Multifunctional Laser-Induced Graphene-Based Microfluidic Chip for High-Performance Oocyte Cryopreservation with Low Concentration of Cryoprotectants.

Oocyte cryopreservation is essential in the field of assisted reproduction, but due to the large size and poor environmental tolerance of oocytes, cell freezing technology needs further improvement. Here, a Y-shaped microfluidic chip based on 3D graphene is ingeniously devised by combining laser-induced graphene (LIG) technology and fiber etching technology. The prepared LIG/PDMS microfluidic chip can effectively suppress ice crystal size and delay ice crystal freezing time by adjusting surface hydrophobicity. In addition, LIG endows the microfluidic chip with an outstanding photothermal effect, which allows to sharply increase its surface temperature from 25 to 71.8 °C with 10 s of low-power 808 nm laser irradiation (0.4 W cm-2). Notably, the LIG/PDMS microfluidic chip not only replaces the traditional cryopreservation carriers, but also effectively reduces the dosage of cryoprotectants (CPAs) needed in mouse oocyte cryopreservation. Even when the concentration of CPAs is cut in half (final concentration of 7.5% ethylene glycol (EG) and 7.5% dimethyl sulfoxide (DMSO)), the survival rate of oocytes is still as high as 92.4%, significantly higher than the control group's 85.8%. Therefore, this work provides a novel design strategy to construct multifunctional microfluidic chips for high-performance oocytes cryopreservation.

Weakly-Supervised Segmentation-Based Quantitative Characterization of Pulmonary Cavity Lesions in CT Scans.

OBJECTIVE: Pulmonary cavity lesion is one of the commonly seen lesions in lung caused by a variety of malignant and non-malignant diseases. Diagnosis of a cavity lesion is commonly based on accurate recognition of the typical morphological characteristics. A deep learning-based model to automatically detect, segment, and quantify the region of cavity lesion on CT scans has potential in clinical diagnosis, monitoring, and treatment efficacy assessment. METHODS: A weakly-supervised deep learning-based method named CSA2-ResNet was proposed to quantitatively characterize cavity lesions in this paper. The lung parenchyma was firstly segmented using a pretrained 2D segmentation model, and then the output with or without cavity lesions was fed into the developed deep neural network containing hybrid attention modules. Next, the visualized lesion was generated from the activation region of the classification network using gradient-weighted class activation mapping, and image processing was applied for post-processing to obtain the expected segmentation results of cavity lesions. Finally, the automatic characteristic measurement of cavity lesions (e.g., area and thickness) was developed and verified. RESULTS: the proposed weakly-supervised segmentation method achieved an accuracy, precision, specificity, recall, and F1-score of 98.48%, 96.80%, 97.20%, 100%, and 98.36%, respectively. There is a significant improvement (P < 0.05) compared to other methods. Quantitative characterization of morphology also obtained good analysis effects. CONCLUSIONS: The proposed easily-trained and high-performance deep learning model provides a fast and effective way for the diagnosis and dynamic monitoring of pulmonary cavity lesions in clinic. Clinical and Translational Impact Statement: This model used artificial intelligence to achieve the detection and quantitative analysis of pulmonary cavity lesions in CT scans. The morphological features revealed in experiments can be utilized as potential indicators for diagnosis and dynamic monitoring of patients with cavity lesions.

Probing the Size Effect of Graphene Oxide Nanosheets on Ice Crystal Regulation and Laser-Assisted Rapid Rewarming.

Two-dimensional (2D) nanomaterials have attracted many researchers to explore the effect of ice control and rapid deicing due to their functional groups, large specific surface area, and excellent photothermal properties. However, the impact of size effects on ice crystal formation, growth, and photothermal performance has been rarely explored. Here, graphene oxide nanosheets (GO NSs) with controllable sizes were used as a representative of 2D nanomaterials to probe the effect of size on ice crystal regulation and rapid rewarming in cell cryopreservation. All sizes of GO NSs exhibited notable inhibitory effects on ice crystal size during the recrystallization process. Significantly, when the size of GO NSs was smaller than a certain size (<150 nm), they showed a more significant ice recrystallization suppression effects, which could reduce the ice crystal size to about 17% of that of pure water. Meanwhile, the photothermal experiments also indicated that smaller-sized GO NSs exhibited better photothermal behavior, with 90 nm GO NSs (GO-90) heating to 70 °C in just 1 min induced by an 808 nm laser (2 W/cm2). Furthermore, applying GO-90 (200 µg/mL) to cell cryopreservation, cell viability could reach 95.2% and 93% with a low amount of traditional cryoprotectant (2% v/v DMSO) for A549 cells and HeLa cells after recovery, respectively. With the assistance of a 808 nm laser, the rewarming time was also shortened to 20 s, greatly improving the rewarming rate. Our work associated specific sizes of 2D nanomaterials with their ice growth inhibition behaviors during recrystallization and photothermal properties to synergistically improve cell cryopreservation efficiency, providing guidance for effectively designing novel 2D nanomaterials for collaborative control of ice crystals in cell cryopreservation.

