Stem Cell-Based Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients' quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.

Fast growth of inch-sized single-crystalline graphene from a controlled single nucleus on Cu-Ni alloys.

Wafer-scale single-crystalline graphene monolayers are highly sought after as an ideal platform for electronic and other applications. At present, state-of-the-art growth methods based on chemical vapour deposition allow the synthesis of one-centimetre-sized single-crystalline graphene domains in ∼12 h, by suppressing nucleation events on the growth substrate. Here we demonstrate an efficient strategy for achieving large-area single-crystalline graphene by letting a single nucleus evolve into a monolayer at a fast rate. By locally feeding carbon precursors to a desired position of a substrate composed of an optimized Cu-Ni alloy, we synthesized an ∼1.5-inch-large graphene monolayer in 2.5 h. Localized feeding induces the formation of a single nucleus on the entire substrate, and the optimized alloy activates an isothermal segregation mechanism that greatly expedites the growth rate. This approach may also prove effective for the synthesis of wafer-scale single-crystalline monolayers of other two-dimensional materials.

Morphology control in mesoporous carbon films using solvent vapor annealing.

Ordered mesoporous (2-50 nm) carbon films were fabricated using cooperative self-assembly of a phenolic resin oligomer with a novel block copolymer template (poly(styrene-block-N,N-dimethyl-n-octadecylamine p-styrenesulfonate), (PS-b-PSS-DMODA)) synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Due to the high Tg of the PS segment and the strong interactions between the phenolic resin and the PSS-DMODA, the segmental rearrangement is kinetically hindered relative to the cross-linking rate of the phenolic resin, which inhibits long-range ordering and yields a poorly ordered mesoporous carbon with a broad pore size distribution. However, relatively short exposure (2 h) to controlled vapor pressures of methyl ethyl ketone (MEK) yields significant improvements in the long-range ordering and narrows the pore size distribution. The average pore size increases as the solvent vapor pressure during annealing increases, but an upper limit of p/p0 = 0.85 exists above which the films dewet rapidly during solvent vapor annealing. This approach can be extended using mesityl oxide, which has similar solvent qualities to MEK, but is not easily removed by ambient air drying after solvent annealing. This residual solvent can impact the morphology that develops during cross-linking of the films. These results illustrate the ability to fine-tune the mesostructure of ordered mesoporous carbon films through simple changes in the processing without any compositional changes in the initial cast film.

Control of ordering and structure in soft templated mesoporous carbon films by use of selective solvent additives.

The structure of ordered mesoporous carbons fabricated using poly(styrene-block-N,N,-dimethyl-n-octadecylamine p-styrenesulfonate) (PS-b-PSS-DMODA) as the template and phenolic resin (resol) as the carbon source can be easily manipulated by inclusion of low concentrations of low volatility selective solvents in the casting solution. Casting from neat methyl ethyl ketone yields a disordered structure even upon thermal annealing. However, addition of both dioctyl phthalate (DOP, PS selective) and dimethyl sulfoxide (DMSO, resol and PSS-DMODA selective) at modest concentrations to this casting solution provides sufficient mobility to produce highly ordered films with cylindrical mesopores. The DOP acts to swell the hydrophobic domain and can more than double the mesopore size, while the DMSO acts to swell the resol phase. Moreover, the surface area of the mesoporous carbons increases significantly as the meosopore size increases. This is a result of the decrease in wall thickness, which can be ascertained by the constant d-spacing of the mesostructure as the pore size increases. This behavior is counter to the typical effect of pore swelling agents that increase the pore size and decrease the surface area. Moreover, with only 4 wt % DOP/DMSO in the solution (20 wt % relative to solids), the scattering profiles exhibit many orders of diffraction, even upon carbonization, which is not typically observed for soft templated films. Variation in the concentration of DOP and DMSO during casting enables facile tuning of the structure of mesoporous carbon films.

