Meplazumab, a humanized CD147 antibody, showed favorable safety and clinical benefits in phase 1 and phase 2/3 seamless clinical studies. Further evaluation of its therapeutic efficacy in patients with severe COVID-19 is needed. In this phase 3 add-on study, we randomized patients with severe COVID-19 in a 1:1 ratio to receive 0.2 mg/kg meplazumab or placebo via intravenous injection, and evaluated efficacy and safety within 56 days. Between February 2023 and November 2023, 108 patients with severe COVID-19 were randomized to two groups, with their baseline characteristics generally balanced. The primary endpoint, 28-day all-cause mortality was 1.96% in the meplazumab group vs 7.69% in the placebo group (P = 0.1703). Supplementary analysis using composite strategy indicated a significant reduction of 28-day all-cause mortality in meplazumab compared to placebo (3.92% vs 15.38%, P = 0.044). Meplazumab also significantly reduced the mortality in smoking subjects on day 28 (P = 0.047) compared to placebo in supplementary analysis. The secondary endpoint, 56-day all-cause mortality, was 1.96% in the meplazumab group and 11.54% in the placebo group (P = 0.048), which was 3.92% and 15.38%, respectively (P = 0.044) by supplementary analysis. Additional secondary endpoints showed potential benefits, including increased hospital discharge rates, improved clinical outcomes, and improved viral nucleotide conversion rate. Meplazumab demonstrated good safety and tolerability, with no grade ≥ 3 TEAEs observed. These promising results indicate that meplazumab reduces mortality and enhances clinical benefits in severe COVID-19 patients with a good safety profile, providing effective and specific therapeutics for severe COVID-19 (the trial was registered at ClinicalTrials.gov (NCT05679479)).

ETHNOPHARMACOLOGICAL RELEVANCE:Mudan granules (MuD), a time-honored traditional Chinese patent medicine (TCPM), are widely utilized in the clinical treatment of diabetic peripheral neuropathy (DPN). In the field of biomedical diagnostics, both diabetic retinopathy (DR) and DPN are recognized as critical microvascular complications associated with diabetes. According to the principles of traditional Chinese medicine (TCM), these conditions are primarily attributed to a deficiency in Qi and the obstruction of collaterals. Despite this, the protective effects of MuD on DR and the underlying mechanisms remain to be comprehensively elucidated. AIMS OF THE STUDY:The purpose of this study was to investigate the effect of MuD on DR and to further explore the promising therapeutic targets. METHODS:A diabetic mouse model was established by administering 60 mg/kg of streptozotocin (STZ) via intraperitoneal injection for five consecutive days. The therapeutic efficacy of MuD was evaluated using a comprehensive approach, which included electroretinogram (ERG) analysis, histopathological examination, and assessment of serum biochemical markers. Then, the pharmacodynamic mechanisms of MuD were systematically analyzed using Tandem Mass Tags-based proteomics. Meanwhile, the candidate compounds of MuD were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and molecular docking was applied to estimate the affinity of the active ingredient to their potential key targets. In addition, the functional mechanisms identified through bioinformatics analysis were confirmed by molecular biological methods. RESULTS:We demonstrated that MuD provided significant protection to retinal function and effectively mitigated the reduction in retinal thickness observed in the animal model. Through proteomic analysis, we identified a substantial regulation by MuD of 70 biomarkers associated with diabetic retinal damage. These proteins were notably enriched in the tumor necrosis factor (TNF) signaling pathway, a critical mediator in inflammatory processes. A particularly intriguing finding was the significant downregulation of fibrillin-2 (FBN2) in the diabetic retina compared to the control group (0.36 times the level), and its most pronounced upregulation (3.26 times) in the MuD treatment group. This suggests that FBN2 may play a pivotal role in the protective effects of MuD. Molecular docking analyses have unveiled a robust interplay between the components of MuD and TNF-α. Further corroboration was provided by molecular biological methods, which confirmed that MuD could suppress TNF-mediated inflammation and prevent retinal neovascularization and fibrogenesis. CONCLUSION:MuD have the potential to alleviate diabetic retinal dysfunction by effectively curbing the fibrogenesis-associated neoangiogenesis and mitigating the inflammatory response, thereby restoring retinal health and function.