Antioxidant and Anti-Inflammatory Properties of Hydrolyzed Royal Jelly Peptide in Human Dermal Fibroblasts: Implications for Skin Health and Care Applications.

Hydrolyzed royal jelly peptide (RJP) has garnered attention for its health-promoting functions. However, the potential applications of RJP in skincare have not been fully explored. In this study, we prepared RJP through the enzymatic hydrolysis of royal jelly protein with trypsin and investigated its antioxidant and anti-inflammatory properties on primary human dermal fibroblasts (HDFs). Our results demonstrate that RJP effectively inhibits oxidative damage induced by H2O2 and lipid peroxidation triggered by AAPH and t-BuOOH in HDFs. This effect may be attributed to the ability of RJP to enhance the level of glutathione and the activities of catalase and glutathione peroxidase 4, as well as its excellent iron chelating capacity. Furthermore, RJP modulates the NLRP3 inflammasome-mediated inflammatory response in HDFs, suppressing the mRNA expressions of NLRP3 and IL-1ß in the primer stage induced by LPS and the release of mature IL-1ß induced by ATP, monosodium urate, or nigericin in the activation stage. RJP also represses the expressions of COX2 and iNOS induced by LPS. Finally, we reveal that RJP exhibits superior antioxidant and anti-inflammatory properties over unhydrolyzed royal jelly protein. These findings suggest that RJP exerts protective effects on skin cells through antioxidative and anti-inflammatory mechanisms, indicating its promise for potential therapeutic avenues for managing oxidative stress and inflammation-related skin disorders.

Comparative effects of pectin and hydrolyzed pectin coating as pre-frying treatments on acrylamide formation in potato chips.

This study aimed to compare the effects of pectin and hydrolyzed pectin coating as pre-frying treatments on acrylamide content and quality characteristics of fried potato chips. The hydrolyzed pectin with molecular weight (Mw) of 8.81 ± 0.49 kDa was obtained through partial degradation of pectin (Mw: 747.57 ± 6.73 kDa) using pectinase. Results showed that both pectin and hydrolyzed pectin coating significantly inhibited acrylamide formation and inhibition rates exceeded 90 %. Hydrolyzed pectin had stronger inhibitory activity against acrylamide formation than pectin, especially when the concentration of hydrolyzed pectin was >2 %, its inhibitory rate exceeded 95 %. Compared to pectin coating, hydrolyzed pectin coating endow fried potato chips with smaller browning, higher crispness, less moisture but higher oil content. Overall, hydrolyzed pectin had better application prospects than pectin in inhibiting acrylamide formation of fried potato chips.

Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury.

BACKGROUND: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.

Mapping network connection and direction among symptoms of depression and anxiety in patients with chronic gastritis.

Regarding neurophysiological and developmental findings, anxiety and depression are usual comorbidities of gastritis patients. However, research related to anxiety and depression among chronic gastritis patients was conducted on the disease level while ignoring symptoms. Hence, we rendered the network approach to reveal the symptoms of anxiety and depression among chronic gastritis patients. Three hundred and sixty-nine chronic gastritis patients (female = 139, Mage = 55.87 years) were asked to complete the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Three symptom networks and one directed acyclic graph (DAG) network were formed. First, in the anxiety network of chronic gastritis patients, dizziness was the most influential symptom. In the depression network of chronic gastritis patients, depressed affect and psychomotor retardation were the influential symptoms. Second, panic, easy fatiguability, weakness, palpitation, depressed affect, tachycardia, fatigue, and psychomotor agitation bridged the anxiety-depression network of chronic gastritis patients. Third, DAG networks showed that anxiousness and hopelessness could trigger other symptoms in the anxiety-depression networks of chronic gastritis patients. The current study provided insightful information on patients with chronic gastritis by examining the structures of symptoms.

