Clinical management of acute corneal alkali burns is limited by tear washout and the failure of monotherapies to break the inflammation-neovascularization cycle. To address this, we developed a thermosensitive hydrogel (PRP/QR@gel) co-loaded with platelet-rich plasma (PRP) and quercetin (QR). The low-viscosity precursor adaptively fills irregular defects and solidifies around ocular surface temperature, establishing a tear-resistant drug depot. Mechanistically, the rapid release of hydrophilic PRP drives ordered corneal remodeling via the PI3K/Akt/mTOR pathway. Concurrently, the sustained release of hydrophobic QR scavenges ROS, suppresses NF-κB-mediated inflammation, and blocks HIF-1α/VEGF-driven pathological neovascularization. In a rabbit alkali burn model, PRP/QR@gel accelerated complete epithelialization within 7 days and reduced clinical opacity scores by 50%. This in situ-forming hydrogel offers a translatable solution for severe ocular chemical injuries.

ObjectiveThis study aimed to preliminarily evaluate the clinical efficacy and safety of carbon dioxide laser-assisted deep sclerectomy (CLASS) in patients with medically refractory Posner-Schlossman Syndrome (PSS).MethodsSix patients (six eyes) with poorly controlled PSS were included. All patients underwent CLASS under local anesthesia and were followed up for 18 months. Primary outcome measures included intraocular pressure (IOP), best-corrected visual acuity (BCVA), retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness, visual field parameters, and surgical complications.ResultsThe mean preoperative IOP was 28.30 ± 5.16 mmHg. Postoperative IOP decreased significantly, with a mean IOP of 14.56 ± 1.82 mmHg at the final 18-month follow-up. Visual acuity recovered to or exceeded preoperative levels in all cases. No statistically significant differences were observed in RNFL or GCC thickness at any postoperative time point (6, 12, and 18 months) compared to preoperative values. Visual field indices (MD, PSD) remained stable throughout follow-up. Postoperative complications included transient hypotony (three eyes), peripheral anterior synechiae (two eyes, successfully treated with laser), transient shallow anterior chamber (one eye), and mild anterior chamber reaction (one eye). All complications were managed conservatively without sequelae, and no serious adverse events occurred.ConclusionCLASS surgery provides effective and sustained IOP reduction in patients with refractory PSS. It demonstrates favorable structural and functional preservation of the optic nerve over the mid-term follow-up, with a manageable profile of minor complications. These preliminary findings suggest CLASS is a promising minimally invasive surgical option for this condition, though its long-term efficacy warrants confirmation in larger prospective studies.

Objective:Langerhans cell histiocytosis (LCH) is a rare neoplastic proliferative disorder and there are relatively few studies on the treatment of pediatric patients in early childhood with orbital LCH. Materials and Methods:This case report describes the treatment experiences of two pediatric patients with LCH who presented with similar clinical characteristics. They each had temporal orbital lesions, but the severity of their symptoms varied. Both patients underwent subtotal tumor resection. Postoperatively, only Patient 1 received low-dose chemotherapy and corticosteroid therapy. Results:During the six-year follow-up period, Patient 1 exhibited no recurrence, whereas Patient 2 who developed recurrent systemic symptoms including cranial and cutaneous manifestations was subsequently treated with chemotherapy and hormonal therapy in the pediatrics department. Conclusion:Based on our case observations and literature review, we realize that the early and accurate diagnosis of pediatric focal orbital LCH remains challenging. Meanwhile, the combination of surgery and chemotherapy yields satisfactory outcomes in young pediatric patients with orbital LCH, with a low recurrence rate.

