Effects of UV/H2O2 degradation on Moringa oleifera Lam. leaves polysaccharides: Composition, in vitro fermentation and prebiotic properties on gut microorganisms.

Moringa oleifera Lam. leaves are a new raw food material rich in polysaccharides. These polysaccharides exhibit various biological properties, including antioxidant, hypoglycemic and immunoregulatory effects. However, the use of Moringa oleifera Lam. leaves polysaccharides (MOLP) may be limited by their large molecular weight (MW) and presence of numerous impurities, such as pigments. Research has indicated that degraded polysaccharides usually exhibit high biological activity because of changes in physical structure and chemical properties. In this study, we focused on the extraction of a degraded-modified fraction from MOLP using the Ultraviolet/ Hydrogen peroxide (UV/H2O2) method. Specifically, the physicochemical properties and glycosidic bond composition of a particular fraction (UV/H2O2 degraded Moringa oleifera Lam. leaves polysaccharides in 3 h called DMOLP-3) were investigated. In addition, in vitro simulated digestion experiments showed that DMOLP-3 was only partially degraded during gastrointestinal digestion, indicating that DMOLP-3 can be utilised by gut microorganisms. Furthermore, the prebiotic properties of MOLP and DMOLP-3 was studied using an in vitro faecal fermentation model. The results indicated that compared with MOLP, DMOLP-3 led to a decrease in both the colour and MW of the polysaccharides. In addition, this model exhibited enhanced solubility and antioxidant capabilities while also influencing the surface morphology. Moreover, DMOLP-3 can facilitate the proliferation of advantageous microorganisms and enhance the synthesis of short-chain fatty acids (SCFAs). These results provide valuable insights into the utilization of bioactive components in Moringa oleifera Lam. leaves for the intestinal health.

Intestinal epithelial Krüppel-like factor 4 alleviates endotoxemia and atherosclerosis through improving NF-κB/miR-34a-mediated intestinal permeability.

Maintenance of intestinal barrier function contributes to gastrointestinal homeostasis and therefore cardiovascular diseases. A number of studies show that intestinal permeability is affected by excessive inflammatory responses. Krüppel-like factor (KLF) 4 is one of the critical transcriptional factors, which controls multiple immune responses. In this study we investigated the role of KLF4 in regulating intestinal inflammation and permeability during the atherosclerotic process. Atherosclerotic model was established in ApoE-/- mice by feeding a high fat high cholesterol (HFHC) diet. We showed that colon expression levels of KLF4 and tight junction proteins were significantly decreased whereas inflammatory responses increased in atherosclerotic mice. Overexpression of colon epithelial Klf4 decreased atherosclerotic plaque formation and vascular inflammation in atherosclerotic mice, accompanied by remarkable suppression of intestinal NF-κB activation. We found that overexpression of epithelial Klf4 in atherosclerotic mice significantly increased intestinal tight junction expression and ameliorated endotoxemia, whereas replenishment of LPS abolished these benefits. Overexpression of Klf4 reversed LPS-induced permeability and downregulation of ZO-1 and Occludin in Caco-2 cells in vitro. HFHC diet stimulated the expression of epithelial microRNA-34a, whereas silence of epithelial Klf4 abolished the benefits of microRNA-34a sponge, a specific miR-34a inhibitor, on intestinal permeability and atherosclerotic development. A clinical cohort of 24 atherosclerotic patients supported colon KLF4/NF-κB/tight junction protein axis mediated intestine/cardiovascular interaction in patients with atherosclerosis. Taken together, intestinal epithelial KLF4 protects against intestinal inflammation and barrier dysfunction, ameliorating atherosclerotic plaque formation.

Photosensitizer-loaded hydrogels: A new antibacterial dressing.