Effects of the Pituitary-targeted Gland Axes on Hepatic Lipid Homeostasis in Endocrine-associated Fatty Liver Disease-A Concept Worth Revisiting.

Hepatic lipid homeostasis is not only essential for maintaining normal cellular and systemic metabolic function but is also closely related to the steatosis of the liver. The controversy over the nomenclature of non-alcoholic fatty liver disease (NAFLD) in the past three years has once again sparked in-depth discussions on the pathogenesis of this disease and its impact on systemic metabolism. Pituitary-targeted gland axes (PTGA), an important hormone-regulating system, are indispensable in lipid homeostasis. This review focuses on the roles of thyroid hormones, adrenal hormones, sex hormones, and their receptors in hepatic lipid homeostasis, and summarizes recent research on pituitary target gland axes-related drugs regulating hepatic lipid metabolism. It also calls on researchers and clinicians to recognize the concept of endocrine-associated fatty liver disease (EAFLD) and to re-examine human lipid metabolism from the macroscopic perspective of homeostatic balance.

Discovery of a Potent Antiosteoporotic Drug Molecular Scaffold Derived from Angelica sinensis and Its Bioinspired Total Synthesis.

Angelica sinensis, commonly known as Dong Quai in Europe and America and as Dang-gui in China, is a medicinal plant widely utilized for the prevention and treatment of osteoporosis. In this study, we report the discovery of a new category of phthalide from Angelica sinensis, namely falcarinphthalides A and B (1 and 2), which contains two fragments, (3R,8S)-falcarindiol (3) and (Z)-ligustilide (4). Falcarinphthalides A and B (1 and 2) represent two unprecedented carbon skeletons of phthalide in natural products, and their antiosteoporotic activities were evaluated. The structures of 1 and 2, including their absolute configurations, were established using extensive analysis of NMR spectra, chemical derivatization, and ECD/VCD calculations. Based on LC-HR-ESI-MS analysis and DFT calculations, a production mechanism for 1 and 2 involving enzyme-catalyzed Diels-Alder/retro-Diels-Alder reactions was proposed. Falcarinphthalide A (1), the most promising lead compound, exhibits potent in vitro antiosteoporotic activity by inhibiting NF-κB and c-Fos signaling-mediated osteoclastogenesis. Moreover, the bioinspired gram-scale total synthesis of 1, guided by intensive DFT study, has paved the way for further biological investigation. The discovery and gram-scale total synthesis of falcarinphthalide A (1) provide a compelling lead compound and a novel molecular scaffold for treating osteoporosis and other metabolic bone diseases.

Mitigating phospholipid peroxidation of macrophages in stress-induced tumor microenvironment by natural ALOX15/PEBP1 complex inhibitors.

BACKGROUND: The intricate interactions between chronic psychological stress and susceptibility to breast cancer have been recognized, yet the underlying mechanisms remain unexplored. Danzhi Xiaoyao Powder (DZXY), a traditional Chinese medicine (TCM) formula, has found clinical utility in the treatment of breast cancer. Macrophages, as the predominant immune cell population within the tumor microenvironment (TME), play a pivotal role in orchestrating tumor immunosurveillance. Emerging evidence suggests that lipid oxidation accumulation in TME macrophages, plays a critical role in breast cancer development and progression. However, a comprehensive understanding of the pharmacological mechanisms and active components of DZXY related to its clinical application in the treatment of stress-aggravated breast cancer remains elusive. PURPOSE: This study sought to explore the plausible regulatory mechanisms and identify the key active components of DZXY contributing to its therapeutic efficacy in the context of breast cancer. METHODS: Initially, we conducted an investigation into the relationship between the phagocytic capacity of macrophages damaged by psychological stress and phospholipid peroxidation using flow cytometry and LC-MS/MS-based phospholipomics. Subsequently, we evaluated the therapeutic efficacy of DZXY based on the results of the tumor size, tumor weight, the phospholipid peroxidation pathway and phagocytosis of macrophage. Additionally, the target-mediated characterization strategy based on binding of arachidonate 15-lipoxygenase (ALOX15) to phosphatidylethanolamine-binding protein-1 (PEBP1), including molecular docking analysis, microscale thermophoresis (MST) assay, co-immunoprecipitation analysis and activity verification, has been further implemented to reveal the key bio-active components in DZXY. Finally, we evaluated the therapeutic efficacy of isochlorogenic acid C (ICAC) based on the results of tumor size, tumor weight, the phospholipid peroxidation pathway, and macrophage phagocytosis in vivo. RESULTS: The present study demonstrated that phospholipid peroxides, as determined by LC-MS/MS-based phospholipidomics, triggered in macrophages, which in turn compromised their capacity to eliminate tumor cells through phagocytosis. Furthermore, we elucidate the mechanism behind stress-induced PEBP1 to form a complex with ALOX15, thereby mediating membrane phospholipid peroxidation in macrophages. DZXY, demonstrates potent anti-breast cancer therapeutic effects by disrupting the ALOX15/PEBP1 interaction and inhibiting phospholipid peroxidation, ultimately enhancing macrophages' phagocytic capability towards tumor cells. Notably, ICAC emerged as a promising active component in DZXY, which can inhibit the ALOX15/PEBP1 interaction, thereby mitigating phospholipid peroxidation in macrophages. CONCLUSION: Collectively, our findings elucidate stress increases the susceptibility of breast cancer by driving lipid peroxidation of macrophages and suggest the ALOX15/PEBP1 complex as a promising intervention target for DZXY.

