Diverse functions and pathogenetic role of Crumbs in retinopathy.

The Crumbs protein (CRB) family plays a crucial role in maintaining the apical-basal polarity and integrity of embryonic epithelia. The family comprises different isoforms in different animals and possesses diverse structural, localization, and functional characteristics. Mutations in the human CRB1 or CRB2 gene may lead to a broad spectrum of retinal dystrophies. Various CRB-associated experimental models have recently provided mechanistic insights into human CRB-associated retinopathies. The knowledge obtained from these models corroborates the importance of CRB in retinal development and maintenance. Therefore, complete elucidation of these models can provide excellent therapeutic prospects for human CRB-associated retinopathies. In this review, we summarize the current animal models and human-derived models of different CRB family members and describe the main characteristics of their retinal phenotypes.

Andrographolide Improves ApoE4-Mediated Blood-Brain Barrier Injury by Alleviating Inflammation.

The pathological and physiological studies of Alzheimer's disease (AD) have been in-depth, and apolipoprotein E4 (ApoE4) has been proven to be highly correlated with AD, and clinical and experimental data show that ApoE4 can cause blood-brain barrier (BBB) injury, and the change of BBB permeability is an important factor affecting the development of AD. Andrographolide (Andro), as the active component of the natural plant Andrographis paniculata, has been proven to have anti-inflammatory and antioxidant effects, which have potential neuroprotective effects. To verify the protective effect of Andro on BBB in a short term, our research group used atorvastatin (Atorva)-mediated zebrafish brain injury model and the ApoE4-mediated cell co-culture model of BBB injury to explore the protective effects and mechanisms of Andro on BBB injury. Studies have shown that Andro can inhibit the activation of CypA/NF-κB/MMP-9 signaling pathway and has achieved the effect of antagonizing the inhibition of ApoE4 on intercellular tight junction proteins (occludin, claudin-5, and ZO-1). At the same time, Andro can inhibit the secretion of cell adhesion molecules (VCAM-1 and ICAM-1) in cells, thereby delaying the occurrence and progression of neuroinflammation and playing a protective role in BBB. In conclusion, Andro is a potent natural product which can protect the blood-brain barrier.

Nuciferine reduces inflammation induced by cerebral ischemia-reperfusion injury through the PI3K/Akt/NF-κB pathway.

BACKGROUND: Cerebral ischemia has the characteristics of high incidence, mortality, and disability, which seriously damages people's health. Cerebral ischemia-reperfusion injury is the key pathological injury of this disease. However, there is a lack of drugs that can reduce cerebral ischemia-reperfusion injury in clinical practice. At present, a few studies have provided some evidence that nuciferine can reduce cerebral ischemia-reperfusion injury, but its specific mechanism of action is still unclear, and further research is still needed. OBJECTIVE: In this study, PC12 cells and SD rats were used to construct OGD/R and MCAO/R models, respectively. Combined with bioinformatics methods and experimental verification methods, the purpose of this study was to conduct a systematic and comprehensive study on the effect and mechanism of nuciferine on reducing inflammation induced by cerebral ischemia-reperfusion injury. RESULTS: Nuciferine can improve the cell viability of PC12 cells induced by OGD/R, reduce apoptosis, and reduce the expression of inflammation-related proteins; it can also improve the cognitive and motor dysfunction of MCAO/R-induced rats by behavioral tests, reduce the area of cerebral infarction, reduce the release of inflammatory factors TNF-α and IL-6 in serum and the expression of inflammation-related proteins in brain tissue. CONCLUSION: Nuciferine can reduce the inflammatory level of cerebral ischemia-reperfusion injury in vivo and in vitro models by acting on the PI3K/Akt/NF-κB signaling pathway, and has the potential to be developed as a drug for the treatment of cerebral ischemia-reperfusion injury.

Andrographolide derivative Andro-III modulates neuroinflammation and attenuates neuropathological changes of Alzheimer's disease via GSK-3ß/NF-κB/CREB pathway.

Andrographolide has anti-inflammatory and neuroprotective effects, making it a potential therapeutic option for Alzheimer's disease (AD). Our research group optimized its structure in a previous study to minimize the risk of renal toxicity, which would beneficial for future clinical research. This study aims to examine the impact of Andro-III on enhancing cognitive learning ability in 3xTg-AD mice, as well as the mechanisms involved. Andro-III improved spatial learning ability, prevented the loss of Nysted's vesicles, reduced the accumulation of ß-amyloid (Aß) and tau proteins, and suppressed microglial activation. Further research found that the expression of nuclear factor kappa-B RelA (NF-κB p65) expression and glycogen synthase kinase-3ß (GSK-3ß) activity were inhibited, while CREB was upregulated in brain tissue treated with Andro-III. Moreover, Andro-III downregulated the expression of IBA1 and inflammatory factors in microglial cells of mice induced by Aß. The regulation of the GSK-3ß/NF-κB/CREB pathway was similar to that observed in 3xTg-AD mice. Therefore, Andro-III modulates neuroinflammation and attenuates neuropathological changes of AD via the GSK-3ß/NF-κB/CREB pathway.