Bacterial wound infection has emerged as a pivotal threat to human health worldwide, and the situation has worsened owing to the gradual increase in antibiotic-resistant bacteria caused by the improper use of antibiotics. To reduce the use of antibiotics and avoid the increase in antibiotic-resistant bacteria, researchers are increasingly paying attention to  photodynamic therapy, which uses light to produce reactive oxygen species to kill bacteria. Treating bacteria-infected wounds by photodynamic therapy requires fixing the photosensitizer (PS) at the wound site and maintaining a certain level of wound humidity. Hydrogels are materials with a high water content and are well suited for fixing PSs at wound sites for antibacterial photodynamic therapy. Therefore, hydrogels are often loaded with PSs for treating bacteria-infected wounds via antibacterial photodynamic therapy. In this review, we systematically summarised the antibacterial mechanisms and applications of PS-loaded hydrogels for treating bacteria-infected wounds via photodynamic therapy. In addition, the recent  studies and the research status progresses of novel antibacterial hydrogels are discussed. Finally, the challenges and future prospects of PS-loaded hydrogels are reviewed.

Integrative group psychotherapy for patients with somatic symptom disorder: A randomized controlled trial.

The study aimed to determine whether specific integrative group psychotherapy (IGPT), based on CBT, combined with techniques of psychodynamic therapy and mindful body and emotional awareness is more effective than non-specific supportive group psychotherapy (SGPT) and treatment as usual (TAU) alone. A total of 120 SSD patients were randomly assigned to IGPT, SGPT or TAU groups. Both IGPT and SGPT showed significantly lower SSD-12 scores at the 4, 8, and 12-week follow-ups compared to TAU. No significant differences were observed between IGPT and SGPT at any follow-up point. These findings highlight the potential benefits of group psychotherapy in SSD treatment.

Inhibitory receptors and checkpoints on NK cells: Implications for cancer immunotherapy.

With the success of immunosuppressive checkpoint in tumor therapy, the corresponding adverse response and drug resistance defects have been exposed. T cells and NK cells are the body's immune system of the two substantial main forces. in recent years, study of T cell checkpoints appeared a certain block, such as PD-1 the effect not benign, on the distribution of NK cell surface excitatory and inhibitory receptors under normal conditions to maintain steady, could be targeted in the tumor treatment blockade have therapeutic effect. This paper reviews the function of NK cells and the effects of corresponding receptors in various types of tumors, providing a direction for the selection of appropriate gate control sites for future treatment.

A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review.

BACKGROUND: Mitochondrial complex III (CIII) deficiency is an autosomal recessive disease characterized by symptoms such as ataxia, cognitive dysfunction, and spastic paraplegia. Multiple genes are associated with complex III defects. Among them, the mutation of TTC19 is a rare subtype. METHODS: We screened a Chinese boy with weakness of limbs and his non-consanguineous parents by whole exome sequencing and targeted sequencing. RESULTS: We report a Chinese boy diagnosed with mitochondrial complex III defect type 2 carrying a homozygous variant (c.719-732del, p.Leu240Serfs*17) of the TTC19 gene. According to the genotype analysis of his family members, this is an autosomal recessive inheritance. We provide his clinical manifestation. CONCLUSIONS: A new type of TTC19 mutation (c.719-732del, p.Leu240Serfs*17) was found, which enriched the TTC19 gene mutation spectrum and provided new data for elucidating the pathogenesis of CIII-deficient diseases.

ALA-PDT shortens the course of antibiotic therapy for skin infection caused by Mycobacterium marinum.

BACKGROUND: Recently, the number of cases of Mycobacterium marinum infection has increased. Due to the nonspecific clinical manifestations and lack of standardized treatment guidelines, these infections are often misdiagnosed and are challenging to treat. METHODS: In this study, four patients had M. marinum skin infections accompanied by a high-risk exposure history and were diagnosed by bacterial culture and gene chip. Two patients were treated with antibiotic therapy alone, and the other two patients were treated with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with antibiotics. RESULTS: All four patients enrolled in the study were cured with 100 % efficacy. Two patients were cured after receiving two active antibiotics for 4 months. The other two patients, having considered the drug resistance and intolerance described above, were cured after receiving two active antibiotics for 1-1.5 months along with combination therapy with ALA-PDT. CONCLUSION: Combination therapy with ALA-PDT and antibiotics was chosen to shorten the duration of antibiotic treatment and reduce the occurrence of adverse reactions.

Single neurons on microelectrode array chip: manipulation and analyses.