Unveiling the antioxidant superiority of α-tocopherol: Implications for vitamin E nomenclature and classification.

Since the discovery of tocopherols a century ago, α-tocopherol has been distinguished for its unique biological functions. In this study, we aim to elucidate the unique characteristics of α-tocopherol from a chemical perspective. Utilizing density functional theory (DFT) calculations, we evaluated the thermodynamic and kinetic properties of tocopherols, tocotrienols and their oxidation products. Our findings highlight the superior thermodynamic and kinetic properties of α-tocopherol. Although tocopherol substrates generally exhibit similar reactivities, α-tocopherol is distinguished by a larger gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) in intermediates, indicating a potential for greater energy release and favoring reaction progression. Moreover, α-tocopherol shows enhanced efficiency in quenching radical intermediates, especially when combined with vitamin C. All these dates provide valuable support for the naming of vitamin E.

B-mode ultrasound to elastography synthesis using multiscale learning.

Elastography is a promising diagnostic tool that measures the hardness of tissues, and it has been used in clinics for detecting lesion progress, such as benign and malignant tumors. However, due to the high cost of examination and limited availability of elastic ultrasound devices, elastography is not widely used in primary medical facilities in rural areas. To address this issue, a deep learning approach called the multiscale elastic image synthesis network (MEIS-Net) was proposed, which utilized the multiscale learning to synthesize elastic images from ultrasound data instead of traditional ultrasound elastography in virtue of elastic deformation. The method integrates multi-scale features of the prostate in an innovative way and enhances the elastic synthesis effect through a fusion module. The module obtains B-mode ultrasound and elastography feature maps, which are used to generate local and global elastic ultrasound images through their correspondence. Finally, the two-channel images are synthesized into output elastic images. To evaluate the approach, quantitative assessments and diagnostic tests were conducted, comparing the results of MEIS-Net with several deep learning-based methods. The experiments showed that MEIS-Net was effective in synthesizing elastic images from B-mode ultrasound data acquired from two different devices, with a structural similarity index of 0.74 ± 0.04. This outperformed other methods such as Pix2Pix (0.69 ± 0.09), CycleGAN (0.11 ± 0.27), and StarGANv2 (0.02 ± 0.01). Furthermore, the diagnostic tests demonstrated that the classification performance of the synthetic elastic image was comparable to that of real elastic images, with only a 3 % decrease in the area under the curve (AUC), indicating the clinical effectiveness of the proposed method.

Prenatal hormone stress triggers embryonic cardiac hypertrophy outcome by ubiquitin-dependent degradation of mitochondrial mitofusin 2.

Prenatal stress has been extensively documented as a contributing factor to adverse cardiac development and function in fetuses and infants. The release of glucocorticoids (GCs), identified as a significant stressor, may be a potential factor inducing cardiac hypertrophy. However, the underlying mechanism remains largely unknown. Herein, we discovered that corticosterone (CORT) overload induced cardiac hypertrophy in embryonic chicks and fetal mice in vivo, as well as enlarged cardiomyocytes in vitro. The impaired mitochondria dynamics were observed in CORT-exposed cardiomyocytes, accompanied by dysfunction in oxidative phosphorylation and ATP production. This phenomenon was found to be linked to decreased mitochondrial fusion protein mitofusin 2 (MFN2). Subsequently, we found that CORT facilitated the ubiquitin-proteasome-system-dependent degradation of MFN2 with an enhanced binding of appoptosin to MFN2, serving as the underlying cause. Collectively, our findings provide a comprehensive understanding of the mechanisms by which exposure to stress hormones induces cardiac hypertrophy in fetuses.

