High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN‐γ‐induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain‐binding protein 1‐like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN‐γ/JAK1/STAT1/PD‐L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell‐mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD‐L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient‐derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202206792

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Colorectal cancer is a prevalent malignant tumor with a complex and diverse pathogenesis. In recent years, natural products have shown promising application prospects as sources of anticancer drugs. BBR, a class of benzoquinoline alkaloids extracted from various plants, is widely used in disease treatments owing to its pharmacological activities, including antibacterial, anti-inflammatory, antioxidant, anticancer, and anti-angiogenesis properties. Research has demonstrated that BBR exerts an anti-Salmonella and -Escherichia coli infection effect, attenuating inflammatory reactions by inhibiting harmful bacteria. During the stage of colorectal precancerous lesions, BBR inhibits the activity of cell cyclin by regulating the PI3K/AKT, MAPK, and Wnt signaling pathways, thereby decelerating the cell cycle progression of polyp or adenoma cells. Moreover, the inhibitory effect of BBR on colorectal cancer primarily occurs through the regulation of the cancer cell cycle, anti-angiogenesis, gut microbiota, and antioxidant pathways. The specific involved pathways include the MPK/ERK, NF-kB, and EGFR signaling pathways, encompassing the regulation of Bcl-2 family proteins, vascular endothelial growth factor, and superoxide dismutase. This study reviews and summarizes, for the first time, the specific mechanisms of action of BBR in the carcinogenesis process of colorectal cancer, providing novel insights for its clinical application in intestinal diseases. 

Berberine: An inspiring resource for the treatment of colorectal diseases.

Background Evidence from previous studies reporting on the relationship between tea consumption and its preventive effect on coronary artery disease (CAD) has conflicting outcomes. With the accumulation of new clinical evidence, we conducted this meta-analysis to assess tea consumption and CAD risk. Methods We searched PubMed, EMBASE, Cochrane Library, and Medline databases for published observational studies from their inception to May 2022. A random-effects model was used to calculate risk ratios with 95% confidence intervals. We also conducted linear and non-linear dose-response meta-analyses to analyze the association. We regarded that one cup equals 237 mL. Subgroup analyses and univariate meta-regression were conducted to explore the source of heterogeneity. Results A total of 35 studies, including 24 on green tea and 11 on black tea consumption, were included in this meta-analysis. An inverse association for the risk of CAD was observed for black tea (RR: 0.85; 95% CI: 0.76, 0.96) and green tea (RR: 0.93; 95% CI: 0.88, 0.99). The dose-response meta-analysis showed that drinking less than four cups of black tea daily may effectively prevent CAD, while more than 4–6 cups/d will promote disease risk. Furthermore, the dose-response relationship between green tea consumption and the prevention of CAD showed that the risk of CAD gradually decreased as green tea consumption increased. We also demonstrated that the more cups of green tea consumed, the lower the risk of CAD. In the subgroup analysis by continent, a significant negative correlation between CAD risk and green tea consumption was observed in the Asian population (RR: 0.92; 95% CI: 0.85, 0.99) but not in the western population [North America (RR: 0.97; 95% CI: 0.92, 1.03), Europe/Oceana (RR: 0.91; 95% CI: 0.78, 1.07)]. Conclusions Higher green tea consumption was associated with reduced CAD risk, but drinking more than 4–6 cups of black tea per day may increase the risk. This study offers new insight into the relationship between tea consumption and its preventive effect on CAD. However, further large prospective cohort studies are needed to validate these findings. Systematic review registration The protocol of this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) system (CRD42022348069).

/pdf/association-between-tea-consumption-and-prevention-of-1a2qg04r.pdf

Association between tea consumption and prevention of coronary artery disease: A systematic review and dose-response meta-analysis

Ginseng is a valuable herb in traditional Chinese medicine. Modern research has shown that it has various benefits, including tonifying vital energy, nourishing and strengthening the body, calming the mind, improving cognitive function, regulating fluids, and returning blood pressure, etc. Rg1 is a primary active component of ginseng. It protects hippocampal neurons, improves synaptic plasticity, enhances cognitive function, and boosts immunity. Furthermore, it exhibits anti-aging and anti-fatigue properties and holds great potential for preventing and managing neurodegenerative diseases (NDDs).The objective of this study was to examine the role of Rg1 in treating chronic inflammatory NDDs and its molecular mechanisms.In vivo, we investigated the protective effects of Rg1 against chronic neuroinflammation and cognitive deficits in mice induced by 200 μg/kg lipopolysaccharide (LPS) for 21 days using behavioral tests, pathological sections, Western blot, qPCR and immunostaining. In vitro experiments involved the stimulation of HT22 cells with 10 μg/ml of LPS, verification of the therapeutic effect of Rg1, and elucidation of its potential mechanism of action using H2DCFDA staining, BODIPY™ 581/591 C11, JC-1 staining, Western blot, and immunostaining.Firstly, it was found that Rg1 significantly improved chronic LPS-induced behavioral and cognitive dysfunction in mice. Further studies showed that Rg1 significantly attenuated LPS-induced neuronal damage by reducing levels of IL-6, IL-1β and ROS, and inhibiting AIM2 inflammasome. Furthermore, chronic LPS exposure induced the onset of neuronal ferroptosis by increasing the lipid peroxidation product MDA and regulating the ferroptosis-associated proteins Gpx4, xCT, FSP1, DMT1 and TfR, which were reversed by Rg1 treatment. Additionally, Rg1 was found to activate Nrf2 and its downstream antioxidant enzymes, such as HO1 and NQO1, both in vivo and in vitro. In vitro studies also showed that the Nrf2 inhibitor ML385 could inhibit the anti-inflammatory, antioxidant, and anti-ferroptosis effects of Rg1.This study demonstrated that Rg1 administration ameliorated chronic LPS-induced cognitive deficits and neuronal ferroptosis in mice by inhibiting neuroinflammation and oxidative stress. The underlying mechanisms may be related to the inhibition of AIM2 inflammasome and activation of Nrf2 signaling. These findings provide valuable insights into the treatment of chronic neuroinflammation and associated NDDs. 