BACKGROUND:Alcohol consumption leads to the accumulation of acetaldehyde and reactive oxygen species (ROS), collectively contribute to the development of alcoholic liver disease (ALD). Formononetin (FN), a major isoflavone derived from Astragalus membranaceus, has demonstrated therapeutic potential in metabolic disorders. However, its role in ALD remains unknown. PURPOSE:This study aimed to investigate the hepatoprotective effect of FN in ALD and elucidate its underlying molecular mechanism. MATERIALS AND METHODS:ALD was induced in mice via chronic alcohol administration, with or without FN treatment. Liver histopathology, oxidative stress markers, acetaldehyde accumulation, mitochondrial function, and lipid profiles were assessed. Untargeted metabolomics and RNA sequencing were performed to identify FN-regulated pathways. Direct protein targets were identified using limited proteolysis-coupled mass spectrometry (LiP-MS) and virtual screening, validated by surface plasmon resonance (SPR) and microscale thermophoresis (CETSA). Functional validation was conducted using siRNA knockdown and pharmacological inhibitors. RESULTS:FN significantly attenuated alcohol-induced liver injury, fibrosis, lipid accumulation, and oxidative stress. It reduced hepatic ROS and acetaldehyde levels, improved mitochondrial integrity, and restored glutathione homeostasis. Metabolomics and transcriptomic analyses revealed that FN regulated NAD+ metabolism, cysteine and methionine metabolism, and activated the Nrf2 antioxidant pathway. Mechanistically, FN directly bound to aldehyde dehydrogenase 2 (ALDH2), enhancing its detoxifying activity. ALDH2 activation further promoted ERK1/2 and AP-1 phosphorylation, contributing to Nrf2-mediated glutathione biosynthesis and antioxidant defense. CONCLUSION:FN ameliorated alcohol-induced liver damage by directly targeting ALDH2 to promote acetaldehyde detoxification and indirectly activating the ALDH2-ERK1/2-Nrf2 axis to enhance antioxidant capacity. FN might serve as a promising therapeutic candidate for the treatment of ALD.

BACKGROUND:Sodium of Danshensu (SDSS), extract of salvia miltiorrhiza root, has been shown to have neuroprotective effects on ischemic stroke (IS) in our previous studies. However, its therapeutic time window and mechanism of action remain unclear. Ferroptosis exerts a crucial feature in the development and progression of IS. Nuclear factor-E2-related factor 2 (Nrf2) can positively regulate the transcription of Recombinant Solute Carrier Family 7, member 11 (SLC7A11) and glutathione peroxidase (GPX4) genes that combat lipid peroxidation in ferroptosis. PURPOSE:The current study aimed to assess therapeutic time window of SDSS and the pharmacological mechanism involved in Nrf2-mediated oxidative stress and ferroptosis. METHODS:Mice with transient middle cerebral artery occlusion (MCAO) and HT22 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) were induced to simulate IS. Mice were administered SDSS at 1, 3, 6 or 9 h after MCAO to determine the therapeutic time window of SDSS. MicroRNA-seq was conducted to analyze differentially expressed genes in both the MCAO and the SDSS treatment group. The interaction between SDSS and Nrf2 was also investigated using molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) experiments. Furthermore, the neuroprotection of SDSS was investigated in Nrf2-deficient mice to assess the activation mechanism of the Nrf2/GPX4 axis by SDSS. The biomarkers (Fe2 + content, ROS, MDA, GSH, GSH/GSSG), mitochondrial structure, these proteins (Nrf2, SLC7A11, GPX4, FTH1, HO-1, ACSL4 and TFRC) expression were detected by commercial kits, transmission electron microscope (TEM) and Western blotting, respectively. RESULTS:The therapeutic time window of SDSS should be within 6 hours after MCAO, beyond which SDSS cannot play a therapeutic role. SDSS played a neuroprotective affection in mice and HT22 cells by restraining ROS, MDA and Fe2+ content, elevating GSH level and GSH/GSSG ratio. At the molecular mechanism, SDSS can bind to Nrf2, improve Nrf2 activity and nuclear expression, further enhance SLC7A11, GPX4, FTH1, HO-1 expression and reduce ACSL4 and TFRC expression. However, the neuroprotective effects of SDSS and its effect on ferroptosis-related proteins were partially reversed in Nrf2-deficient mice. CONCLUSION:The therapeutic time window of SDSS for ischemic stroke is relatively wide. The administration of SDSS can potentially mitigate brain damage through the inhibition of oxidative damage and ferroptosis, which is partly regulated by the Nrf2/GPX4 axis. Therefore, SDSS is a promising candidate for the treatment of ischemic stroke.