Retinal pigment epithelial (RPE) cells are vulnerable to hypoxia-related and oxidative stress. Cobalt chloride (CoCl₂) is widely used as a chemical hypoxia mimetic; however, an appropriate concentration window for producing measurable RPE injury without the more extensive damage associated with higher concentrations remains incompletely defined. Aldehyde dehydrogenase 2 (ALDH2) contributes to reactive-aldehyde detoxification and cellular stress defense. ARPE-19 cells were exposed to 0, 10, 100, 500, 1000, or 2000 µM CoCl₂. Scratch-wound recovery and representative morphology were evaluated for up to 72 h, and relative CCK-8 metabolic activity was quantified at 24, 48, and 72 h. The 500 µM condition was selected for molecular and pharmacological experiments based on the integrated dose-response profile. Culture-supernatant 4-HNE and VEGF-A were measured by ELISA, whereas HIF-1α, ALDH2, and BAX were assessed by Western blotting. Alda-1 and Daidzin were used as an ALDH2 activator/chemical chaperone and an enzymatic inhibitory comparator, respectively. CoCl₂ caused concentration- and time-associated impairment of scratch-wound recovery. Wound closure was largely preserved at 0–100 µM, whereas 500–2000 µM produced wound-closure failure. The CCK-8 profile showed that 500 µM retained a nonmaximal metabolic signal compared with the substantially greater late reductions observed at 1000 and 2000 µM. Thus, 500 µM represented the lowest tested concentration producing significant functional injury while avoiding the more extensive injury phenotype observed at higher concentrations. Under 500 µM CoCl₂, HIF-1α increased early, ALDH2 protein abundance decreased, and culture-supernatant 4-HNE and VEGF-A increased at the later time point. Alda-1 improved wound recovery and restored ALDH2 protein abundance, whereas Daidzin aggravated the functional injury phenotype and shifted extracellular stress-marker readouts in an unfavorable direction. CoCl₂ produced a concentration-resolved, hypoxia-related and aldehyde-associated RPE injury phenotype. Alda-1 improved wound recovery and increased ALDH2 protein abundance, whereas Daidzin aggravated the functional injury phenotype. These findings support ALDH2-associated aldehyde-detoxifying defense as a modulatory component of CoCl₂-induced RPE stress.

This study investigated the protective effects of aldehyde dehydrogenase 2 (ALDH2) activation (via Alda-1), ALDH2 inhibition (via Daidzin), and the modulation of sirtuin 1 (SIRT1) and endoplasmic reticulum stress (ERS) on methyl-nitrosourea (MNU)-induced retinal damage in C57BL/6 mice. Seventy-two mice were randomly assigned to eight groups, including a control group, a MNU-alone group, and various treatment combination groups. Mice were administered with intraperitoneal injections of agonists and inhibitors targeting the ALDH2-SIRT1-ERS axis, respectively. Body weight, retinal layer thickness, and aldehyde metabolism biomarkers were assessed on the second and fourth day post-treatment. MNU administration induced retinal degeneration, resulting in significant body weight loss in all groups except the control. Treatment with Alda-1 attenuated retinal damage, while Daidzin exacerbated it. Pharmacological inhibition of SIRT1 (via EX-527) diminished the protective effects of Alda-1, and ERS induction (via TUN) nearly abolished its benefits. Conversely, SIRT1 activation (via SRT1720) mitigated the adverse effects of Daidzin, while ERS inhibition (via 4-PBA) partially alleviated Daidzin's impact. Furthermore, MNU increased levels of aldehyde metabolism markers (malondialdehyde [MDA] and 4-hydroxy-2-nonenal [4-HNE]), with Alda-1 reducing and Daidzin elevating these levels. Besides, pharmacological modulation of the SIRT1/ERS pathways intervened in the regulatory effects of Alda-1 and Daidzin on the aldehyde metabolism. Overall, ALDH2 activation protected retinal structure and regulated aldehyde metabolism, highlighting the critical role of the ALDH2-SIRT1/ERS signaling axis in mitigating retinal degeneration.