Chips-based platforms intended for single-cell manipulation are considered powerful tools to analyze intercellular interactions and cellular functions. Although the conventional cell co-culture models could investigate cell communication to some extent, the role of a single cell requires further analysis. In this study, a precise intercellular interaction model was built using a microelectrode array [microelectrode array (MEA)]-based and dielectrophoresis-driven single-cell manipulation chip. The integrated platform enabled precise manipulation of single cells, which were either trapped on or transferred between electrodes. Each electrode was controlled independently to record the corresponding cellular electrophysiology. Multiple parameters were explored to investigate their effects on cell manipulation including the diameter and depth of microwells, the geometry of cells, and the voltage amplitude of the control signal. Under the optimized microenvironment, the chip was further evaluated using 293T and neural cells to investigate the influence of electric field on cells. An examination of the inappropriate use of electric fields on cells revealed the occurrence of oncosis. In the end of the study, electrophysiology of single neurons and network of neurons, both differentiated from human induced pluripotent stem cells (iPSC), was recorded and compared to demonstrate the functionality of the chip. The obtained preliminary results extended the nature growing model to the controllable level, satisfying the expectation of introducing more elaborated intercellular interaction models.

Disruption of Dopamine Homeostasis Associated with Alteration of Proteins in Synaptic Vesicles: A Putative Central Mechanism of Parkinson's Disease Pathogenesis.

Vestigial dopaminergic cells in PD have selectivity for a sub-class of hypersensitive neurons with the nigrostriatal dopamine (DA) tract. DA is modulated in pre-synaptic nerve terminals to remain stable. To be specific, proteins at DA release sites that have a function of synthesizing and packing DA in cytoplasm, modulating release and reingestion, and changing excitability of neurons, display regional discrepancies that uncover relevancy of the observed sensitivity to neurodegenerative changes. Although the reasons of a majority of PD cases are still indistinct, heredity and environment are known to us to make significant influences. For decades, genetic analysis of PD patients with heredity in family have promoted our comprehension of pathogenesis to a great extent, which reveals correlative mechanisms including oxidative stress, abnormal protein homeostasis and mitochondrial dysfunction. In this review, we review the constitution of presynaptic vesicle related to DA homeostasis and describe the genetic and environmental evidence of presynaptic dysfunction that increase risky possibility of PD concerning intracellular vesicle transmission and their functional outcomes. We summarize alterations in synaptic vesicular proteins with great involvement in the reasons of some DA neurons highly vulnerable to neurodegenerative changes. We generalize different potential targets and therapeutic strategies for different pathogenic mechanisms, providing a reference for further studies of PD treatment in the future. But it remains to be further researched on this recently discovered and converging mechanism of vesicular dynamics and PD, which will provide a more profound comprehension and put up with new therapeutic tactics for PD patients.

Periodic, n-soliton and variable separation solutions for an extended (3+1)-dimensional KP-Boussinesq equation.

An extended (3+1)-dimensional Kadomtsev-Petviashvili-Boussinesq equation is studied in this paper to construct periodic solution, n-soliton solution and folded localized excitation. Firstly, with the help of the Hirota's bilinear method and ansatz, some periodic solutions have been derived. Secondly, taking Burgers equation as an auxiliary function, we have obtained n-soliton solution and n-shock wave. Lastly, we present a new variable separation method for (3+1)-dimensional and higher dimensional models, and use it to derive localized excitation solutions. To be specific, we have constructed various novel structures and discussed the interaction dynamics of folded solitary waves. Compared with the other methods, the variable separation solutions obtained in this paper not only directly give the analytical form of the solution u instead of its potential [Formula: see text], but also provide us a straightforward approach to construct localized excitation for higher order dimensional nonlinear partial differential equation.

Role of Circular RNAs in Atherosclerosis through Regulation of Inflammation, Cell Proliferation, Migration, and Apoptosis: Focus on Atherosclerotic Cerebrovascular Disease.