Lycium barbarum polysaccharides (LBP) have shown renal protection effects. However, research on other active components of L. barbarum extract (ELB) for the therapy of chronic kidney disease (CKD) is limited. This study aims to investigate the renoprotective effects and molecular mechanisms of ELB in CKD. ELB was extracted from L. barbarum fruits using 85% ethanol reflux, followed by vacuum concentration and sequential extraction to remove polysaccharides. Chemical components and target genes were identified using TCMSP and UniProt databases, followed by pharmacology network construction and GO/KEGG pathway analysis. A 5/6 nephrectomy model in Sprague-Dawley rats was used to study the renoprotective effects of ELB, with H&E staining and biochemical analyses. Western blot analysis assessed IL-6 and VEGF expression in renal tissues. Chemical analysis of ELB identified 188 components, with 45 meeting screening criteria, and 34 linked to 94 target genes. The intersection with CKD-related genes yielded 39 overlapping genes, with quercetin having the most targets. GO/KEGG pathway analyses highlighted significant biological processes and pathways. A PPI network identified IL-6, VEGFA, CASP3, EGFR, ESR1, and PPARG as hub genes. In a 5/6 nephrectomy rat model, ELB treatment significantly reduced renal damage, serum BUN and SCr levels, as well as IL-6 and VEGF expression in renal tissues, validating its renoprotective effects and supporting bioinformatics predictions. This work identified the intricate components and pharmacological actions of ELB, which is devoid of LBP. The findings preliminarily confirm the potential of ELB as a novel therapeutic agent for preventing and managing CKD.

Background: QiShenYiQi (QSYQ) is commonly accepted to treat ischemic stroke (IS) in clinical settings, yet the underlying mechanism of action of QSYQ is largely unknown. Methods: By combining systems pharmacology with experimental assessment, we examined the key targets, bioactive components, and mechanisms of QSYQ against IS. Results: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform predicted a total number of 254 targets that were potentially related to QSYQ, whereas 699 targets associated with IS were gathered from Therapeutic Target Database, Comparative Toxicogenomics Database, Gene Cards, Online Mendelian Inheritance in Man, and National Center for Biotechnology Information databases, and 83 of these targets overlap with QSYQ-related targets. Importantly, through the analysis of Gene Ontology functional annotation, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein-protein interaction network, we identified 20 related signaling pathways along with 4 hub genes. Subsequently, our molecular docking results revealed that QSYQ might interact with PTGS2, PTGS1, SCN5A, and HSP90AB1. We observed dose-dependent beneficial effects of QSYQ in significantly improving neurological function and alleviating histopathological damage in middle cerebral artery occlusion model, while decreasing infarct volume. Notablely, QSYQ markedly downregulates tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta. Overall, this study demonstrates the synergetic effects of QSYQ on regulating multi-targets in IS through inhibiting inflammatory processes and neuronal apoptosis, these findings may expand the understanding of QSYQ and provide guidance for its clinical application in treating IS. Conclusion: Current study reveals the protective roles of QSYQ against IS through modulating PTGS2/PTGS1/SCN5A/HSP90AB1 and TNF signaling pathways.

Context Angiogenesis is one of the essential protective mechanisms that promote neural repair and regeneration after ischemic stroke (IS). Salvianolic Acid B (SAB) and Benzoyl paeoniflorin (BP) are compounds extracted from the Chinese medicines Salvia miltiorrhiza Bunge and Paeonia suffruticosa Andrews, respectively.Objective We investigated whether SAB combined with BP alleviated IS by promoting micrangium angiogenesis and determined the potential molecular mechanisms.Materials and methods The impact of SAB-BP on angiogenesis after IS was investigated in middle cerebral artery occlusion (MCAO) rat model, ponatinib-induced ischemic stroke in zebrafish, and human umbilical vein endothelial cells (HUVECs). The neuroprotective effect of SAB-BP in rats was assessed using behavior tests and histopathological staining. The cerebral thrombosis assessment and angiogenesis assay were performed in the zebrafish model. Cell proliferation and angiogenesis in oxygen-glucose deprivation and reperfusion (OGD/R) HUVECs were assessed through cell viability, tube formation, migration, and invasion assays. Western blot analysis and immunofluorescence staining were used to determine the protein expression levels of Nrf2, HO-1, and VEGFA.Results The findings indicated that SAB-BP significantly reduced neurological impairment following IS and promoted the formation of functional vessels in the cerebral ischemic penumbra. Furthermore, SAB-BP up-regulated the protein expression of Nrf2, HO-1, HIF-1α, and VEGFA. Intriguingly, the pro-angiogenic effect of SAB-BP markedly restrained by adding the inhibitor of Nrf2 (ML385).Discussion and conclusion Our study demonstrates that SAB-BP enhances angiogenesis following IS by modulating the Nrf2/HO-1/VEGFA signaling axis both in vivo and in vitro. SAB-BP could serve as a promising therapeutic agent for IS recovery.

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (UCr) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.

Abnormal aggregation and fibrillogenesis of amyloid-β protein (Aβ) can cause Alzheimerʼs disease (AD). Thus, the discovery of effective drugs that inhibit Aβ fibrillogenesis in the brain is crucial for the treatment of AD. Luteoloside, as one of the polyphenolic compounds, is found to have a certain therapeutic effect on nervous system diseases. However, it remains unknown whether luteoloside is a potential drug for treating AD by modulating Aβ aggregation pathway. In this study, we performed diverse biophysical and biochemical methods to explore the inhibition of luteoloside on Aβ1–42 which is linked to AD. The results demonstrated that luteoloside efficiently prevented amyloid oligomerization and cross-β-sheet formation, reduced the rate of amyloid growth and the length of amyloid fibrils in a dose-dependent manner. Moreover, luteoloside was able to influence aggregation and conformation of Aβ1–42 during different fiber-forming phases, and it could disintegrate already preformed fibrils of Aβ1–42 and convert them into nontoxic aggregates. Furthermore, luteoloside protected cells from amyloid-induced cytotoxicity and hemolysis, and attenuated the level of reactive oxygen species (ROS). The molecular docking study showed that luteoloside interacted with Aβ1–42 mainly via Conventional Hydrogen Bond, Carbon Hydrogen Bond, Pi-Pi T-shaped, Pi-Alkyl and Pi-Anion, thereby possibly preventing it from forming the aggregates. These observations indicate that luteoloside, a natural anti-oxidant molecule, may be applicable as an effective inhibitor of Aβ, and promote further exploration of the therapeutic strategy against AD.

Ischemic stroke (IS), primarily caused by cerebrovascular occlusion, poses a significant public health challenge with limited effective therapeutic options. Evidence suggests that salvianolic acids (SAs), mainly from Salvia miltiorrhiza Bunge, have been formulated into injections and are widely used in clinical treatments for cardiovascular and cerebrovascular diseases, including stroke. The pharmacological properties of SAs include reducing neuroinflammation, alleviating oxidative stress injury, inhibiting cellular apoptosis, preserving endothelial function, maintaining blood-brain barrier integrity, and promoting angiogenesis. Salvianolic acids for injection (SAFI) serve as a safe and effective treatment option for cardiovascular and cerebrovascular conditions by influencing various signaling pathways and molecular targets associated with these diseases. In this review, we first discuss the pathogenesis of IS, then summarize the classification of SAs, elaborate detailed molecular mechanisms of their efficacy, and the related clinical applications of SAFI. We also emphasize the recent pharmacological advancements and therapeutic possibilities of this promising drug preparation derived from herbs for cerebrovascular conditions.

Ischemic stroke (IS) can cause severe harm, inducing oxidative stress, inflammation, and pyroptotic death. IS treatment efficacy remains limited, and microglia are important regulators of IS-related blood-brain barrier (BBB) damage. It is thus vital that new therapeutic agents capable of targeting microglia be identified to treat ISrelated damage to the BBB. Acteoside (ACT), which is a compound derived from Cistanche tubulosa (Schenk) Wight., offers promising bioactivity, but its ability to protect against central nervous system injury remains to be documented. To clarify the protective benefits and mechanisms through which ACT can protect against damage to the BBB, a rat middle cerebral artery occlusion (MCAO) model system was herein employed. These in vivo analyses demonstrated that ACT was able to significantly reduce cerebral infarct size while improving their neurological scores and altering neurotrophic and inflammatory factor release. RNA sequencing and molecular docking studies highlighted the ability of ACT to exert its protective benefits via the HMGB1/TLR4/NLRP3 axis. Western immunoblotting and immunofluorescent staining for tight junction proteins additionally confirmed the ability of ACT to preserve BBB integrity. The underlying mechanisms were then explored with an oxygen-glucose deprivation (OGD) model in vitro with BV2 cells. This strategy thus confirmed that the ability of ACT to suppress microglial inflammatory and pyroptotic activity was HMGB1/TLR4/NLRP3 pathway-dependent. These data thus offer novel evidence that ACT can protect against IS-related damage to the BBB through the abrogation of inflammatory and pyroptotic activity, underscoring its promise as a novel lead compound for the therapeutic treatment of IS.

It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke. As a result, the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers. This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke, with a focus on the PI3K/AKT signaling pathway. The key findings include the following: (1) The complex pathological mechanisms of ischemic stroke can be categorized into five major types: excitatory amino acid toxicity, Ca 2+ overload, inflammatory response, oxidative stress, and apoptosis. (2) The PI3K/AKT-mediated signaling pathway is closely associated with the occurrence and progression of ischemic stroke, which primarily involves the NF-κB, NRF2, BCL-2, mTOR, and endothelial NOS signaling pathways. (3) Natural products, including flavonoids, quinones, alkaloids, phenylpropanoids, phenols, terpenoids, and iridoids, show great potential as candidate substances for the development of innovative anti-stroke medications. (4) Recently, novel therapeutic techniques, such as electroacupuncture and mesenchymal stem cell therapy, have demonstrated the potential to improve stroke outcomes by activating the PI3K/AKT signaling pathway, providing new possibilities for the treatment and rehabilitation of patients with ischemic stroke. Future investigations should focus on the direct regulatory mechanisms of drugs targeting the PI3K/AKT signaling pathway and their clinical translation to develop innovative treatment strategies for ischemic stroke.

Ischemic stroke (IS), predominantly triggered by blockages in cerebral blood flow, is increasingly recognized as a critical public health issue. The combination of Salvia miltiorrhiza (SM) and Cortex moutan (CM), traditional herbs in Eastern medicine, are frequently used for managing heart and brain vascular conditions. However, the exact mechanisms by which this herb pair (SC) combats IS remain largely unexplored. This investigation focuses on pinpointing the active constituents in SC that contribute to its protective role and deciphering the mechanisms countering cerebral ischemia, particularly in a middle cerebral artery occlusion (MCAO) rat model. We employed UPLC-Q-TOF-MS/MS alongside network pharmacology for predicting SC’s target actions against IS. Key ingredients were examined for their interaction with principal targets using molecular docking. The therapeutic impact was gauged through H&E, TUNEL, and Nissl staining, complemented by transcriptomic and metabolomic integration for mechanistic insights, with vital genes confirmed via western blot. UPLC-Q-TOF-MS/MS analysis revealed that the main components of SC included benzoylpaeoniflorin, salvianolic acid B, oxypaeoniflora, salvianolic acid A, and others. Network pharmacology analysis indicated that SC’s mechanism in treating IS primarily involves inflammation, angiogenesis, and cell apoptosis-related pathways, potentially through targets such as AKT1, TNF, PTGS2, MMP9, PIK3CA, and VEGFA. Molecular docking underscored strong affinities between these constituents and their targets. Our empirical studies indicated SC’s significant role in enhancing neuroprotection in IS, with transcriptomics suggesting the involvement of the VEGFA/PI3K/AKT pathway and metabolomics revealing improvements in various metabolic processes, including amino acids, glycerophospholipids, sphingomyelin, and fatty acids metabolisms.

Although strides have been made, the challenge of preventing and treating ischemic stroke continues to persist globally. For thousands of years, the natural substances Frankincense and Myrrh have been employed in Chinese and Indian medicine to address cerebrovascular diseases, with the key components of 11-keto-β-boswellic acid (KBA) and Z-Guggulsterone (Z-GS) being the active agents. In this study, the synergistic effect and underlying mechanism of KBA and Z-GS on ischemic stroke were examined using single-cell transcriptomics. Fourteen cell types were identified in KBA-Z-GS-treated ischemic penumbra, and microglia and astrocytes account for the largest proportion. They were further re-clustered into six and seven subtypes, respectively. GSVA analysis reflected the distinct roles of each subtype. Pseudo-time trajectory indicated that Slc1a2 and Timp1 were core fate transition genes regulated by KBA-Z-GS. In addition, KBA-Z-GS synergistically regulated inflammatory reactions in microglia and cellular metabolism and ferroptosis in astrocytes. Most notably, we established an innovative drug-gene synergistic regulation pattern, and genes regulated by KBA-Z-GS were divided into four categories based on this pattern. Finally, Spp1 was demonstrated as the hub target of KBA-Z-GS. Taken together, this study reveals the synergistic mechanism of KBA and Z-GS on cerebral ischemia, and Spp1 may be the synergistic target for that. Precise drug development targeting Spp1 may offer a potential therapeutic approach for treating ischemic stroke.

The pathogenesis of ischemic stroke is complex, and PI3K/Akt signaling is considered to play a crucial role in it. The PI3K/Akt pathway regulates inflammation, oxidative stress, apoptosis, autophagy, and vascular endothelial homeostasis after cerebral ischemia; therefore, drug research targeting the PI3K/Akt pathway has become the focus of scientists. In this review, we analyzed the research reports of antiischemic stroke drugs targeting the PI3K/Akt pathway in the past two decades. Because of the rich sources of natural products, increasing studies have explored the value of natural compounds, including Flavonoids, Quinones, Alkaloids, Phenylpropanoids, Phenols, Saponins, and Terpenoids, in alleviating neurological impairment and achieved satisfactory results. Herbal extracts and medicinal formulas have been applied in the treatment of ischemic stroke for thousands of years in East Asian countries. These precious clinical experiences provide a new avenue for research of antiischemic stroke drugs. Finally, we summarize and discuss the characteristics and shortcomings of the current research and put forward prospects for further in‐depth exploration.

Ethnopharmacological relevance: Mudan granule (MuD), a patent compound traditional Chinese medicine (TCM), is broadly clinically used for diabetic peripheral neuropathy (DPN) treatment in China. Since diabetic retinopathy (DR) and DPN are both 'Qi deficiency' and collaterals obstruction syndrome in TCM theory, it is worthwhile to investigate the specific pharmacological effects of MuD on DR.Aim of the study: DR is a serious neurovascular complication of diabetic mellitus (DM). The present study is to investigate the effects of MuD on DR, and further explore the potential therapeutic targets.Materials and methods: Diabetic mice model was induced by the intraperitoneal injection of 60 mg/kg streptozotocin for five consecutive days. 8 weeks later, MuD was administered to diabetic mice (MuD group), while the untreated diabetic mellitus mice (DM group) and age-matched healthy mice (CON group) were administered with the equal volume saline. After 6-week intervention, the retinal function and morphological changes were observed. Then the molecule profiling of the ocular tissues was systematically analyzed through TMT-based proteomics. Furthermore, western blotting and immunofluorescence staining detections were applied to validate the differentially expressed proteins.Results: The MuD treatment in DR mice actively protected retinal function and inhibited the retinal thickness decreasing. 109 differentially expressed proteins were screened in DM compared to CON, 56 of which were up-regulated and 53 were down-regulated (fold change > 1.2, p < 0.05). MuD significantly regulated 70 biomarkers of diabetic retinal damage. Bioinformatics analysis showed that these proteins were significantly enriched in the TNF/TNFR/NF-κB signaling pathway which was related to inflammatory reaction. Interestingly, our study revealed that fibrillin 2 (FBN2) was the key diminished biomarker in DM retina compared to CON (0.36 times), and the most significantly upregulated (3.26 times) differential protein in the MuD group compared to DM. Molecular biological methods further confirmed that MuD could depress inflammation (TNF-α, NFκB and IL-6) and impede retinal neovascularization and fibrogenesis by upregulation of FBN2 level and down-regulation of TGF-β/VEGFA axis.Conclusion: MuD could ameliorate diabetic mice retinal dysfunction through strengthening FBN2 activation and inhibiting TNF signaling pathway. The suppression of the neoangiogenesis and fibrogenesis triggered by the FBN2/TGF-β/VEGFA signaling pathway, and the inflammatory reactions activated by the TNF-α/NF-κB/IL-6 signaling pathway might provide effective targets for pharmacological intervention treating DR.

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.

Kai-Xin-San (KXS) is a Chinese medicine formulation that is commonly used to treat depression caused by dual deficiencies in the heart and spleen. Recent studies indicated that miRNAs were involved in the pathophysiology of depression. However, there have been few studies on the mechanism underlying the miRNAs directly mediating antidepressant at clinical level, especially in nature drugs and TCM compound. In this study, we identified circulating miRNAs defferentially expressed among the depression patients (DPs), DPs who underwent 8weeks of KXS treatment and health controls (HCs). A total of 45 miRNAs (17 were up-regulated and 28 were down-regulated) were significantly differentially expressed among three groups. Subsequently, qRT-PCR was used to verify 10 differentially expressed candidate miRNAs in more serum samples, and the results showed that 6 miRNAs (miR-1281, miR-365a-3p, miR-2861, miR-16-5p, miR-1202 and miR-451a) were consistent with the results of microarray. Among them, miR-1281, was the novel dynamically altered and appeared to be specifically related to depression and antidepressant effects of KXS. MicroRNA-gene-pathway-net analysis showed that miR-1281-regulated genes are mostly key nodes in the classical signaling pathway related to depression. Additionally, our data suggest that ADCY1 and DVL1 were the targets of miR-1281. Thus, based on the discovery of miRNA expression profiles in vivo, our findings suggest a new role for miR-1281 related to depression and demonstrated in vitro that KXS may activate cAMP/PKA/ERK/CREB and Wnt/β-catenin signal transduction pathways by down-regulating miR-1281 that targets ADCY1 and DVL1 to achieve its role in neuronal cell protection.

Cerebral ischemia-reperfusion injury (CI/RI) is the main cause of disability and death in stroke without satisfactory therapeutic effect. Inflammation mediated by activation of astrocytes and microglia is the main pathological mechanism of CI/RI. Danshensu (DSS) has been shown to exert anti-inflammatory effects against brain injury. However, limited by its poor cellular permeability and low bioavailability, it is still needed the new DSS preparations with the ability to cross the blood-brain barrier (BBB) and target inflammatory glial cells. In this study, we developed phosphatidylserine (PS) and transferrin (TF) modified liposomes carrying DSS (TF/PS/DSSLPs) to improve the therapeutic efficacy against ischemic stroke. First, TF molecules targeted transferrin receptor (TfR) that is overexpressed in the BBB. Following the liposomes enter the brain, PS modification allowed the liposomes to target and bind to the overexpressed phosphatidylserine-specific receptors (PSRs) on the surface of astrocytes and microglia. Furthermore, it enhanced the uptake of TF/PS/DSS-LPs by astrocytes and microglia, while polarizing astrocytes from A1 to A2 and microglia from M1 to M2, reducing neuronal inflammation, and ultimately ameliorating cerebral ischemic injury. Thus, TF/PS/DSS-LPs could potentially serve as a promising strategy for the CI/RI treatment.