Solvent-controlled synthesis of hydrophilic and hydrophobic carbon dots.

Hydrophilicity and hydrophobicity are of paramount importance in surface chemistry. In this study, a solvent-controlled synthesis of hydrophilic and hydrophobic carbon dots (CDs) was prepared via a solvothermal process using pentafluorobenzyl alcohol as the carbon source in either deionized water or N,N-dimethylformamide (DMF) medium. By simply varying the reaction solvent to control the doping of nitrogen and fluorine elements, the hydrophilicity or hydrophobicity of the CDs could be regulated. Hydrophobic and hydrophilic CDs showed blue and green light under a UV lamp, respectively. Besides, we regulated the volume ratio of water/DMF (1 : 2, 1 : 1 and 2 : 1) in the reaction solvent to prepare amphiphilic CDs and further studied their hydrophilicity and hydrophobicity. Furthermore, the sensitivity of hydrophobic CDs to water was investigated. In water detection, the photoluminescent intensity of the blue peak and green peak showed high linearity within the water content of 4-80% and 10-80%, respectively (limit of detection = 0.08%, v/v, in DMF).

Andrographolide exerts a neuroprotective effect by regulating the LRP1-mediated PPARγ/NF-κB pathway.

Low-density lipoprotein receptor-associated protein 1 (LRP1) is widely expressed in neurons, microglia and astrocytes. Studies have revealed that the suppression of LRP1 expression in the brain significantly exacerbates Alzheimer's disease (AD)-related neuropathology. Andrographolide (Andro) has been demonstrated to possess neuroprotective properties, although its underlying mechanisms remain largely unknown. This study aims to investigate whether Andro can inhibit neuroinflammation in AD by modulating the LRP1-mediated PPARγ/NF-κB pathway. In Aß-induced BV-2 cells, Andro was found to increase cell viability and enhance the expression of LRP1, while decreasing the expression of p-NF-κB (p65) and NF-κB(p65), as well as IL-1ß, IL-6 and TNF-α levels. In addition, when Aß was cotreatment with Andro to BV2 cells with either LRP1 or PPARγ knockdown, increased mRNA and protein expression of p-NF-κB(p65) and NF-κB(p65), NF-κB DNA binding activity as well as IL-1ß, IL-6 and TNF-α levels were observed. These findings suggested that Andro could attenuate Aß induced cytotoxicity by reducing neuroinflammation which may be partly attributed to its effects on this LRP1 mediated PPARγ/NF-κB pathway.

ApoE4-mediated blood-brain barrier damage in Alzheimer's disease: Progress and prospects.

Late-onset Alzheimer's disease (AD), a neurodegenerative disease, is expected in the elderly population and adversely affects families and society. The extensive debate on the deposition of amyloid (Aß), abnormal phosphorylation of Tau protein, and neuroinflammation hypothesis in the pathogenesis of AD has been recognized by many scholars. The blood-brain barrier (BBB) is an essential physical barrier that protects the brain from external material interference, and its integrity affects the process of AD. Apolipoprotein E4 (ApoE4) has shown a critical regulatory role in many studies and is a crucial protein that affects AD. Numerous current studies on ApoE4 are based on complementary hypotheses to the three hypotheses above, ignoring the effect of ApoE4 on BBB constitutive cells and the role of the BBB in AD. In this review, we summarize the findings of the role of ApoE4 in the composition of the BBB and the value of ApoE4 for maintaining BBB integrity, which may play an essential role in changing the progression of the disease.

Medicinal fungus Phellinus igniarius alleviates gout in vitro by modulating TLR4/NF-kB/NLRP3 signaling.

Background: Phellinus igniarius (P. igniarius) is a valuable medicinal and edible fungus with various biological activities such as anti-inflammation, antioxidation, and immune regulation. In this study, we explored the effects of P. igniarius on a gout model in vitro. Methods: The DPPH, ABTS, and FRAP methods were combined to determine and compare the antioxidant activities of wild P. igniarius total polyphenols (WPP) and cultivated P. igniarius total polyphenols (CPP) in vitro. Spectrophotometry was used to compare the inhibitory effect of WPP and CPP on xanthine oxidase (XO) activity to evaluate anti-hyperuricemia activity in vitro. HUVECs were stimulated with monosodium urate (MSU) crystals for 24 h to establish an acute gouty inflammation model in vitro. The protective effects were compared by measuring cell viability; the contents of ICAM-1, IL-1ß, IL-6 and VCAM-1; the protein expressions of TLR4 and NLRP3; reactive oxygen species production; and the nuclear translocation of NF-κB p65. UHPLC-QE-MS technology was used to explore the potential metabolic mechanism of P. igniarius against gout. Results: WPP and CPP had strong antioxidant capacity, and the antioxidant capacity of CPP was similar to that of WPP. In a comparative experiment of xanthine oxidase activity inhibition by WPP and CPP, the IC50 values were 88.19 µg/ml and 108.0 µg/ml, respectively. At a dose of 40 µg/ml, WPP and CPP significantly improved the decrease in cell viability induced by monosodium urate (150 µg/ml) and inhibited the increase in inflammatory factors such as ICAM-1, IL-1ß, IL-6, and VCAM-1. The increase in TLR4 and NLRP3 protein expression induced by MSU crystals in HUVECs was also significantly inhibited by total polyphenols from wild and cultivated P. igniarius. In addition, both significantly improved MSU-induced ROS overproduction and NF-κB p65 nuclear translocation. WPP and CPP may primarily be involved in phenylalanine metabolism and lysophosphatidylcholine metabolism in their role in the treatment of gout. Conclusion: CPP and WPP both showed good antioxidant activity and xanthine oxidase inhibitory activity and had good therapeutic effects on the gout model in vitro. Furthermore, this study indicated that cultivated P. igniarius had a protective effect similar to that of wild P. igniarius, which would be expected to improve the shortage of wild P. igniarius and promote the development of the cultivated P. igniarius industry and product development.

Emerging advances in identifying signal transmission molecules involved in the interaction between Mycobacterium tuberculosis and the host.

Tuberculosis caused by Mycobacterium tuberculosis (MTB) is an ancient chronic infectious disease and is still the leading cause of death worldwide due to a single infectious disease. MTB can achieve immune escape by interacting with host cells through its special cell structure and secreting a variety of effector proteins. Innate immunity-related pattern recognition receptors (PPR receptors) play a key role in the regulation of signaling pathways. In this review, we focus on the latest research progress on related signal transduction molecules in the interaction between MTB and the host. In addition, we provide new research ideas for the development of new anti-tuberculosis drug targets and lead compounds and provide an overview of information useful for approaching future tuberculosis host-oriented treatment research approaches and strategies, which has crucial scientific guiding significance and research value.

Nonsteroidal anti-inflammatory drugs for retinal neurodegenerative diseases.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common prescription drugs for inflammation, and topical NSAIDs are often used in ophthalmology to reduce pain, photophobia, inflammation, and edema. In recent years, many published reports have found that NSAIDs play an important role in the treatment of retinal neurodegenerative diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, pathological myopia, and retinitis pigmentosa (RP). The aim of the current review is to provide an overview of the role of various NSAIDs in the treatment of retinal neurodegenerative diseases and the corresponding mechanisms of action. This review highlighted that the topical application of NSAIDs for the treatment of retinal degenerative diseases has been studied to a remarkable extent and that its beneficial effects in many diseases have been proven. In the future, prospective studies with large study populations are required to extend these effects to clinical settings.

Anti-Gout Effects of the Medicinal Fungus Phellinus igniarius in Hyperuricaemia and Acute Gouty Arthritis Rat Models.

Background: Phellinus igniarius (P. igniarius) is an important medicinal and edible fungus in China and other Southeast Asian countries and has diverse biological activities. This study was performed to comparatively investigate the therapeutic effects of wild and cultivated P. igniarius on hyperuricaemia and gouty arthritis in rat models. Methods: UPLC-ESI-qTOF-MS was used to identify the chemical constituents of polyphenols from wild P. igniarius (WPP) and cultivated P. igniarius (CPP). Furthermore, WPP and CPP were evaluated in an improved hyperuricaemia rat model induced by yeast extract, adenine and potassium oxonate, which was used to examine xanthine oxidase (XO) activity inhibition and anti-hyperuricemia activity. WPP and CPP therapies for acute gouty arthritis were also investigated in a monosodium urate (MSU)-induced ankle swelling model. UHPLC-QE-MS was used to explore the underlying metabolic mechanisms of P. igniarius in the treatment of gout. Results: The main active components of WPP and CPP included protocatechuic aldehyde, hispidin, davallialactone, phelligridimer A, hypholomine B and inoscavin A as identified by UPLC-ESI-qTOF-MS. Wild P. igniarius and cultivated P. igniarius showed similar activities in reducing uric acid levels through inhibiting XO activity and down-regulating the levels of UA, Cr and UN, and they had anti-inflammatory activities through down-regulating the secretions of ICAM-1, IL-1ß and IL-6 in the hyperuricaemia rat model. The pathological progression of kidney damage was also reversed. The polyphenols from wild and cultivated P. igniarius also showed significant anti-inflammatory activity by suppressing the expression of ICAM-1, IL-1ß and IL-6 and by reducing the ankle joint swelling degree in an MSU-induced acute gouty arthritis rat model. The results of metabolic pathway enrichment indicated that the anti-hyperuricemia effect of WPP was mainly related to the metabolic pathways of valine, leucine and isoleucine biosynthesis and histidine metabolism. Additionally, the anti-hyperuricemia effect of CPP was mainly related to nicotinate and nicotinamide metabolism and beta-alanine metabolism. Conclusions: Wild P. igniarius and cultivated P. igniarius both significantly affected the treatment of hyperuricaemia and acute gouty arthritis models in vivo and therefore may be used as potential active agents for the treatment of hyperuricaemia and acute gouty arthritis.

Analysis of risk factors for progressive fibrovascular proliferation in proliferative diabetic retinopathy.

PURPOSE: To investigate the risk factors associated with progressive fibrovascular proliferation (FVP) in proliferative diabetic retinopathy (PDR). METHODS: We retrospectively reviewed the clinical data of patients who underwent pars plana vitrectomy for PDR between August 2017 and October 2019 at our department of ophthalmology. The FVP was divided into five grades based on the coverage area of proliferative membrane. Then we compared the patients with different severities of FVP to analyze the risk factors for higher grade of FVP in PDR. RESULTS: Univariate analysis showed that positive urinary protein (p = 0.007), higher levels of serum blood urea nitrogen (BUN) (p < 0.001) and serum creatinine (p < 0.001), more severe stage of estimated glomerular filtration rate (p < 0.001), age < 45 years (p = 0.005), longer duration of diabetic retinopathy (p = 0.007), history of hypertension (p = 0.034) and smoking (p = 0.008) were related to FVP grade ≥ 3. Multivariate analysis showed that the level of BUN, age < 45 years and smoking were independent risk factors for FVP grade ≥ 3 in PDR patients. CONCLUSION: This study demonstrated that BUN (odds ratio [OR] = 1.318, 95% confidence interval [CI] = 1.150-1.511, p < 0.001), age ≤ 45 years (OR = 3.774, 95% CI = 1.762-8.082, p = 0.001) and smoking (OR = 2.111, 95% CI = 1.040-4.288, p = 0.039) were independent risk factors for progressive FVP in PDR among northeastern Chinese patients.

Effects of Bacillus subtilis C-3102 on production, hatching performance, egg quality, serum antioxidant capacity and immune response of laying breeders.

To investigate the supplemental effects of Bacillus subtilis C-3102 on the production, hatching performance, egg quality, serum antioxidant capacity and immune response of laying breeders, a total of 480 Xuefeng black-bone (25-week-old) hens were randomly assigned into four treatment groups: Hens fed the basal diets with 0 (CON), 3.0 × 105 (BS-1), 6.0 × 105  cfu/g (BS-2) and 9.0 × 105 (BS-3) cfu/g of B. subtilis C-3102. As the B. subtilis C-3102 level increased, egg weight (linear, p < 0.01; quadratic, p = 0.003), fertility (linear, p = 0.021; quadratic, p = 0.059), hatchability (linear, p = 0.038; quadratic, p = 0.119) and yolk colour (linear, p = 0.006; quadratic, p = 0.021) increased in a linear or quadratic manner. Yolk index increased quadratically (linear, p = 0.054; quadratic, p = 0.017), and eggshell thickness (linear, p = 0.036; quadratic, p = 0.128), the activity of GSH-Px (linear, p = 0.024; quadratic, p = 0.078), the concentration of IgM (linear, p = 0.016; quadratic, p = 0.056) and the level of AIV-Ab (linear, p = 0.034; quadratic, p = 0.103) in the serum increased linearly as dietary supplementation of B. subtilis C-3102 increased. The results showed that dietary treatments did not affect egg production, feed conversion ratio, egg mass, hatchability of fertile eggs, eggshell-breaking strength, egg-shape index, yolk percentage, Haugh unit, T-SOD, T-AOC, MDA, IgA and IgG concentrations and the level of NDV-Ab in the serum. In conclusion, dietary supplementation of 9.0 × 105  cfu/g B. subtilis C-3102 in laying breeders diets may be a feasible means of effectively increasing egg weight, fertility and hatchability, and improving egg quality such as eggshell thickness, yolk index and yolk colour. Besides, B. subtilis C-3102 can enhance the activity of GSH-Px, the concentration of IgM and the level of AIV-Ab in the serum.