Atherosclerosis (AS) is a disease dangerous to human health and the main pathological cause of ischemic cardiovascular diseases. Although its pathogenesis is not fully understood, numerous basic and clinical studies have shown that AS is a chronic inflammatory disease existing in all stages of atherogenesis. It may be a common link or pathway in the pathogenesis of multiple atherogenic factors. Inflammation is associated with AS complications, such as plaque rupture and ischemic cerebral infarction. In addition to inflammation, apoptosis plays an important role in AS. Apoptosis is a type of programmed cell death, and different apoptotic cells have different or even opposite roles in the process of AS. Unlike linear RNA, circular RNA (circRNA) a covalently closed circular non-coding RNA, is stable and can sponge miRNA, which can affect the stages of AS by regulating downstream pathways. Ultimately, circRNAs play very important roles in AS by regulating inflammation, apoptosis, and some other mechanisms. The study of circular RNAs can provide new ideas for the prediction, prevention, and treatment of AS.

Myeloid-derived suppressor cells: Key immunosuppressive regulators and therapeutic targets in cancer.

Myeloid-derived suppressor cell (MDSC) mainly exists in tumor microenvironment (TME) and interferes with normal immune response of the body. These immature differentiated cells cooperate with tumor cells for immune escape and proliferation. The subtypes of MDSC are different in different organisms, and STAT become a high priority for the signaling pathway mediating the regulation of MDSC. The surface of MDSC cell population contains a variety of signal molecular receptors, and its differentiation degree is toilless to be chemotaxis by different factors. The role of MDSC in silencing T cells and promoting regulatory T cells (Treg) is particularly significant. This review mainly contains the origin of MDSC, the characteristics of subgroups, the focus of the study on MDSC heat molecules and signaling pathways, the relationship between MDSC and carcinoma, prognosis and hope to propose an overview of current MDSCs- targeting therapies so as to provide new ideas for cancer treatment.

The Mechanism of Peach Gum Polysaccharide Preventing UVB-Induced Skin Photoaging by Regulating Matrix Metalloproteinanse and Oxidative Factors.

Exposure to ultraviolet light can cause oxidative damage and accelerate skin aging and is one of the main causes of skin aging. Peach gum polysaccharide (PG) is a natural edible plant component that has many biological activities, such as regulating blood glucose and blood lipids and improving colitis, as well as antioxidant and anticancer properties. However, there are few reports on the antiphotoaging effect of peach gum polysaccharide. Therefore, in this paper, we study the basic composition of the raw material peach gum polysaccharide and its ability to improve UVB-induced skin photoaging damage in vivo and in vitro. The results show that peach gum polysaccharide is mainly composed of mannose, glucuronic acid, galactose, xylose, and arabinose, and its molecular weight (Mw) is 4.10 × 106 g/mol. The results of the in vitro cell experiments show that PG could significantly alleviate UVB-induced apoptosis of human skin keratinocytes, promote cell growth repair, reduce the expression of intracellular oxidative factors and matrix metal collagenase, and improve the extent of oxidative stress repair. Moreover, the results from the in vivo animal experiments showed that PG could not only effectively improve the phenotype of UVB-induced photoaged skin in model mice but also significantly improve their oxidative stress status, regulate the contents of ROS and the levels of SOD and CAT, and repair the oxidative skin damage induced by UVB in vivo. In addition, PG improved UVB-induced photoaging-mediated collagen degradation in mice by inhibiting the secretion of matrix metalloproteinases. The above results indicate that peach gum polysaccharide has the ability to repair UVB-induced photoaging and may be used as a potential drug and antioxidant functional food to resist photoaging in the future.

Mitophagy associated self-degradation of phosphorylated MAP4 guarantees the migration and proliferation responses of keratinocytes to hypoxia.

