSOFLA administration resulted in a significant decline in serum levels of total cholesterol, triglycerides, and low density lipoprotein-cholesterol. TSOFLA improved the hepatic and serum antioxidant status as assessed by superoxide dismutase, glutathione peroxidase activities, and reduced the levels of lipid peroxidation. Hematoxylin-eosin staining of liver and aorta tissue has shown a marked reduction of the hyperlipidemia-induced lesions by gavage TSOFLA. Compared with TSO and FLA, TSOFLA has more significant hypolipidemic and antioxidant activities, which effects may be correlated to the synergy between TSO and FLA. PRACTICAL APPLICATIONS: Dyslipidemia is a common metabolic disorder, which is characterized by triglyceride levels increased, total cholesterol, and low-density lipoprotein cholesterol. Lipid-lowering treatment can reduce the expansion of coronary atherosclerosis, and particular the dietary lipids have important roles in controlling the concentrations of these risk factors. This is the first study evaluating the hypolipidemic and antioxidant activities effects of Trichosanlhes kirilowii Maxim seed oil (TSO), flavonoids (FLA), and TSO combined with FLA (TSOFLA) intake on hyperlipemia mice caused by a high-fat diet. The pharmacological effects of dietary TSOFLA are correlated to its high content of unsaturated fatty acids and flavonoids. This information can be of interest to the development of food supplements in the field of diseases associated with high-fat intakes such as cardiovascular diseases and adiposis.

Nanoparticle encapsulated core-shell hydrogel for on-site BMSCs delivery protects from iron overload and enhances functional recovery.

The local microenvironment may influence the success of stem cell therapy. Iron overload occurs in many hemorrhagic injuries due to hemolysis and hemoglobin degradation, which not only mediates local cell injury, but also induces damage to the transplanted cells. Here, an injectable nanoparticle encapsulated core-shell hydrogel was fabricated for simultaneous iron overload clearance and bone marrow mesenchymal stem cells (BMSCs) transplantation following intracerebral hemorrhage (ICH). The iron chelator-loaded low-molecular-weight keratin hydrogel with quick degradation property was selected as the outer shell to eliminate iron overload, and BMSCs implantation with high-molecular-weight keratin hydrogel was selected as the inner core. The epidermal growth factor and the basic fibroblast growth factor were entrapped within the poly (lactic-co-glycolic acid) (PLGA) nanoparticle, which was then encapsulated into the core hydrogel to support the BMSC growth and differentiation. The core-shell hydrogel can be easily formed by programmed injections, and the core-shell hydrogel displayed a strong protective effect against the toxicity of hemoglobin in cell experiments. Furthermore, more BMSCs survived in the core-shell hydrogel group in vivo as compared to that in the core hydrogel group and the vehicle group. Less iron deposition and ventricular enlargement, lower brain water content, and faster neurological recovery were also observed. The data demonstrated that this core-shell hydrogel is an effective strategy for promoting transplanted cell survival under the condition of an iron overload.

Establishment of an Experimental Intracerebral Haemorrhage Model for Mass Effect Research using a Thermo-sensitive Hydrogel.

The mechanical response of brain tissue closely relates to cerebral blood flow and brain diseases. During intracerebral haemorrhage (ICH), a mass effect occurs during the initial bleeding and results in significant tissue deformation. However, fewer studies have focused on the brain damage mechanisms and treatment approaches associated with mass effects compared to the secondary brain injuries after ICH, which may be a result of the absence of acceptable animal models mimicking a mass effect. Thus, a thermo-sensitive poly (N-isopropylacrylamide) (PNIPAM) hydrogel was synthesized and injected into the rat brain to establish an ICH model for mass effect research. The PNIPAM hydrogel or autologous blood was injected to establish an ICH animal model, and the space-occupying volumes, brain tissue elasticity, brain oedema, neuronal cell death, iron deposition and behavioural recovery were evaluated. The lower critical solution temperature of PNIPAM hydrogel was 32 °C, and the PNIPAM hydrogel had a rough surface with similar topography and pore structure to a blood clot. Furthermore, the ICH model animals who received an injection of PNIPAM and blood produced similar lesion volumes, elasticity changes and mechanically activated ion channel piezo-2 upregulation in brain tissue. Meanwhile, slight iron deposition, neuronal cell death and brain oedema were observed in the PNIPAM hydrogel model compared to the blood model. In addition, the PNIPAM hydrogel showed good biocompatibility and stability in vivo via subcutaneous implantation. Our findings show that PNIPAM hydrogel cerebral infusion can form a mass effect similar to haematoma and minimize the interference of blood, and the establishment of a mass effect ICH model is beneficial for understanding the mechanism of primary brain injury and the role of mass effects in secondary brain damage after ICH.

Human Hair Keratin Hydrogels Alleviate Rebleeding after Intracerebral Hemorrhage in a Rat Model.

Surgery is an important therapeutic strategy for intracerebral hemorrhage (ICH) in the clinic and is theoretically beneficial for the outcome of ICH by decreasing hematoma, reducing nervous tissue damage, and removing harmful chemicals. However, the outcome of ICH surgery is always unsatisfactory due to postoperative rebleeding. We hypothesized that the injection of hemostatic agents in situ after aspiration surgery could immediately activate hemostasis once rebleeding occurs. Therefore, keratin hydrogels (K-gels) were easily prepared as a hemostatic material via a rehydration method and had a porous structure. Collagenase was injected into the basal lamina to mimic ICH rebleeding, and the K-gels were then injected into the same injured site after 2 h for hemostatic therapy. The hematoma volume was significantly reduced by K-gel treatment, indicating that in situ infusion of the K-gels inhibited hematoma enlargement when rebleeding occurred. Moreover, brain damage, including cell apoptosis, neuroinflammatory reactions, and neurological deficits, was also relieved after K-gel treatment. These results suggested that in situ injection of the K-gels into the hematoma area after ICH surgery improves the therapeutic outcome by stopping postoperative rebleeding. K-gels have great potential for clinical hemostatic application because of their excellent hemostatic properties and biocompatibility.