The role and mechanism of flavonoid herbal natural products in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine that presents clinically with abdominal pain, mucopurulent stools, and posterior urgency. The lesions of UC are mainly concentrated in the rectal and colonic mucosa and submucosa. For patients with mild to moderate UC, the best pharmacological treatment includes glucocorticoids, immunosuppressants, antibiotics, and biologics, but the long-term application can have serious toxic side effects. Currently, nearly 40% of UC patients are treated with herbal natural products in combination with traditional medications to reduce the incidence of toxic side effects. Flavonoid herbal natural products are the most widely distributed polyphenols in plants and fruits, which have certain antioxidant and anti-inflammatory activities. Flavonoid herbal natural products have achieved remarkable efficacy in the treatment of UC. The pharmacological mechanisms are related to anti-inflammation, promotion of mucosal healing, maintenance of intestinal immune homeostasis, and regulation of intestinal flora. In this paper, we summarize the flavonoid components of anti-ulcerative colitis and their mechanisms reported in the past 10 years, to provide a basis for rational clinical use and the development of new anti-ulcerative colitis drugs.

The gut microbes in inflammatory bowel disease: Future novel target option for pharmacotherapy.

Gut microbes constitute the main microbiota in the human body, which can regulate biological processes such as immunity, cell proliferation, and differentiation, hence playing a specific function in intestinal diseases. In recent years, gut microbes have become a research hotspot in the pharmaceutical field. Because of their enormous number, diversity, and functional complexity, gut microbes have essential functions in the development of many digestive diseases. Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease with a complex etiology, the exact cause and pathogenesis are unclear. There are no medicines that can cure IBD, and more research on therapeutic drugs is urgently needed. It has been reported that gut microbes play a critical role in pathogenesis, and there is a tight and complex association between gut microbes and IBD. The dysregulation of gut microbes may be a predisposing factor for IBD, and at the same time, IBD may exacerbate gut microbes' disorders, but the mechanism of interaction between the two is still not well defined. The study of the relationship between gut microbes and IBD is not only important to elucidate the pathogenesis but also has a positive effect on the treatment based on the regimen of regulating gut microbes. This review describes the latest research progress on the functions of gut microbes and their relationship with IBD, which can provide reference and assistance for further research. It may provide a theoretical basis for the application of probiotics, fecal microbiota transplantation, and other therapeutic methods to regulate gut microbes in IBD.

Natural products modulate NLRP3 in ulcerative colitis.

Ulcerative colitis (UC) is a clinically common, progressive, devastating, chronic inflammatory disease of the intestine that is recurrent and difficult to treat. Nod-like receptor protein 3 (NLRP3) is a protein complex composed of multiple proteins whose formation activates cysteine aspartate protease-1 (caspase-1) to induce the maturation and secretion of inflammatory mediators such as interleukin (IL)-1ß and IL-18, promoting the development of inflammatory responses. Recent studies have shown that NLRP3 is associated with UC susceptibility, and that it maintains a stable intestinal environment by responding to a wide range of pathogenic microorganisms. The mainstay of treatment for UC is to control inflammation and relieve symptoms. Despite a certain curative effect, there are problems such as easy recurrence after drug withdrawal and many side effects associated with long-term medication. NLRP3 serves as a core link in the inflammatory response. If the relationship between NLRP3 and gut microbes and inflammation-associated factors can be analyzed concerning its related inflammatory signaling pathways, its expression status as well as specific mechanism in the course of IBD can be elucidated and further considered for clinical diagnosis and treatment of IBD, it is expected that the development of lead compounds targeting the NLRP3 inflammasome can be developed for the treatment of IBD. Research into the prevention and treatment of UC, which has become a hotbed of research in recent years, has shown that natural products are rich in therapeutic means, and multi-targets, with fewer adverse effects. Natural products have shown promise in treating UC in numerous basic and clinical trials over the past few years. This paper describes the regulatory role of the NLRP3 inflammasome in UC and the mechanism of recent natural products targeting NLRP3 against UC, which provides a reference for the clinical treatment of this disease.

Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes.

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or ß3 adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.

Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a rare, recurrent, and intractable inflammation obstruction of the stomach tract, usually accompanied by inflammation of cell proliferation and inflammation of the colon and carries a particular cause of inflammation. The clinical use of drugs in western countries affects IBD treatment, but various adverse effects and high prices limit their application. For these reasons, Traditional Chinese Medicine (TCM) is more advantageous in treating IBD. This paper reviews the mechanism and research status of TCM and natural products in IBD treatment by analyzing the relevant literature to provide a scientific and theoretical basis for IBD treatment.

Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment.

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the intestine, including Crohn's disease (CD) and ulcerative colitis (UC), whose etiology and pathogenesis have not been fully understood. Due to its prolonged course and chronic recurrence, IBD imposes a heavy economic burden and psychological stress on patients. Traditional Chinese Herbal Medicine has unique advantages in IBD treatment because of its symptomatic treatment. However, the advantages of the Chinese Herbal Medicine Formula (CHMF) have rarely been discussed. In recent years, many scholars have conducted fundamental studies on CHMF to delay IBD from different perspectives and found that CHMF may help maintain intestinal integrity, reduce inflammation, and decrease oxidative stress, thus playing a positive role in the treatment of IBD. Therefore, this review focuses on the mechanisms associated with CHMF in IBD treatment. CHMF has apparent advantages. In addition to the exact composition and controlled quality of modern drugs, it also has multi-component and multi-target synergistic effects. CHMF has good prospects in the treatment of IBD, but its multi-agent composition and wide range of targets exacerbate the difficulty of studying its treatment of IBD. Future research on CHMF-related mechanisms is needed to achieve better efficacy.

Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.

Unidirectional self-assembly of soft templated mesoporous carbons by zone annealing.

Surfactant or block copolymer-templated mesoporous films have been extensively explored, but achieving mesostructure coherence and unidirectional orientation over macroscopic dimensions has remained quite challenging for these self-assembled systems. Here, we extend the concepts associated with zone refinement of crystalline materials to soft templated mesoporous carbon films based on the cooperative assembly of commercial non-ionic surfactants (block copolymers) and phenolic resin oligomers (resol) to provide macroscopic alignment of both cubic (FDU-16) and hexagonal (FDU-15) mesostructures. The average orientation of these mesophases is determined from rotation grazing incidence small angle X-ray scattering (GISAXS) measurements. For FDU-15 templated by Pluronic P123, the orientation factor for the zone-annealed film is 0.98 based on the average of the second Legendre polynomial, but this orientation deteriorates significantly during carbonization. Notably, a thermal stabilization step following zone annealing preserves the orientation of the mesostructure during carbonization. The orientation factor for an isotropic cubic structure (FDU-16 templated by Pluronic F127) is only 0.48 (based on the 111 reflection with incident angle 0.15°) for the same zone annealing protocol, but this illustrates the versatility of zone annealing to different mesostructures. Unexpectedly, zone annealing of FDU-15 templated by Pluronic F127 leads to stabilization of the mesostructure through carbonization, whereas this structure collapses fully during carbonization even after extended oven annealing; despite no clear macroscopic orientation of the cylindrical mesostructure from zone annealing. Thermal zone annealing provides a simple methodology to produce highly ordered and macroscopically oriented stable mesoporous carbon films, but the efficacy is strongly tied to the mobility of the template during the zone annealing.

Facile control of long range orientation in mesoporous carbon films with thermal zone annealing velocity.

Ordered mesoporous carbons exhibit appealing properties for many applications, but their function and performance can depend critically on their structure. The in-plane orientation of 2D cylinders from the cooperative assembly of Pluronic P123 and resol has been controlled by application of cold zone annealing (CZA). By varying the moving rate, the preferential in-plane orientation of the self-assembled cylinders can be tuned through the entire 180° range possible from ϕ = 50° to ϕ = -130° (relative to the moving direction). At a moving rate of 2 µm s(-1), this simple and easy CZA process leads to cylinders that are well aligned parallel to the moving direction with a high orientational factor of S = 0.98. Moreover, the in-plane oriented cylinders can be nearly perfectly aligned transverse to the moving direction (S = 0.95) by simply decreasing the moving velocity to 0.5 µm s(-1). We attribute the parallel alignment to the flow that develops from the motion of the thermal gradients, while the transverse alignment is related to flow cessation (inertial effect). The preferential orientation is retained through the carbonization process, but there is some degradation in orientation due to insufficient crosslinking of the resol during CZA; this effect is most prominent for the higher moving rates (less time for crosslinking), but can be overcome by post-CZA annealing at uniform elevated temperatures to further crosslink the resol. CZA is a simple and powerful method for fabricating well-aligned and self-assembled mesoporous carbon films over large areas.