Our previous study has announced that phosphorylated microtubule-associated protein 4 (p-MAP4) accelerated keratinocytes migration and proliferation under hypoxia through depolymerizing microtubules. However, p-MAP4 should exhibit inhibitory effects on wound healing, for it also impaired mitochondria. Thus, figuring out the outcome of p-MAP4 after it impaired mitochondria and how the outcome influenced wound healing were far-reaching significance. Herein, the results revealed that p-MAP4 might undergo self-degradation through autophagy in hypoxic keratinocytes. Next, p-MAP4 activated mitophagy which was unobstructed and was also the principal pathway of its self-degradation triggered by hypoxia. Moreover, both Bcl-2 homology 3 (BH3) and LC3 interacting region (LIR) domains had been verified in MAP4, and they endowed MAP4 with the capability to synchronously function as a mitophagy initiator and a mitophagy substrate receptor. And, mutating any one of them ruined hypoxia-induced self-degradation of p-MAP4, resulting in destroyed proliferation and migration responses of keratinocytes to hypoxia. Our findings unviewed that p-MAP4 experienced mitophagy-associated self-degradation through utilizing its BH3 and LIR domains under hypoxia. As a result, the mitophagy-associated self-degradation of p-MAP4 guaranteed the migration and proliferation responses of keratinocytes to hypoxia. Together, this research provided a bran-new pattern of proteins in regulating wound healing, and offered a new direction for intervening wound healing.

USP18 regulates the malignant phenotypes of glioblastoma stem cells.

Glioblastoma (GBM) is the most malignant primary brain tumor. The 5-year survival rate of the patients is poor, and they are prone to relapse and the treatment is limited. Therefore, the search for biological targets is one of the key measures for the treatment and prognosis of GBM. Ubiquitin-specific peptidase 18 (USP18) plays a regulatory role in tumorigenesis. In this study, we found that USP18 was up-regulated in GBM, promoted the growth and proliferation of glioblastoma stem cells (GSCs), affected the epithelial-mesenchymal transition (EMT), and was associated with poor clinical prognosis of patients. Finally, our findings reveal a critical role for USP18 in GBM malignancy, targeting USP18 may open new avenues for GBM treatment.

The transcription factor GhTCP7 suppresses petal expansion by interacting with the WIP-type zinc finger protein GhWIP2 in Gerbera hybrida.

Petal size is a critical factor in plant reproduction and horticulture, and is largely determined by cell expansion. Gerbera hybrida is an important horticultural plant and serves as a model for studying petal organogenesis. We have previously characterized GhWIP2, a Trp-Ile-Pro (WIP)-type zinc protein, that constrains petal size by suppressing cell expansion. However, the underlying molecular mechanism remains largely unclear. Using yeast two-hybrid screening, bimolecular fluorescence complementation, and co-immunoprecipitation, we identified a TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) family transcription factor, GhTCP7, that interacts with GhWIP2 both in vitro and in vivo. Using reverse genetic approaches, we elucidated the function of the GhTCP7-GhWIP2 complex in controlling petal expansion. GhTCP7 overexpression severely reduced cell expansion and petal size, whereas GhTCP7 silencing resulted in increased cell expansion and petal size. GhTCP7 showed similar expression patterns to GhWIP2 in various types of G. hybrida petals. We further identified GhIAA26, which encodes an auxin signalling regulator, that is activated by the GhTCP7-GhWIP2 complex, leading to the suppression of petal expansion. Our findings reveal a previously unknown transcriptional regulatory mechanism that involves protein-protein interactions between two different transcription factor families to activate a negative regulator of petal organogenesis.

Association of Tirofiban With Functional Outcomes After Thrombectomy in Acute Ischemic Stroke Due to Intracranial Atherosclerotic Disease.

BACKGROUND AND OBJECTIVE: To investigate the efficacy and safety of IV infusion of tirofiban before endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerotic disease. The secondary objective was to identify potential mediators for the clinical effect of tirofiban. METHODS: Post hoc exploratory analysis of the Endovascular Treatment With versus Without Tirofiban for Patients with Large Vessel Occlusion Stroke (RESCUE BT) trial, which was a randomized, double-blinded, placebo-controlled trial at 55 centers in China from October 2018 to October 2021. Patients with occlusion of the internal carotid artery or middle cerebral artery due to intracranial atherosclerosis were included. The primary efficacy outcome was the proportion of patients achieving functional independence (defined as modified Rankin scale 0-2) at 90 days. Binary logistic regression and causal mediation analyses were used to estimate the treatment effect of tirofiban and the potential mediators. RESULTS: This study included 435 patients, of whom 71.5% were men. The median age was 65 (interquartile range [IQR] 56-72) years, with a median NIH Stroke Scale of 14 (IQR 10-19). Patients in the tirofiban group had higher rates of functional independence at 90 days than patients in the placebo group (adjusted odds ratio 1.68; 95% CI 1.11-2.56, p = 0.02) without an increased risk of mortality or symptomatic intracranial hemorrhage. Tirofiban was associated with fewer thrombectomy passes (median [IQR] 1 [1-2] vs 1 [1-2], p = 0.004), which was an independent predictor of functional independence. Mediation analysis showed tirofiban-reduced thrombectomy passes explained 20.0% (95% CI 4.1%-76.0%) of the effect of tirofiban on functional independence. DISCUSSION: In this post hoc analysis of the RESCUE BT trial, tirofiban was an effective and well-tolerated adjuvant medication of endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerosis. These findings need to be confirmed in future trials. TRIAL REGISTRATION INFORMATION: The RESCUE BT trial was registered on the Chinese Clinical Trial Registry: chictr.org.cn, ChiCTR-INR-17014167. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tirofiban plus endovascular therapy improves 90-day outcome for patients with large vessel occlusion due to intracranial atherosclerosis.

In vivo overexpression of synaptogyrin-3 promotes striatal synaptic dopamine uptake in LRRK2R1441G mutant mouse model of Parkinson's disease.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) mutation is a common genetic risk factor of Parkinson's disease (PD). Presynaptic dysfunction is an early pathogenic event associated with dopamine (DA) dysregulation in striatum of the brain. DA uptake activity of DA uptake transporter (DAT) affects synaptic plasticity and motor and non-motor behavior. Synaptogyrin-3 (SYNGR3) is part of the synaptogyrin family, especially abundant in brain. Previous in vitro studies demonstrated interaction between SYNGR3 and DAT. Reduced SYNGR3 expression was observed in human PD brains with unclear reasons. METHODS: Here, we further explored whether inducing SYNGR3 expression can influence (i) cellular DA uptake using differentiated human SH-SY5Y neuronal cells, (ii) striatal synaptosomal DA uptake in a mutant LRRK2R1441G  knockin mouse model of PD, and (iii) innate rodent behavior using the marble burying test. RESULTS: Young LRRK2 mutant mice exhibited significantly lower SYNGR3 levels in striatum compared to age-matched wild-type (WT) controls, resembling level in aged WT mice. SYNGR3 is spatially co-localized with DAT at striatal presynaptic terminals, visualized by immuno-gold transmission electron microscopy and immunohistochemistry. Their protein-protein interaction was confirmed by co-immunoprecipitation. Transient overexpression of SYNGR3 in differentiated SH-SY5Y cells increased cellular DA uptake activity without affecting total DAT levels. Inducing SYNGR3 overexpression by adeno-associated virus-7 (AAV7) injection in vivo into striatum increased ex vivo synaptosomal DA uptake in LRRK2 mutant mice and improved their innate marble burying behavior. CONCLUSION: Brain SYNGR3 expression may be an important determinant to striatal DA homeostasis and synaptic function. Our preliminary behavioral test showed improved innate behavior after SYNGR3 overexpression in LRRK2 mutant mice, advocating further studies to determine the influence of SYNGR3 in the pathophysiology of DA neurons in PD.

Generation of a human iPSC line (CIBi014-A) from a patient with Parkinson's disease carrying a novel heterozygotic PARK8 (LRRK2) mutation.

Leucine-rich repeat kinase 2 (LRRK2), also known as Dardarin (derived from the Basque word "dardara," meaning tremor), is a protein kinase encoded by the PARK8 gene. This protein is mainly distributed in the cytoplasm; however, it is also present in the mitochondrial outer membrane. Mutations in the LRRK2 protein cause Parkinson's disease (PD). We generated a human induced pluripotent stem cell (iPSC) line (CIBi014-A) expressing pluripotency markers. This cell line exhibited a normal karyotype and could be differentiated into three germ layers in vitro. This line will be valuable for investigating the mechanism underlying PD and identifying potential therapeutic targets.