This study aimed to utilize Mendelian randomization (MR) analysis to investigate potential genetic targets related to aldehyde metabolism in the context of retinitis pigmentosa (RP) and to identify possible therapeutic options. Genome-wide association study data for RP were obtained for MR analysis. We employed various statistical methods, including inverse-variance weighted analysis, to evaluate potential causal associations with RP risk, followed by rigorous sensitivity analysis. Two-sample MR analysis identified a significant causal relationship between aflatoxin B1 (AFB1) aldehyde reductase and the risk of RP, with genetically predicted AFB1 aldehyde reductase contributing to a decreased risk of RP (odds ratio: 0.875; P = .008) based on inverse-variance weighted analysis. Sensitivity analysis suggested no evidence of heterogeneity or horizontal pleiotropy in the observed associations (P > .05). Additionally, the leave-one-out validation confirmed the robustness of these findings without significant alterations. The results from the reverse analysis for the causal relationship between the accidence of RP and AFB1 aldehyde reductase showed no significant statistical differences. Our findings highlighted the role of AFB1 aldehyde reductase in the pathogenesis of RP, proposing it as a promising protective measure for future treatment strategies.

ObjectiveMyocardial fibrosis (MF) is a pathological process often triggered by chronic inflammation and pressure overload. This study aimed to investigate the therapeutic potential of ranitidine, a histamine H2 receptor antagonist, on MF and explore its underlying mechanisms, focusing on the FAK/Src pathway and inflammatory responses.MethodsA mouse model of MF was established by transverse aortic constriction (TAC). Cardiac function was assessed by echocardiography. Histopathological changes, collagen deposition, mast cell infiltration, and the expression of histamine and its H2 receptor were examined. In vitro, NIH/3T3 fibroblasts were stimulated with TGF-β1 to induce fibrotic activation. The effects of ranitidine on collagen synthesis, the expression of fibrotic markers (α-SMA, Collagen I/III), and the phosphorylation of FAK/Src were evaluated.Key FindingsRanitidine treatment significantly improved TAC-induced cardiac dysfunction and attenuated myocardial fibrosis, as evidenced by reduced collagen deposition. It also markedly decreased mast cell infiltration and the expression of histamine and H2 receptor in cardiac tissues. In TGF-β1-stimulated fibroblasts, ranitidine dose-dependently reduced collagen synthesis, downregulated α-SMA, Collagen I, and Collagen III expression, and suppressed the activation of the FAK/Src pathway.ConclusionOur findings demonstrate that ranitidine ameliorates pressure overload-induced myocardial fibrosis, likely in association with attenuation of histamine/H2 receptor-related inflammatory responses and reduced FAK/Src activation. This study suggests the repurposing potential of ranitidine for treating MF.

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:Metabolic dysregulation involving nicotinamide adenine dinucleotide (NAD) has been implicated in the pathogenesis of various diseases; however, its role in diabetic retinopathy (DR) remains poorly understood. This study aimed to identify NAD-associated biomarkers and elucidate their molecular mechanisms in DR. METHODS:DR-related data were retrieved from public databases. NAD-associated biomarkers were identified through differential expression analysis, NAD-related gene (NAD-RG) score comparison, Mendelian randomization (MR) analysis, and experimental validation. Functional enrichment and immune microenvironment analyses were conducted to explore the mechanisms underlying biomarker involvement in DR. Single-cell RNA sequencing (scRNA-seq) was employed to identify key cell types, and pseudo-temporal trajectory analysis was performed to assess dynamic biomarker expression during cellular differentiation. Reverse transcription quantitative PCR (RT-qPCR) was used to validate biomarker expression levels. RESULTS:CCDC88A and GPD2 were identified as DR potential biomarkers and risk factors for disease progression. These genes were co-enriched in key pathways, including oxidative phosphorylation. CCDC88A exhibited the strongest positive correlation with monocytes (cor = 0.35, p < 0.05). scRNA-seq analysis highlighted microglia as key cells in DR. During microglia differentiation, CCDC88A expression initially decreased before rising, while GPD2 expression increased initially, declined, and then slowly increased in later stages. RT-qPCR confirmed significantly elevated expression of CCDC88A and GPD2 in the DR group (P < 0.05). CONCLUSION:This study integrates bulk and single-cell transcriptomic analyses to identify CCDC88A and GPD2 as DR potential biomarkers and microglia as key cellular players, providing new insights into DR pathogenesis and potential diagnostic strategies.