Establishing an integrated, four-dimensional quality assessment system for traditional Chinese medicine: A case study of Shuanghuanglian oral liquid.

The quality of traditional Chinese medicine (TCM) is the premise to ensure its safety and effectiveness in clinical application. In this study, a complete quality control system for four-dimensional fingerprinting of TCM was innovatively constructed based on multiple detection techniques, and the quality of Shuanghuanglian oral liquid (SHL) was evaluated. Electrochemical fingerprinting (ECFP) as an emerging method without pretreatment provides rich and quantifiable information for SHL samples. The first quantitative ECFP of SHL was developed by the B-Z oscillation system. Eight characteristic parameters were analyzed and a good linear relationship was found between the oscillation lifetime and sample volume, by which the calculated values of the added sample volume (VL) showed different fluctuations between samples. What is more, high-performance liquid chromatography five-wavelength fusion fingerprint (HPLC-FWFP), GC fingerprint (GC-FP), and UV quantum fingerprint (UV-QFP) was established. Meanwhile, the purity of the peaks of the HPLC-FWFP was verified by the dual-wavelength absorption coefficient ratio spectrum (DWAR). Equal weighted ratio quantitative fingerprinting method (EWRQFM) was successfully proposed to extract all potential features for the overall quality assessment of the samples. Finally, a comprehensive evaluation strategy was proposed, namely the variation coefficient weighting algorithm (VCWA). The results of qualitative and quantitative evaluation of HPLC-FWFP, GC-FP, electrochemical quantum fingerprints (EC-QFP), and UV-QFP were integrated by this method. The established evaluation system is also a suitable strategy to control the quality of other TCM preparations.

Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson's disease susceptibility.

Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.

Thorough evaluation of the Chinese medicine preparations and intermediates using high performance liquid chromatography fingerprints and ultraviolet quantum fingerprints along with antioxidant activity: Shuanghuanglian oral solution as an example.

The growing global popularity of traditional Chinese medicine (TCM) has generated a growing interest in the quality control of TCM products. Shuanghuanglian Oral Liquid (SHL) is a commonly used TCM formula for treating respiratory tract infections. In this study, we present a thorough evaluation method for the quality of SHL and its intermediates. We assessed the quality through multi-wavelength fusion high-performance liquid chromatogram (HPLC) fingerprints of 40 batches of SHL samples and 15 batches of intermediates. Meanwhile, we introduced a new method called multi-markers assay by monolinear method (MAML) to quantify ten components in SHL, and revealed quality transmitting of ten components from intermediates to formulations. This information allowed us to establish a quality control system for intermediates, ensuring their quality consistency. Furthermore, we proposed UV quantum fingerprinting as an orthogonal complement to the quality evaluation by HPLC fingerprint. The relationship between fingerprinting and antioxidant capacity was also established. Overall, this study presented a novel and integrated approach for the quality evaluation of TCM products, providing valuable information for ensuring the safety and efficacy of TCM products for consumers.

Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1.

Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis mechanisms. In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid (RA) in vivo and in vitro. Mice were administered RA (11.7, 23.4 mg·kg-1·d-1, i.g.) or acyclovir (ACV, 206 mg·kg-1·d-1, i.g.) for 23 days. The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7. At the end of RA or ACV treatment, mouse plasma samples and brain tissues were collected for analysis. We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice. In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone (CORT) plus HSV-1, RA (100 µM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of viral proteins and genes. We demonstrated that CORT (50 µM) triggered lipoxygenase 15 (ALOX15)-mediated redox imbalance in the neuronal cells, increasing the level of 4-HNE-conjugated STING, which impaired STING translocation from the endoplasmic reticulum to Golgi; the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility. We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15, thus RA could rescue stress-weakened neuronal innate immune response, thereby reducing HSV-1 susceptibility in vivo and in vitro. This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.

ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis.

Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.), which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKCα-phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons.