The Aging Immune System: A Critical Attack on Ischemic Stroke.

Ischemic stroke caused by cerebrovascular embolism is an age-related disease with high rates of disability and mortality. Although the mechanisms of immune and inflammatory development after stroke have been of great interest, most studies have neglected the critical and unavoidable factor of age. As the global aging trend intensifies, the number of stroke patients is constantly increasing, emphasizing the urgency of finding effective measures to address the needs of elderly stroke patients. The concept of "immunosenescence" appears to explain the worse stroke outcomes in older individuals. Immune remodeling due to aging involves dynamic changes at all levels of the immune system, and the overall consequences of central (brain-resident) and peripheral (non-brain-resident) immune cells in stroke vary according to the age of the individual. Lastly, the review outlines recent strategies aimed at immunosenescence to improve stroke prognosis.

Buyang huanwu decoction alleviates stroke-induced immunosuppression in MCAO mice by reducing splenic T cell apoptosis triggered by AIM2 inflammasome.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is a serious disabling and fatal disease that places a heavy burden on the world. Stroke induces a state of systemic immunosuppression that is strongly associated with an increased risk of infection and severe outcomes. Buyang Huanwu Decoction (BYHWD) is an ancient Chinese traditional formula with a good clinical and experimental basis. However, the role of BYHWD on post-stroke immunomodulation, especially immunosuppression, is unclear. AIM OF THE STUDY: The aim of this study was to investigate the pharmacological mechanism of BYHWD to alleviate ischemic stroke by analyzing splenic T cells apoptosis triggered by the AIM2 inflammasome activation cascade. MATERIALS AND METHODS: An ischemic stroke model in C57BL/6 J mice was constructed using the MCAO method. The mNSS test and the hanging wire test were conducted to evaluate neurological impairment in mice. Histopathological damage was visualized by Nissl staining and HE staining. The protective effects of BYHWD on the spleen were determined by splenic index and spleen HE staining. The inhibition of AIM2 inflammasome cascade by BYHWD were explored through immunofluorescence (IF), flow cytometry, enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Flow cytometry was used to assess the apoptosis of splenic T cells. RESULTS: BYHWD significantly reduced infarct size, improved neurological function scores, and alleviated histopathological damage in middle cerebral artery occlusion (MCAO) mice. At the same time, BYHWD salvaged spleen atrophy. BYHWD significantly ameliorated apoptosis of splenic T lymphocytes. Key proteins and factors in the AIM2/IL-1ß/FasL/Fas axis are effectively inhibited from expression after BYHWD treatment. CONCLUSION: It is the first study to demonstrate that BYHWD can improve stroke-induced immunosuppression by down-regulating Fas-dependent splenic T-cell apoptosis triggered by peripheral AIM2 inflammasome-driven signaling cascade.

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology.

Background: Qiguiyin decoction (QGYD) is a traditional Chinese medicine (TCM) and its combined application with levofloxacin (LVFX) has been confirmed effective in the clinical treatment of multidrug-resistant Pseudomonas aeruginosa (MDR PA) infection. This study investigated the therapeutic effect and possible mechanism of QGYD in sensitizing LVFX against MDR PA infection. Materials and Methods: Pulmonary infections were induced in rats by MDR PA. The changes in pharmacokinetics-pharmacodynamics (PK-PD) parameters of LVFX after combined with QGYD were investigated in MDR PA-induced rats. Subsequently, the correlation between PK and PD was analyzed and PK-PD models were established to elucidate the relationship between QGYD-induced alterations in LVFX metabolism and its sensitization to LVFX. Antibody chip technology was used to detect the levels of inflammatory factors, suggesting the relationship between the beneficial effect of immune regulation and the sensitization of QGYD. Results: QGYD significantly enhanced the therapeutic efficacy of LVFX against MDR PA infection. The combination of QGYD changed the PK parameters of LVFX such as Tmax, t1/2, MRT, Vd/F, CL/F and PD parameters such as MIC, AUC0-24h/MIC. Predicted results from PK-PD models demonstrated that the antibacterial effect of LVFX was significantly enhanced with the combination of QGYD, consistent with experimental findings. Antibody chip results revealed that the combination of QGYD made IL-1 ß, IL-6, TNF- α, IL-10, and MCP-1 levels more akin to those of the blank group. Conclusion: These findings indicated that QGYD could change the PK-PD behaviors of LVFX and help the body restore immune balance faster. This implied that a potential drug interaction might occur between QGYD and LVFX, leading to improved clinical efficacy when combined.