Ginsenoside Rg1 alleviates chronic inflammation-induced neuronal ferroptosis and cognitive impairments via regulation of AIM2 - Nrf2 signaling pathway.

Atherosclerosis (AS) with iron and lipid overload and systemic inflammation is a risk factor for Alzheimer's disease. M1 macrophage/microglia participate in neuronal pyroptosis and recently have been reported to be the ferroptosis-resistant phenotype. Quercetin plays a prominent role in preventing and treating neuroinflammation, but the protective mechanism against neurodegeneration caused by iron deposition is poorly understood. ApoE-/- mice were fed a high-fat diet with or without quercetin treatment. The Morris water maze and novel object recognition tests were conducted to assess spatial learning and memory, and nonspatial recognition memory, respectively. Prussian blue and immunofluorescence staining were performed to assess the iron levels in the whole brain and in microglia, microglia polarization, and the degree of microglia/neuron ferroptosis. In vitro, we further explored the molecular biological alterations associated with microglial polarization, neuronal pyroptosis, and ferroptosis via Western blot, flow cytometry, CCK8, LDH, propidium iodide, and coculture system. We found that quercetin improved brain lesions and spatial learning and memory in AS mice. Iron deposition in the whole brain or microglia was reversed by the quercetin treatment. In the AS group, the colocalization of iNOS with Iba1 was increased, which was reversed by quercetin. However, the colocalization of iNOS with PTGS2/TfR was not increased in the AS group, suggesting a character resisting ferroptosis. Quercetin induced the expression of Arg-1 and decreased the colocalizations of Arg-1 with PTGS2/TfR. In vitro, ox-LDL combined with ferric ammonium citrate treatment (OF) significantly shifted the microglial M1/M2 phenotype balance and increased the levels of free iron, ROS, and lipid peroxides, which was reversed by quercetin. M1 phenotype induced by OF caused neuronal pyroptosis and was promoted to ferroptosis by L-NIL treatment, which contributed to neuronal ferroptosis as well. However, quercetin induced the M1 to M2 phenotype and inhibited M2 macrophages/microglia and neuron pyroptosis or ferroptosis. In summary, quercetin alleviated neuroinflammation by inducing the M1 to M2 phenotype to inhibit neuronal pyroptosis and protected neurons from ferroptosis, which may provide a new idea for neuroinflammation prevention and treatment.

Quercetin Inhibits Neuronal Pyroptosis and Ferroptosis by Modulating Microglial M1/M2 Polarization in Atherosclerosis.

BACKGROUND
Berberine (BBR) is a natural alkaloid extracted from the herb Coptis chinensis. This compound has the ability to penetrate the blood-brain barrier (BBB) and exhibit neuroprotective value in the treatment of Alzheimer's disease (AD). AD is a neurodegenerative disease characterized by β-amyloid (Aβ) deposition, hyperphosphorylated tau and other characters. Iron accumulation and ferroptosis were also detected in AD brain, which can result in neuronal damage. However, it is still unclear whether BBR can suppress ferroptosis in AD and alleviate its underlying pathology.


PURPOSE
This study investigated whether BBR may affect ferroptosis and related signaling pathways in triple transgenic AD (3 × Tg-AD) mice.


METHODS
Four-month-old 3 × Tg-AD mice received oral administration of BBR at a dose of 50 mg/kg for 7.5 months. Cognitive function and anxiety levels in mice were assessed using the morris water maze test, open field test, and novel object recognition test. Western blot, immunohistochemistry, and ICP-MS were employed to assess the pathology of AD, brain iron metabolism, and ferroptosis signaling pathways. Transmission electron microscopy was used to detect mitochondrial changes. The synergistic effects of BBR combined with Nrf2 were investigated using molecular docking programs and surface plasmon resonance technology. Co-inmunoprecipitation assay was used to examine the effect of BBR on the binding ability of Nrf2 and Keap1.


RESULTS
The results indicated that chronic treatment of BBR mitigated cognitive disorders in 3 × Tg-AD model mice. Reductions in Aβ plaque, hyperphosphorylated tau protein, neuronal loss, and ferroptosis in the brains of 3 × Tg-AD mice suggested that BBR could alleviate brain injury. In addition, BBR treatment attenuated ferroptosis, as evidenced by decreased levels of iron, MDA, and ROS, while enhancing SOD, GSH, GPX4, and SLC7A11. Consistent with the in vivo assay, BBR inhibited RSL3-induced ferroptosis in N2a-sw cells. BBR increased the expression levels of GPX4, FPN1 and SLC7A11 by regulating Nrf2 transcription levels, thereby inhibiting ferroptosis. Molecular docking programs and surface plasmon resonance technology demonstrated the direct combination of BBR with Nrf2. Co-inmunoprecipitation analysis showed that BBR inhibited the interaction between Keap1 and Nrf2.


CONCLUSION
For the first time, these results showed that BBR could inhibit iron levels and ferroptosis in the brains of 3 × Tg-AD model mice and partially protect against RSL3-induced ferroptosis via the activation of Nrf2 signaling.

Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice

SCOPE
As a natural dietary low-molecular-weight thiol, pantethine helps maintain brain homeostasis and function in AD mice. The current study aimed to investigate the protective effects and underlying mechanisms of pantethine on the mitigation of cognitive deficits and pathology in a triple transgenic AD mouse model.


METHODS AND RESULTS
Compared to control mice, oral administration of pantethine improved spatial learning and memory ability, relieved anxiety, and reduced the production of Aβ, neuronal damage, and inflammation in 3×Tg-AD mice. Pantethine reduced body weight, body fat, and the production of cholesterol in 3×Tg-AD mice by inhibiting SREBP2 signal pathway and APOE expression; lipid rafts in the brain, which are necessary for the processing of the Aβ precursor APP, were also decreased. In addition, pantethine regulated the composition, distribution, and abundance of characteristic flora in the intestine; these flora are considered protective and anti-inflammatory in the gastrointestinal tract, suggesting a possible improvement in the gut flora of 3×Tg-AD mice.


CONCLUSION
This study highlights the potential therapeutic effect of pantethine in AD by reducing cholesterol and lipid raft formation and regulating intestinal flora, suggesting a new option for the development of clinical drugs for AD. This article is protected by copyright. All rights reserved.

Pantethine ameliorates recognition impairment in a mouse model of Alzheimer's disease by modulating cholesterol content and intestinal flora species.

Purpose: This study was designed to evaluate the associations between retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), and the severity of diabetic retinopathy (DR) by using optical coherence tomographic angiography (OCTA). Methods: In this prospective cross-sectional study, 1,282 ocular-treatment-naive patients with type 2 diabetes mellitus (DM) (1,059 without DR and 223 with DR) registered in the community of Guangzhou, China, were enrolled. OCTA was used to measure FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression analyses were performed to analyze the correlation of FD and BVT in different layers with DR severity. Results: In this study, 1,282 patients with DM (1,282 eyes), with a mean age of 64.2 ± 7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in patients with DR compared with those in patients without DR, even after adjusting for confounding factors (p < 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, whereas the BVT progressively increased with worsening DR severity (p < 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group, and severe DR group (p < 0.01). Conclusions: FD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression.

Macular Vascular Complexity Analysis of Diabetes Mellitus by Swept-Source Optical Coherence Tomographic Angiography

ChatGPT has garnered significant attention for its impressive capabilities across various domains, including medicine and mechanobiology. In order to facilitate the integration of ChatGPT into research, this paper explores the applications of ChatGPT in these domains, focusing on its usage in (1) reading and writing, (2) retrieval and knowledge management, and (3) computation, simulation, and visualization. Meanwhile, this study acknowledges the limitations and challenges associated with ChatGPT’s usage. We investigate the interaction between ChatGPT and external tools in these applications and advocate for the integration of more powerful tools in these research areas into ChatGPT to further expand its potential applications in medicine and mechanobiology. 

ChatGPT for mechanobiology and medicine: A perspective

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Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Pantethine ameliorates recognition impairment in a mouse model of Alzheimer's disease by modulating cholesterol content and intestinal flora species.

Macular Vascular Complexity Analysis of Diabetes Mellitus by Swept-Source Optical Coherence Tomographic Angiography

ChatGPT for mechanobiology and medicine: A perspective

Minyu Chen

Author Tools

Chat about Author

Papers

Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Pantethine ameliorates recognition impairment in a mouse model of Alzheimer's disease by modulating cholesterol content and intestinal flora species.

Macular Vascular Complexity Analysis of Diabetes Mellitus by Swept-Source Optical Coherence Tomographic Angiography

ChatGPT for mechanobiology and medicine: A perspective

Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice