Norkurarinone and isoxanthohumol inhibit high glucose and hypoxia-induced angiogenesis via improving oxidative stress and regulating autophagy in human retinal microvascular endothelial cells.

Diabetic retinopathy (DR) is one of the most serious complications of diabetic microangiopathy. Recent studies have shown its close association with high glucose-induced oxidative stress and autophagy disorder. Previous studies showed that various compounds of flavonoids of Sophora flavescens Aiton extracted using ethyl acetate (SFE) could cross the blood-retinal barrier, exerting favorable effects on retinal tissue disorders and angiogenesis in rats with DR. However, the mechanism and the specific material basis for SFE are still unclear. Here, we established the in vitro DR model of human retinal microvascular endothelial cell (HRMECs) induced by high glucose and hypoxia (HGY), screened out the potential pharmacodynamic components of SFE viz. norkurarinone (NKR) and isoxanthohumol (IXM), and proved that they could improve the pathological features of angiogenesis. Further, we explored the mechanism of action of NKR and IXM, investigating their effects on cellular oxidative stress and autophagy levels under HGY conditions. Finally, the role of the PI3K/AKT/mTOR signaling pathway in the regulation of cell autophagy by NKR and IXM was evaluated. Collectively, NKR and IXM could improve cellular oxidative stress state and activate PI3K/AKT/mTOR signaling pathway to regulate autophagy dysregulation, thus playing a significant role in protecting HRMECs from HGY-caused angiogenesis.

Characterization of the chemical composition of different parts of Dolichos lablab L. and revelation of its anti-ulcerative colitis effects by modulating the gut microbiota and host metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a non-specific inflammatory disease characterized by long duration and easy relapse. Dolichos lablab L. (DLL) belongs to the family Fabaceae, was listed in a famous Chinese medical classic, Compendium of Materia Medic, and described as possessing features that invigorate the spleen, alleviate dampness, provide diarrhea relief, and other effects. The DLL-dried white mature seeds (DS) and dried flower (DF), which hold significant medicinal value in China, were used in clinical prescriptions to prevent and treat UC. DS and DF have appeared in different editions of the Pharmacopoeia of the People's Republic of China from 1977 to 2020. However, their chemical composition, pharmacological effects, and mechanism of treating UC are unclear. AIM OF THE STUDY: This study aimed to characterize the chemical composition of different parts of DLL (seeds and flowers), further explore their pharmacological effects, and elaborate its underlying mechanism of treating UC. METHODS: The chemical composition of DS and DF crude polysaccharides (DSP and DFP) and ethanolic extracts (DSE and DFE) were characterized by high-performance anion-exchange chromatography (HPAEC), ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), and gas chromatography-mass spectrometry (GC-MS). Then, based on the acute UC mice model, the pharmacodynamic effects were investigated by Western blotting, ELISA, and other methods. Finally, the 16S rRNA gene sequencing and metabonomic analysis were used to explore the regulatory effects of DS and DF on intestinal microbiota and host metabolism. RESULTS: DSE and DFE inhibited the oxidative stress response, reducing proinflammatory factor production and maintaining intestinal barrier integrity in UC mice. The 16S rRNA gene sequencing and metabonomic analysis revealed that DS and DF treated UC by regulating the intestinal microbiota structure and reversing the abnormal metabolism of the host. CONCLUSION: This study suggested that different parts of DLL (flowers and seeds) may be potential medicines for treating UC, which exert their therapeutic effects through various active ingredients and might contribute significantly to reducing the economic pressures and challenges of UC treatment worldwide.

Curcumin/TGF-ß1 siRNA loaded solid lipid nanoparticles alleviate cerebral injury after intracerebral hemorrhage by transnasal brain targeting.

Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disorder. The inflammation induced by cerebral hemorrhage plays a crucial role in the secondary injury of ICH and often accompanied by a poor prognosis, leading to disease exacerbation. However, blood-brain barrier (BBB) limiting the penetration of therapeutic drugs to the brain. In this paper, our primary objective is to develop an innovative, non-invasive, safe, and targeted formulation. This novel approach aims to synergistically harness the combined therapeutic effects of drugs to intervene in inflammation via a non-injectable route, thereby significantly mitigating the secondary damage precipitated by inflammation following ICH. Thus, a novel "anti-inflammatory" cationic solid lipid nanoparticles (SLN) with targeting ability were constructed, which can enhance the stability of curcumin(CUR) and siRNA. We successfully developed SLN loaded with TGF-ß1 siRNA and CUR (siRNA/CUR@SLN) that adhere to the requirements of drug delivery system by transnasal brain targeting. Through the characterization of nanoparticle properties, cytotoxicity assessment, in vitro pharmacological evaluation, and brain-targeting evaluation after nasal administration, siRNA/CUR@SLN exhibited a nearly spherical structure with a particle size of 125.0±1.93 nm, low cytotoxicity, high drug loading capacity, good sustained release function and good stability. In vitro anti-inflammatory results showcasing its remarkable anti-inflammatory activity. Moreover, in vivo pharmacological studies revealed that siRNA/CUR@SLN can be successfully delivered to brain tissue. Furthermore, it also elicited an effective anti-inflammatory response, alleviating brain inflammation. These results indicated that favorable brain-targeting ability and anti-inflammatory effects of siRNA/CUR@SLN in ICH model mice. In conclusion, our designed siRNA/CUR@SLN showed good brain targeting and anti-inflammatory effect ability after nasal administration, which lays the foundation for the treatment of inflammation caused by ICH and offers a novel approach for brain-targeted drug delivery and brings new hope.

Total flavonoids of Sophora flavescens and kurarinone ameliorated ulcerative colitis by regulating Th17/Treg cell homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is relevant to dysregulation of inflammation and immune processes. Sophora flavescens Aiton is a classic medicine widely used in the treatment of UC in ancient and modern China, alkaloids and flavonoids are the main components. Previous studies reveal that Sophora flavescens Aiton total flavonoids extracts (SFE) exert an anti-UC effect by regulating the intestinal microbe structure and restoring the balance of the "host-microbe" co-metabolic network in UC mice. However, whether SFE influences immune inflammation remains unclear, which is the core link to UC disease. It also remains to be verified flavonoids are the material basis that plays a role in SFE. AIM OF THE STUDY: To identify the action mechanism of the immune-inflammatory regulation of SFE and its main active component Kurarinone against UC. METHODS: This study constructed UC mice and abnormal immune RAW 264.7 cell models, and subsequently used western blotting and flow cytometry (FCM) to evaluate the effects of SFE on the NF-κB pathway and the regulation of immunity in UC mice. Kurarinone was screened from flavonoid compounds of SFE by lipopolysaccharide (LPS)-induced RAW 264.7 cells, and its effect was subsequently investigated in UC mice. Western blotting, ELISA, FCM, and RT-PCR were used to determine the regulation of Kurarinone on the Th17/Treg differentiation and the JAK2/STAT3 signaling pathway. RESULTS: SFE regulated the differentiation of Th17/Treg in peripheral blood and inhibited immune-inflammatory response to treat UC. Various flavonoid components in SFE inhibited the synthesis of IL-6 and TNF-α in RAW 264.7 cells, among which Kurarinone had better effect. This study revealed the therapeutic effects of Kurarinone in UC mice for the first time. Kurarinone promoted the secretion of SIgA to improve the regulation of the intestinal mucosal barrier and resistance to pathogens. It also regulated the transcription level of RORγt and Foxp3 in colon, decreased the expression of pro-inflammatory factor IL-17A and up-regulated the expression of immunosuppressive factors TGF-ß1 and IL-10 in colon. Furthermore, Kurarinone restored intestinal immune system homeostasis by down-regulating the JAK2/STAT3 signaling pathway and regulating the balance of Th17/Treg cell differentiation in UC. CONCLUSIONS: SFE, especially the flavonoid ingredients represented by Kurarinone, has significant effects on immunoregulation against UC. And their mechanism of effect is related to inhibiting the activation of JAK2/STAT3 signaling pathway and regulating differentiation of Th17/Treg cells. KEYWORK: Immunoregulatory; Kurarinone; Th17 cells; Treg cells; Ulcerative colitis.

Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy.

Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.

Emergent Single Burr Hole Evacuation for Traumatic Acute Subdural Hematoma with Cerebral Herniation: A Retrospective Cohort Comparison Analysis.

OBJECTIVE: To investigate the clinical benefits of emergent single burr hole evacuation technology in traumatic acute subdural hematoma (ASDH) with cerebral herniation cases. METHODS: We conducted a review comparing patients with ASDH with cerebral herniation who underwent single burr hole evacuation followed by decompressive craniectomy and intracranial hematoma removal surgery (n = 45, group A) and those who underwent decompressive craniectomy and intracranial hematoma removal surgery after rapid infusion of mannitol 250 mL (n = 53, group B) in our institution. Pre- and postoperative assessments included Glasgow Coma Scale (GCS), Glasgow Outcome Scale (GOS), activities of daily living (ADLs), and common complication incidences. RESULTS: At 1 and 6 months after operation, the median GCS score of group A was significantly higher than group B (P = 0.04 and P = 0.03, respectively). After 6 months, the GOS score and ADLs between the 2 groups had significant differences (P < 0.05). There were no differences between the 2 groups in the common complication incidences. CONCLUSIONS: Emergent single burr hole evacuation in combination with decompressive craniectomy surgery is a useful treatment for ASDH with cerebral herniation, which can achieve reduction of intracranial pressure as soon as possible and improve the prognosis.