Objective:With the aids of ophthalmic imaging techniques for animals, the spatiotemporal characterization of MNU-induced retinitis pigmentosa (RP) rats were performed. Methods:Sprague-Dawley (SD) rats were randomly divided into normal group (N), MNU-low-dose group (L) and MNU-high-dose group (H). Rats in the L and H group were given intraperitoneally injection with 40 and 60 mg/kg of MNU, a kind of alkylating agent, respectively. The body weight, electroretinogram (ERG) and retinal structure were observed on day one (D1), D3, and D7 after MNU administration. FFA, OCT, TUNEL staining, and immunostaining of Iba1 were also performed. Results:After MNU injection, the weight and ERG amplitudes of rats in both L and H groups decreased gradually, compared to those of the normal group (P < 0.05). Fundus imaging revealed enlargement of the optical disc and slightly reduced shadow of retinal vessels in both L and H groups, which were more obvious on D7. No significant morphological changes of retinal vessels were found under FFA. OCT and retinal histological examination revealed that outer nuclear layers (ONL) became thinner gradually in both L and H groups, and disappeared in H group at D7. MNU administration increased the numbers of apoptotic cells and Iba1-positive cells in the retinas gradually, showing a dose-dependent effect. Conclusion:MNU gradually reduced the ONL thickness and the ERG amplitudes in the MNU-induced RP model revealed by various ophthalmic imaging techniques, along with the increased apoptosis of photoreceptors, the microglia cells activation, which provide indicators for new intervention effect for RP.

With the development of modern medicine, the importance of continuous and reliable pulse wave monitoring has increased significantly in physiological evaluation and disease diagnosis. Among them, the 3D reconstruction of the pulse wave is indispensable, and needs rely on ultra-high resolution sensor arrays, that is, high spatial resolution, temporal resolution, and force resolution. Herein, a flexible high-density 32 x 32 tactile sensor array based on pressure-sensitive tunneling mechanism is develpoed. Conformal graphene nanowalls (GNWs) pattern arrays are deposited on micro-pyramidal structural Si substrate via mask-assisted plasma enhanced chemical vapor deposition (PECVD) method and are adopted as pressure-sensitive electrode, exhibiting a spatial resolution of 64 dots/cm2, high sensitivity (222.36 kPa-1) and short response time (2 ms). More importantly, HfO2 tunneling layer can effectively suppress noise current, which made it sense weak pressure signals with 1/1000 force resolution and SNR of 36.32 dB. By leveraging its high-resolution array, more holistic pulse signals are acquired and the 3D shape of the pulse wave are successfully replicated. This work shows high-resolution sensors have significant promise for applications in remote intelligent diagnostics. Herein, a flexible high-density tactile sensor array based on pressure-sensitive tunnelling mechanism is developed. The sensor exhibits high spatial and temporal resolution. More importantly, HfO2 tunneling layer can effectively suppress noise current to realize force resolution of 1/1000. The 3D dynamic pulse images of pressure-spatial distribution are reconstructed. This research provides a visualization method for pulse wave diagnosis. image

Dementia treatment has become a global research priority, driven by the increase in the aging population. Punicalagin, the primary polyphenol found in pomegranate fruit, exhibits a variety of benefits. Today, a growing body of research is showing that punicalagin is a nutraceutical for the prevention of mild cognitive impairment (MCI). However, a comprehensive review is still lacking. The aim of this paper is to provide a comprehensive review of the physicochemical properties, origin and pharmacokinetics of punicalagin, while emphasizing the significance and mechanisms of its potential role in the prevention and treatment of MCI. Preclinical and clinical studies have demonstrated that Punicalagin possesses the potential to effectively target and enhance the treatment of MCI. Potential mechanisms by which punicalagin alleviates MCI include antioxidative damage, anti-neuroinflammation, promotion of neurogenesis, and modulation of neurotransmitter interactions. Overall, punicalagin is safer and shows potential as a therapeutic compound for the prevention and treatment of MCI, although more rigorous randomized controlled trials involving large populations are required.