Ultra-high sensitive dual-parameter sensor based on double-hole fiber for simultaneous detection of magnetic field and temperature.

An ultra-high sensitive dual-parameter sensor based on double-hole fiber (DHF) is proposed for simultaneous detection of magnetic fields and temperatures. The sensor utilizes the DHF containing a Ge-doped core with two large air holes symmetrically arranged at its two sides. To enhance the sensitivity to both a magnetic field and temperature, Al wires with different diameters are embedded on the inner walls of the air holes in the DHF, creating a magnetic field sensing channel filled with magnetic fluid and a temperature sensing channel filled with thermo-sensitive liquid. Structural parameters and metal materials of the sensor are optimized by using the finite element method. Numerical results demonstrate that this DHF-based dual-parameter sensor can detect magnetic fields ranging from 40 Oe to 130 Oe and temperatures ranging from 24.3 °C to 49.3 °C simultaneously. The maximum magnetic field sensitivity reaches up to 64000 pm/mT, while the maximum temperature sensitivity is approximately 44.6 nm/°C, both exceeding current reports by more than one order of magnitude for simultaneous detection of magnetic field and temperature. With its high sensitivity, low fabrication difficulty, and simple structure, this DHF-based dual-parameter sensor has potential applications in the fields of material characterization analysis, geological environmental monitoring, and aeronautical engineering.

Ultra-high sensitivity weak magnetic field detecting magnetic fluid surface plasmon resonance sensor based on a single-hole fiber.

An ultra-high sensitivity weak magnetic field detecting magnetic fluid surface plasmon resonance (SPR) sensor based on a single-hole fiber (SHF) is proposed for detecting weak magnetic fields. The sensor is constructed with a single-hole fiber in which an exclusive air hole in the cladding is embedded with a metal wire and filled with a magnetic fluid (MF) to enhance the magnetic field sensitivity. The effects of the structural parameters, embedded metals, and refractive index difference between the core and cladding on the magnetic field sensitivity and peak loss are investigated and optimized. The sensitivity, resolution, figure of merit (FOM), and other characteristics of the sensor are analyzed systematically. The numerical results reveal a maximum magnetic field sensitivity of 451,000 pm/mT and FOM of 15.03 mT-1. The ultra-high magnetic field sensitivity renders the sensor capable of detecting weak magnetic fields at the pT level for the first time, in addition to a detection range from 3.5 mT to 17 mT. The SHF-SPR magnetic field sensor featuring high accuracy, simple structure, and ease of filling has immense potential in applications such as mineral resource exploration as well as geological and environmental assessment.

[Normal mouse serum alleviates radiation pneumonitis in mice by inhibiting the focal adhesion signaling pathway].

OBJECTIVE: To evaluate the therapeutic effect of normal mouse serum on radiation pneumonitis in mice and explore the possible mechanism. METHODS: Mouse models of radiation pneumonitis induced by thoracic radiation exposure were given intravenous injections of 100 µL normal mouse serum or normal saline immediately after the exposure followed by injections once every other day for a total of 8 injections. On the 15th day after irradiation, histopathological changes of the lungs of the mice were examined using HE staining, the levels of TNF-α, TGF-ß, IL-1α and IL-6 in the lung tissue and serum were detected using ELISA, and the percentages of lymphocytes in the lung tissue were analyzed with flow cytometry. Highth-roughput sequencing of exosome miRNA was carried out to explore the changes in the signaling pathways. The mRNA expression levels of the immune-related genes were detected by qRT-PCR, and the protein expressions of talin-1, tensin2, FAK, vinculin, α-actinin and paxillin in the focal adhesion signaling pathway were detected with Western blotting. RESULTS: In the mouse models of radiation pneumonitis, injections of normal mouse serum significantly decreased the lung organ coefficient, lowered the levels of TNF-α, TGF-ß, IL-1α and IL-6 in the serum and lung tissues, and ameliorated infiltration of CD45+, CD4+ and Treg lymphocytes in the lung tissue (all P < 0.05). The expression levels of Egfr and Pik3cd genes at both the mRNA and protein levels and the protein expressions of talin-1, tensin2, FAK, vinculin, α?actinin and paxillin were all significantly down-regulated in the mouse models after normal mouse serum treatment. CONCLUSION: Normal mouse serum ameliorates radiation pneumonitis in mice by inhibiting the expressions of key proteins in the Focal adhesion signaling pathway.

Nonlinear association of fibrinogen levels with functional prognosis in patients with acute ischemic stroke: a prospective cohort study.

OBJECTIVE: Fibrinogen, essential in primary hemostasis, platelet aggregation, and leukocyte-endothelial interactions, is also associated with a heightened risk of acute ischemic stroke (AIS). However, its influence on AIS patient outcomes is unclear. This study examines the correlation between fibrinogen levels and the risk of unfavorable outcomes three months post-AIS. METHODS: This is a secondary analysis of a prospective cohort study conducted in Korea. The sample consisted of 1851 AIS patients who received treatment at a Korean hospital between January 2010 and December 2016. Statistical models were established to understand the relationship between fibrinogen levels(mg/dL) and unfavorable outcomes(mRs ≥ 3), including logistic regression models, Generalized Additive Models (GAM), and smooth curve fitting (penalized splines). The log-likelihood ratio test has been utilized to evaluate the best fit. To ensure the robustness of the results, sensitivity analyses were conducted by reanalyzing the relationship after excluding participants with TG > 200 mg/dl and BMI > 25 kg/m2. Subgroup analyses were also performed to assess whether influencing factors modify the association between fibrinogen levels and unfavorable outcomes. RESULTS: After adjusting for multiple covariates including age, BMI, sex, LDL-c, TG, HGB, HDL-c, BUN, FPG, ALB, PLT, AF, hypertension, smoking, DM, mRs score at admission, the binary logistic regression model demonstrated revealed a significant positive association between fibrinogen levels and the risk of unfavorable outcomes in AIS patients (OR = 1.215, 95% CI: 1.032-1.429, p = 0.019). Sensitivity analyses supported these findings, with similar ORs observed in subsets of patients with TG < 200 mg/dL (OR = 1.221, 95% CI: 1.036-1.440) and BMI < 25 kg/m2 (OR = 1.259, 95% CI: 1.051-1.509). Additionally, the relationship between fibrinogen levels and outcomes was nonlinear, with a critical threshold of 2.74 g/L. Below the inflection point, the OR for unfavorable outcomes was 0.666 ((95% CI: 0.360, 1.233, p = 0.196), whereas above it, the OR increased to 1.374 (95% CI: 1.138, 1.659). CONCLUSIONS: This study has provided evidence of a positive and nonlinear correlation between fibrinogen levels and 3-month poor functional outcomes in patients with AIS. When fibrinogen levels exceeded 2.74 g/L, a significant and positive association was observed with the risk of poor outcomes. This study provides a further reference for optimizing rehabilitation exercises and facilitating clinical counseling in patients with acute ischemic stroke.

MaiJiTong granule attenuates atherosclerosis by reducing ferroptosis via activating STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways in LDLR-/- mice.

BACKGROUND AND PURPOSE: Atherosclerosis is the primary pathological basis of cardiovascular disease. Ferroptosis is a regulated form of cell death, a process of lipid peroxidation driven by iron, which can initiate and promote atherosclerosis. STAT6 is a signal transducer that shows a potential role in regulating ferroptosis, but, the exact role in ferroptosis during atherogenesis remains unclear. The Traditional Chinese Medicine Maijitong granule (MJT) is used for treating cardiovascular disease and shows a potential inhibitory effect on ferroptosis. However, the antiatherogenic effect and the underlying mechanism remain unclear. In this study, we determined the role of STAT6 in ferroptosis during atherogenesis, investigated the antiatherogenic effect of MJT, and determined whether its antiatherogenic effect was dependent on the inhibition of ferroptosis. METHODS: 8-week-old male LDLR-/- mice were fed a high-fat diet (HFD) at 1st and 10th week, respectively, to assess the preventive and therapeutic effects of MJT on atherosclerosis and ferroptosis. Simultaneously, the anti-ferroptotic effects and mechanism of MJT were determined by evaluating the expression of genes responsible for lipid peroxidation and iron metabolism. Subsequently, we reanalyzed microarray data in the GSE28117 obtained from cells after STAT6 knockdown or overexpression and analyzed the correlation between STAT6 and ferroptosis. Finally, the STAT6-/- mice were fed HFD and injected with AAV-PCSK9 to validate the role of STAT6 in ferroptosis during atherogenesis and revealed the antiatherogenic and anti-ferroptotic effect of MJT. RESULTS: MJT attenuated atherosclerosis by reducing plaque lesion area and enhancing plaque stability in both preventive and therapeutic groups. MJT reduced inflammation via suppressing inflammatory cytokines and inhibited foam cell formation by lowering the LDL level and promoting ABCA1/G1-mediated lipid efflux. MJT ameliorated the ferroptosis by reducing lipid peroxidation and iron dysregulation during atherogenesis. Mechanistically, STAT6 negatively regulated ferroptosis by transcriptionally suppressing SOCS1/p53 and DMT1 pathways. MJT suppressed the DMT1 and SOCS1/p53 via stimulating STAT6 phosphorylation. In addition, STAT6 knockout exacerbated atherosclerosis and ferroptosis, which abolished the antiatherogenic and anti-ferroptotic effects of MJT. CONCLUSION: STAT6 acts as a negative regulator of ferroptosis and atherosclerosis via transcriptionally suppressing DMT1 and SOCS1 expression and MJT attenuates atherosclerosis and ferroptosis by activating the STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways, which indicated that STAT6 acts a novel promising therapeutic target to ameliorate atherosclerosis by inhibiting ferroptosis and MJT can serve as a new therapy for atherosclerosis treatment.

Extraction methods, multiple biological activities, and related mechanisms of Momordica charantia polysaccharide: A review.

Momordica Charantia Polysaccharide (MCP) is a key bioactive compound derived from bitter melon fruit. This review summarizes the advancements in MCP research, including extraction techniques, biological activities, and mechanisms. MCP can be extracted using various methods, and has demonstrated hypoglycemic, antioxidant, anti-inflammatory, and immunoregulatory effects. Research suggests that MCP may regulate metabolic enzymes, oxidative stress reactions, and inflammatory pathways. The review highlights the potential applications of MCP in areas such as anti-diabetes, antioxidant, anti-inflammatory, and immunoregulatory research. Future research should focus on elucidating the molecular mechanisms of MCP and optimizing extraction methods. This review provides a foundation for further research and utilization of MCP.

Energy-saving and CO2 reduction strategies for new energy vehicles based on the integration approach of voluntary advocacy and system dynamics.

The low-carbon development of new energy vehicles (NEVs) is critical to achieving the goals of carbon peaking and carbon neutrality. As such, combining gray model theory with system dynamics (SD-GM) and based on the bidirectional-cycle prediction theory, we propose a NEV annual average mileage algorithm considering the impact of the epidemic in China, taking private cars as an example. Then, combining a voluntary advocacy strategy (VA) with the SD-GM theory (VA-SD-GM integration), we establish an energy-saving and carbon-reduction management model. To evaluate the proposed algorithm, we performed a dynamic simulation. The results indicate that the enhanced green scenario enabled significant energy-saving and CO2 reduction performance but would cause side effects in the long term. Compared with the enhanced green scenario, the linkage mode reduced the impact of parking space tension, the number of NEV trips, and the intensification of traffic congestion by approximately 33%, 50%, and 34%, respectively. It effectively suppressed the continuous increase in side effects and had a synergistic effect of carbon reduction, energy conservation, congestion alleviation, and side-effect reduction. The study provides a theoretical basis for optimizing the energy-saving and CO2 reduction path of NEVs.

Bone marrow mesenchymal stem cells therapy regulates sphingolipid and glycerophospholipid metabolism to promote neurological recovery in stroke rats: A metabolomics analysis.

Bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential in the subacute/chronic phase of acute ischemic stroke (AIS), but the underlying mechanisms are not yet fully elucidated. There is a knowledge gap in understanding the metabolic mechanisms of BMSCs in stroke therapy. In this study, we administered BMSCs intravenously 24 h after reperfusion in rats with transient cerebral artery occlusion (MCAO). The treatment with BMSCs for 21 days significantly reduced the modified neurological severity score of MCAO rats (P < 0.01) and increased the number of surviving neurons in both the striatum and hippocampal dentate gyrus region (P < 0.01, respectively). Moreover, BMSCs treatment resulted in significant enhancements in various structural parameters of dendrites in layer V pyramidal neurons in the injured hemispheric motor cortex, including total length (P < 0.05), number of branches (P < 0.05), number of intersections (P < 0.01), and spine density (P < 0.05). Then, we performed plasma untargeted metabolomics analysis to study the metabolic changes of BMSCs on AIS. There were 65 differential metabolites identified in the BMSCs treatment group. Metabolic profiling analysis revealed that BMSCs modulate abnormal sphingolipid metabolism and glycerophospholipid metabolism, particularly affecting core members such as sphingomyelin (SM), ceramide (Cer) and sphingosine-1-phosphate (S1P). The metabolic network analysis and pathway-based compound-reaction-enzyme-gene network analysis showed that BMSCs inhibited the Cer-induced apoptotic pathway and promoted the S1P signaling pathway. These findings suggest that the enhanced effects of BMSCs on neuronal survival and synaptic plasticity after stroke may be mediated through these pathways. In conclusion, our study provides novel insight into the potential mechanisms of BMSCs treatment in stroke and sheds light on the possible clinical translation of BMSCs.

Astrocytes in ischemic stroke: Crosstalk in central nervous system and therapeutic potential.

In the central nervous system (CNS), a large group of glial cells called astrocytes play important roles in both physiological and disease conditions. Astrocytes participate in the formation of neurovascular units and interact closely with other cells of the CNS, such as microglia and neurons. Stroke is a global disease with high mortality and disability rate, most of which are ischemic stroke. Significant strides in understanding astrocytes have been made over the past few decades. Astrocytes respond strongly to ischemic stroke through a process known as activation or reactivity. Given the important role played by reactive astrocytes (RAs) in different spatial and temporal aspects of ischemic stroke, there is a growing interest in the potential therapeutic role of astrocytes. Currently, interventions targeting astrocytes, such as mediating astrocyte polarization, reducing edema, regulating glial scar formation, and reprogramming astrocytes, have been proven in modulating the progression of ischemic stroke. The aforementioned potential interventions on astrocytes and the crosstalk between astrocytes and other cells of the CNS will be summarized in this review.

Hydroxyl and amino dual-functionalized core-shell molecular sieves featuring hydrogen bond donor groups for efficient CO2 cycloaddition.

In CO2 cycloaddition reactions, hydrogen bond donor (HBD) groups are considered environmentally friendly substitutes for metals to promote epoxide ring-opening through interactions with nucleophilic anions. A core-shell structured ILs-based catalyst (mSiO2@MCM-NH2-OH) with dual hydrogen bond donors (-OH and -NH2) was synthesized by copolymerization strategy. Through in-depth characterization, it has been demonstrated that the catalyst (mSiO2@MCM-NH2-OH) possesses multiple catalytic active sites including -OH, -NH2, Br- groups, and the synergistic effect of double HBD groups (-OH and -NH2) and Lewis base (Br-) significantly improved the catalytic activity. Meanwhile, the core-shell structure of the catalyst effectively prevents the loss of active components, which makes the yield remain at about 94 % after 10 cycles. Based on Density Functional Theory (DFT) calculations, a synergistic catalytic mechanism, which involves dual hydrogen-bond donors (-OH and -NH2) and Lewis bases (Br-) was proposed. The cooperative interaction between -OH/-NH2 and Br- reduced the ring-opening barrier of epoxide from 58.6 to 32.0 kcal mol-1 significantly, and thereby facilitated the CO2 cycloaddition reaction.

AIM2 inflammasome: A potential therapeutic target in ischemic stroke.

Ischemic stroke (IS) is a significant global public health issue with a high incidence, disability, and mortality rate. A robust inflammatory cascade with complex and wide-ranging mechanisms occurs following ischemic brain injury. Inflammasomes are multiprotein complexes in the cytoplasm that modulate the inflammatory response by releasing pro-inflammatory cytokines and inducing cellular pyroptosis. Among these inflammasomes, the Absent in Melanoma 2 (AIM2) inflammasome shows the ability to detect a wide range of pathogen DNAs, thereby triggering an inflammatory response. Recent studies have indicated that the aberrant expression of AIM2 inflammasome in various cells is closely associated with the pathological processes of ischemic brain injury. This paper summarizes the expression and regulatory role of AIM2 in CNS and peripheral immune cells and discusses current therapeutic approaches targeting AIM2 inflammasome. These findings aim to serve as a reference for future research in this field.

Which transfer day results in the highest live birth rate for PCOS patients undergoing in vitro fertilization?

BACKGROUND: Polycystic ovary syndrome (PCOS) has unusual levels of hormones. The hormone receptors in the endometrium have a hostile effect and make the microenvironment unfavorable for embryo implantation. The use of gonadotropin stimulation during in vitro fertilization (IVF) may have an impact on embryo implantation and live birth rate. According to recent data, the clinical results of day 4 embryo transfer (D4 transfer) were on par with those of day 5 embryo transfer (D5 transfer) in IVF-ET. There are few studies comparing the outcomes of transplants with various etiologies and days. The purpose of this study was to determine which transfer day had the best result for PCOS patients undergoing IVF. METHODS: This retrospective cohort study was conducted in the Xingtai Infertility Specialist Hospital between January 2017 and November 2021. A total of 1,664 fresh ART cycles met inclusion criteria, including 242 PCOS transfers and 1422 tubal factor infertility transfers. CONCLUSIONS: PCOS individuals had the highest live birth rate on D4 transferred. It was not need to culture embryos to blastocysts to optimize embryo transfer for PCOS women. This could be a novel approach to transplantation for PCOS.

Single-cell RNA sequencing of intestinal crypts reveals vital events in damage repair and the double-edged sword effect of the Wnt3/ß-catenin pathway in irradiated mice.

In this study, we executed single-cell RNA sequencing of intestinal crypts. We analyzed the differentially expressed genes (DEGs) at different time points (the first, third, and fifth days) after 13 Gy and 15 Gy abdominal body radiation (ABR) exposure and then executed gene ontology (GO) enrichment analysis, RNA velocity analysis, cell communication analysis, and ligand‒receptor interaction analysis to explore the vital events in damage repair and the multiple effects of the Wnt3/ß-catenin pathway on irradiated mice. Results from bioinformatics analysis were confirmed by a series of biological experiments. Results showed that the antibacterial response is a vital event during the damage response process after 13 Gy ABR exposure; ionizing radiation (IR) induced high heterogeneity in the transient amplification (TA) cluster, which may differentiate into mature cells and stem cells in irradiated small intestine (SI) crypts. Conducting an enrichment analysis of the DEGs between mice exposed to 13 Gy and 15 Gy ABR, we concluded that the Wnt3/ß-catenin and MIF-CD74/CD44 signaling pathways may contribute to 15 Gy ABR-induced mouse death. Wnt3/ß-catenin promotes the recovery of irradiated SI stem/progenitor cells, which may trigger macrophage migration inhibitory factor (MIF) release to further repair IR-induced SI injury; however, with the increase in radiation dose, activation of CD44 on macrophages provides the receptor for MIF signal transduction, initiating the inflammatory cascade response and ultimately causing a cytokine release syndrome. In contrast to previous research, we confirmed that inhibition of the Wnt3/ß-catenin pathway or blockade of CD44 on the second day after 15 Gy ABR may significantly protect against ABR-induced death. This study indicates that the Wnt3/ß-catenin pathway plays multiple roles in damage repair after IR exposure; we also propose a novel point that the interaction between intestinal crypt stem cells (ISCs) and macrophages through the MIF-CD74/CD44 axis may exacerbate SI damage in irradiated mice.

The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.

There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.

Protective effects and mechanisms of Momordica charantia polysaccharide on early-stage diabetic retinopathy in type 1 diabetes.

Momordica charantia polysaccharide (MCP) is a potential drug for the prevention and alleviation of diabetes mellitus (DM) and diabetic retinopathy (DR). This study aimed to investigate the potential protective effects of MCP on early-stage DR and explore the underlying mechanisms. The model group (DM group) and treatment group (D+H group) were established by inducing type 1 DM using a single dose of streptozotocin (STZ) at 60 mg/kg. After modeling, the D+H group was orally administered a 500 mg/kg dose of MCP solution once daily for 12 weeks. Monitoring of systemic indicators (FBG, body weight, general condition) and retinal tissue inflammation and apoptosis (HE staining, IL-6, MCP-1, TNF-α, VEGF, NF-κB, Caspase-3) in this study demonstrated that MCP intervention alleviated both DM and DR. MCP improved the body weight and general condition of DM rats by reducing FBG levels. It also enhanced the anti-inflammatory and anti-apoptotic capabilities of retinal neurons and microvessels by modulating the actions of cytokines, thereby further regulating the inflammation and apoptosis of retinal neurons and microvessels. The underlying mechanisms may be associated with the downregulation of NF-κB and Caspase-3 pathway protein expression, as well as the downregulation of mRNA expression of NF-κB and Caspase-3 pathway genes. Further research is needed to elucidate the potential mechanisms underlying the protective effects of MCP on DR. MCP may emerge as a selective medication for the prevention and alleviation of DM and a novel natural medicine for the prevention and alleviation of DR.

Compound 5 alleviated acute kidney injury without affecting the antitumor effect after cisplatin treatment.

Despite being a powerful weapon against cancer cells, cisplatin's therapeutic potential is hampered by numerous adverse reactions, including acute kidney injury (AKI). Compound 5 has 3-SH fragments at the end of the vertical short alkyl side chain, which is an ROS scavenger synthesized. In this study, we evaluated the protective effect of compound 5 on the kidney after cisplatin administration and its mechanism. The results founded that compound 5 can alleviate serum urea nitrogen and serum creatinine induced by cisplatin administration in vivo. In addition, histopathological analysis of the kidneys showed that compound 5 significantly reduced cisplatin-induced (Cis-induced) renal toxicity compared with the cisplatin group. A mechanism study showed that compound 5 significantly reduces NOX4 levels, improves the activity of antioxidant enzymes (SOD and GSH-Px), reduces Malondialdehyde (MDA) levels, increases the total antioxidant level, reduces oxidative stress, and thus reduces kidney tissue damage. At the same time, compound 5 activated the Nrf2 signaling pathway. In addition, it can increase the expression of Bax, reduce the expression of Bcl-2 and caspase-3, a marker of apoptosis, which is beneficial to the survival of kidney cells. Additionally, compound 5 did not interfere with the antitumor effects of cisplatin in in vivo xenotransplantation models.

KZ02 enhances the radiosensitivity of BRAF-mutated CRC in vitro and in vivo.

Colorectal cancer (CRC) is a common malignant tumor with a high incidence and mortality worldwide. Preoperative chemoradiotherapy is a common treatment for patients with metastatic colorectal cancer (mCRC) as it reduces colostomy and local recurrence. The RAS (rat sarcoma)-RAF (extracellular signal-regulated kinase)-MEK (mitogen-activated protein kinase)-ERK (extracellular signal-regulated kinase) pathway regulates important cellular processes in the CRC. Abnormal ERK activation stimulates cell growth and provides a survival advantage. Our group has previously reported that the compound KZ02 has a stronger ability to inhibit tumor growth than AZD6244 (a MEK inhibitor). In this study, we evaluated the antitumor activity of KZ02 in combination with ionizing radiation (IR) and investigated its mechanism of action in BRAF-mutated colorectal cancer. Our results showed that this combination kills tumor cells better than either radiation or drugs alone, both in vivo and in vitro. Furthermore, studies have shown that KZ02 inhibits ERK overactivation. The combination resulted in a G1 phase arrest, a reduction in the radioresistant S phase, and aggravating DNA damage. It can also inhibit Pim-1 (Moloney murine leukemia virus-1), p-BAD (Bcl-2 associated agonist of cell death), Bcl-2 (B-cell lymphoma 2) and Bcl-XL (B-cell lymphoma-extra large) levels and promote apoptosis when combined with radiation. Our results suggest that KZ02 significantly increases the radiosensitivity of BRAF-mutated CRC cells by perturbing the cell cycle, increasing DNA damage, and promoting tumor apoptosis.