Triphala is renowned for its curative attributes and has been utilized for centuries to address diverse health ailments. Moreover, the active component of Triphala, polyphenols, is widely recognized for its excellent pharmacological activities, such as anti-inflammatory properties, and has been utilized as a potential natural remedy. However, the precise mechanism through which Triphala alleviates cognitive dysfunction and anxiety induced by chronic sleep deprivation (SD) remains restricted. The objective of this investigation is to examine and clarify the potential mechanism of action that underlies the therapeutic benefits of Triphala in addressing cognitive dysfunction and anxiety induced by chronic SD. Our results demonstrated that Triphala significantly alleviates chronic SD-induced behavioral abnormalities. Additionally, Triphala was highly effective at preventing histopathological or morphological damage to neurons located in the hippocampus. The therapeutic effects of Triphala in treating cognitive dysfunction and anxiety induced by chronic SD involve the modulation of several biological pathways, including inflammation and immune responses, oxidative stress, cell growth and differentiation, metabolism, and neurotransmitter communication. Moreover, our study illustrated that Triphala increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and significantly activated the Nrf2/hemeoxygenase-1 (HO-1) axis. Additionally, the neuroprotective properties of Triphala were found to be counteracted by the Nrf2 inhibitor ML385. Our study represented the first to unveil that Triphala exerts therapeutic benefits in alleviating chronic SD-induced cognitive deficits and anxiety by activation of the Nrf2/HO-1 axis. Triphala emerges as a promising nutraceutical ingredient for mitigating cognitive deficits and anxiety linked to chronic SD.

Objective Our research was performed in order to explore the effects of molecular hydrogen (H2), a novelly-established antioxidant, on the retinal degeneration in rd1 mice, an animal model of inherited retinitis pigmentosa (RP).Methods The rd1 mice were divided randomly into control and H2 intervention groups. Mice from other groups received H2 intervention in three modes, two modes of the hydrogen gas (HG) and one model of hydrogen-rich saline (HRS). At 14 days post born (P14) and P21, various indicators were detected in all mice, including eletroretinogram (ERG), fundus phography, optical coherence tomography (OCT), and retinal immunotaining of microglia cells’ marker, Iba1.Results The ERG amplitude in mice from the control and H2 intervention groups showed no statistical differences (p > 0.05). At P14 and P21, no significant difference in the distance from the retinal pigment epithelium to the outer plexiform layer on OCT from mice of the above two groups was found (p > 0.05). The thickness of the outer nuclear layer (ONL) in mice at P14 and P21 showed no statistical differences between the control group and the H2 intervention group (p > 0.05). In the aspect of the number of Iba1-positive cells, we did not found any significant differences between the two groups (p > 0.05).Conclusion Different forms of H2 intervention (hydrogen-rich saline and hydrogen gas) had no obvious effects on the course of retinal degeneration in rd1 mice. The specific mechanism of photoreceptor degeneration in the hereditary RP mouse model may be different, requiring different medical interventions.

EDITORIAL article Front. Neurol., 04 January 2024Sec. Dementia and Neurodegenerative Diseases Volume 14 - 2023 | https://doi.org/10.3389/fneur.2023.1343786

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.

Phyllanthus emblica Linn. fruit that primarily contains many polyphenols, have been considered homologous food for centuries and have been used as a remedy for a variety of ailments, including maintaining brain function. It is, however, unclear what is the mechanism of protective action of Phyllanthus emblica Linn. fruit polyphenols (PEFPs) against cognitive impairment and anxiety induced by acute paradoxical sleep deprivation (SD). Behavioral abnormalities induced by acute paradoxical SD were effectively alleviated by PEFPs, which also prevented histopathological and morphological damage to hippocampal neurons. Acute paradoxical SD-induced cognitive impairments and anxiety are treated by PEFPs through modulating a variety of biological functional modules, such as oxidative stress, inflammation/immune, cell proliferation and differentiation, metabolism, and neurotransmitter signaling. Further results showed that PEFPs markedly counteracted oxidative stress damage and neuroinflammation by activating the Nrf2 pathway. In summary, PEFPs are attractive nutraceutical ingredients for preventing cognitive impairment and anxiety associated with sleep loss.

BACKGROUND:Patients with diabetes mellitus are at higher risk of myocardial ischemia/ reperfusion injury (MI/RI). Shuxin decoction (SXT) is a proven recipe modi-fication from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" according to the traditional Chinese medicine theory. It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting. However, the underlying mechanism is still unclear.AIM:To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.METHODS:This paper presents an ensemble model combining network pharmacology and biology. The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT. In parallel, therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus, DisGeNet, Genecards, Drugbank, OMIM, and PharmGKB. The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery. The major results of bioinformatics analysis were subsequently validated by animal experiments.RESULTS:According to the hypothesis derived from bioinformatics analysis, SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein (LDL) and inhibiting the advanced glycation end products (AGE)-receptor for AGE (RAGE) signaling pathway. Subsequent animal experiments confirmed the hypothesis. The treatment with a dose of SXT (2.8 g/kg/d) resulted in a reduction in oxidized LDL, AGEs, and RAGE, and regulated the level of blood lipids. Besides, the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated, whereas Bcl-2 expression was up-regulated. The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats.CONCLUSION:This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes. Moreover, animal experiments verified that SXT could regulate the level of blood lipids, alleviate cardiomyocyte apoptosis, and improve cardiac function through the AGE-RAGE signaling pathway.

In response to environmental challenges, stress is a common reaction, but dysregulation of the stress response can lead to neuropsychiatric disorders, including depression and cognitive impairment. Particularly, there is ample evidence that overexposure to mental stress can have lasting detrimental consequences for psychological health, cognitive function, and ultimately well-being. In fact, some individuals are resilient to the same stressor. A major benefit of enhancing stress resilience in at-risk groups is that it may help prevent the onset of stress-induced mental health problems. A potential therapeutic strategy for maintaining a healthy life is to address stress-induced health problems with botanicals or dietary supplements such as polyphenols. Triphala, also known as Zhe Busong decoction in Tibetan, is a well-recognized Ayurvedic polyherbal medicine comprising dried fruits from three different plant species. As a promising food-sourced phytotherapy, triphala polyphenols have been used throughout history to treat a variety of medical conditions, including brain health maintenance. Nevertheless, a comprehensive review is still lacking. Here, the primary objective of this review article is to provide an overview of the classification, safety, and pharmacokinetics of triphala polyphenols, as well as recommendations for the development of triphala polyphenols as a novel therapeutic strategy for promoting resilience in susceptible individuals. Additionally, we summarize recent advances demonstrating that triphala polyphenols are beneficial to cognitive and psychological resilience by regulating 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) receptors, gut microbiota, and antioxidant-related signaling pathways. Overall, scientific exploration of triphala polyphenols is warranted to understand their therapeutic efficacy. In addition to providing novel insights into the mechanisms of triphala polyphenols for promoting stress resilience, blood brain barrier (BBB) permeability and systemic bioavailability of triphala polyphenols also need to be improved by the research community. Moreover, well-designed clinical trials are needed to increase the scientific validity of triphala polyphenols' beneficial effects for preventing and treating cognitive impairment and psychological dysfunction.