Cerebral ischemia is a prevalent cerebrovascular disorder, with the restoration of blocked blood vessels serving as the current standard clinical treatment. However, reperfusion can exacerbate neuronal damage and neurological dysfunction, resulting in cerebral ischemia-reperfusion (I/R) injury. Presently, clinical treatment strategies for cerebral I/R injury are limited, creating an urgent need to identify new effective therapeutic targets. The PI3K/AKT signaling pathway, a pro-survival pathway associated with cerebral I/R injury, has garnered significant attention. We conducted a comprehensive review of the literature on the PI3K/AKT pathway in the context of cerebral I/R. Our findings indicate that activation of the PI3K/AKT signaling pathway following cerebral I/R can alleviate oxidative stress, reduce endoplasmic reticulum stress (ERS), inhibit inflammatory responses, decrease neuronal apoptosis, autophagy, and pyroptosis, mitigate blood-brain barrier (BBB) damage, and promote neurological function recovery. Consequently, this pathway ultimately reduces neuronal death, alleviates brain tissue damage, decreases the volume of cerebral infarction, and improves behavioral impairments. These results suggest that the PI3K/AKT signaling pathway is a promising therapeutic target for further research and drug development, holding significant potential for the treatment of cerebral I/R injury.

Stroke poses a threat to the elderly, being the second leading cause of death and the third leading cause of disability worldwide. Ischemic stroke (IS), resulting from arterial occlusion, accounts for ~85% of all strokes. The pathophysiological processes involved in IS are intricate and complex. Currently, tissue plasminogen activator (tPA) is the only Food and Drug Administration‑approved drug for the treatment of IS. However, due to its limited administration window and the risk of symptomatic hemorrhage, tPA is applicable to only ~10% of patients with stroke. Additionally, the reperfusion process associated with thrombolytic therapy can further exacerbate damage to brain tissue. Therefore, a thorough understanding of the molecular mechanisms underlying IS‑induced injury and the identification of potential protective agents is critical for effective IS treatment. Over the past few decades, advances have been made in exploring potential protective drugs for IS. The present review summarizes the specific mechanisms of various forms of programmed cell death (PCD) induced by IS and highlights potential protective drugs targeting different PCD pathways investigated over the last decade. The present review provides a theoretical foundation for basic research and insights for the development of pharmacotherapy for IS.

Antimony (Sb) ore exploitation and the use of Sb-containing drugs pose known health risks. This study investigated the toxicity of environmentally relevant concentrations of Sb (0.12-12 mg L-1) on human umbilical vein endothelial cells (HUVECs). The 50 % lethal concentration (LC50) of Sb to HUVECs was 11.4 mg L-1. Exposing to high level of Sb induced cell cycle arrest by altering the expression of cell cycle regulators, inhibiting the transitions of G0/G1 to S and S to G2/M. At 1.2 mg L-1 Sb, CKD6 and p21 expressions in HUVECs changed to 0.75 and 1.32 folds that of no-Sb control, respectively (p < 0.01). At 12 mg L-1 Sb, CDK2, CKD6, and p27 expressions decreased by 1.54, 4.41, and 1.54 folds (p < 0.001), while p21 expression increased by 3.03 folds (p < 0.001) as compared to control. Sb also led to cell apoptosis, evidenced by Annexin V-FITC/PI staining and changes in the expressions of Bax (1.21-1.30 folds, p < 0.01) and Bcl-2 (0.65-0.83 folds). Oxidative damage was a pivotal factor driving cell apoptosis, probably through down-regulating antioxidant genes (CAT, GPX1, and GSTP1) and up-regulating stress response genes (HO-1, SOD1, and TrxR1). The elevated H2O2 generated in mitochondria likely contributed to cell apoptosis due to the imbalance in H2O2 metabolism. These findings suggest that environmentally relevant concentrations of Sb can exert cytotoxicity to HUVECs, which should be of potential concern for human cardiovascular disease.

This study aimed to investigate the effects of lidocaine on sepsis-induced acute lung injury and its underlying mechanisms.

Thirty C57BL/6 mice were divided into three groups: SHAM, CLP, and LD. The sepsis-induced acute lung injury model was established using cecal ligation and puncture (CLP) surgery, while SHAM mice underwent a sham operation without ligation or puncture. Mice in the LD group were administered lidocaine (10 mg/kg) intravenously through the tail vein. The SHAM and CLP groups were treated with an equal volume of 0.9% sterile saline solution. All mice were sacrificed 24 hours after surgery, and lung tissue and blood samples were collected for subsequent analysis. The wet/dry weight ratio (W/D ratio) was measured to evaluate lung edema. Lung injury and apoptosis were assessed using HE staining and TUNEL assay. The concentrations of inflammatory cytokines IL-6, TNF-α, and HMGB1 were measured by ELISA. The expression of JAK2, STAT3, p-STAT3, Bcl-2, HMGB1, and Bax was analyzed by western blot.

The W/D ratio in the CLP group was significantly higher than the SHAM group, indicating increased lung edema. Pathological examination revealed obvious lung injury, and apoptosis was evident in the CLP group. The expression of HMGB1, IL-6, and TNF-α in lung tissue increased by 24 hours after CLP surgery. Additionally, the levels of JAK2, STAT3, p-STAT3, HMGB1, and Bax were significantly increased, while Bcl-2 expression was reduced. However, lidocaine administration reversed these changes.

Intravenous lidocaine effectively alleviated acute lung injury in septic mice. The anti-inflammatory effects of lidocaine may be attributed to its suppression of the JAK2/STAT3 signaling pathway and its anti-apoptotic effects.

Pediatric nephrotic syndrome remains a complex clinical entity, with incompletely elucidated pathogenetic mechanisms, in which oxidative stress appears to have a substantial etiopathogenic role. Recent evidence supports the involvement of redox imbalance in podocyte damage, impaired glomerular function, and systemic decline. All this suggests that antioxidant interventions can favorably modulate the course of the disease. This narrative review aims to synthesize the most relevant data from the current literature on the interaction between oxidative stress and nephrotic syndrome in children, with a focus on the therapeutic potential of antioxidants. The analysis focuses on the molecular mechanisms by which oxidative stress contributes to the progression of renal dysfunction, the role of oxidative biomarkers in disease monitoring, and the ability of antioxidants to reduce the need for immunosuppressants and corticosteroids, thus contributing to the decrease in associated morbidity. The translational perspectives of antioxidant therapy are also discussed, in the context of the urgent need for effective adjuvant strategies with a safety profile superior to conventional therapies. By integrating these data, the paper supports the valorization of antioxidant interventions as an emerging direction in the management of pediatric nephrotic syndrome and substantiates the need for controlled clinical trials, with rigorous design, in this field.

Poria cocos a traditional Chinese medicinal material with both culinary and therapeutic applications, contains pachymic acid (Pac) as one of its main active compounds, which has demonstrated anti-lipid accumulation and hypoglycemic effects. However, its impact on the biochemical changes in the enterohepatic axis induced by a high-fat diet remains poorly understood. This study investigated the protective mechanism of Pac using a high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse model. 16S rRNA sequencing of gut microbiota revealed that Pac administration reduced the Firmicutes to Bacteroidetes ratio, restored Akkermansia abundance, decreased Desulfovibrio and Streptococcus population, and ameliorated gut dysbiosis. Concurrently, Pac treatment reduced the expression of hepatic inflammatory factors by mainly adjusted LPS/TLR4/MYD88/NFκB pathway. Liver transcriptome analysis indicated that Pac primarily affects genes involved in lipid metabolism, apoptosis, and inflammatory responses. Specifically, Pac inhibited FASN, SREBP1c, and SCD1 expression while upregulating PPARα and CPT1α, thereby improving high-fat diet-induced hepatic steatosis in mice. Additionally, Pac treatment reduced hepatocellular apoptosis. Non-targeted liver metabolomics analysis following Pac intervention revealed increased levels of acylcarnitine and oleic acid. Collectively, these findings suggest that Pac alleviates high-fat diet-induced hepatic lipid accumulation and damage by modulating gut microbiota, lipid metabolism, inflammation, and apoptosis. This comprehensive study provides valuable insights into the therapeutic potential of Pac and offers a reference for the development and utilization of Poria cocos resources in addressing NAFLD.

Testicular torsion/detorsion can cause testis loss and infertility. Aloperine is a major active alkaloid extracted from Sophora alopecuroides Linn. It has been shown to have organ-protective effects. However, the effects of aloperine on the testis and its underlying mechanisms remain unclear.

This study investigated the effect of aloperine on testicular torsion/detorsion injury in rats.

Male Sprague-Dawley rats were randomized to the sham-operated (sham), testicular I/R (TI/R), or aloperine preconditioning (ALOPre) or postconditioning (ALOPost) groups. All rats except for the sham-operated rats were subjected to 3 h of right spermatic cord torsion (720°, clockwise), followed by 3 h of detorsion. Aloperine (10 mg/kg) was intravenously administered before testicular torsion (ALOPre) or at the onset of testicular detorsion (ALOPost). The therapeutic efficacy of aloperine was evaluated by histological analysis, oxidative stress evaluation, inflammatory response examination, apoptosis analysis, protein analysis, and immunohistological assessment.

Compared with TI/R, aloperine protected both the ipsilateral and contralateral testes against unilateral testicular I/R, as evidenced by a reduced testicular weight to body weight (TW/BW) ratio (ALOPre: p = 0.0037; ALOPost: p = 0.0021) and volume (ALOPre: p = 0.0020; ALOPost: p = 0.0009), less structural damage with better Johnsen (ALOPre: p = 0.0013; ALOPost: p = 0.0021), and Cosentino scores (ALOPre: p < 0.0001; ALOPost: p < 0.0001), increased mean seminiferous tubule diameter and mean seminiferous tubule epithelial height, decreased testicular apoptosis, and less oxidative stress and inflammatory response. In addition, aloperine significantly stimulated the phosphorylation of signal transducer and activator of transcription (STAT)-3 in the ipsilateral testes following detorsion. Administration of Ag490 suppressed STAT-3 phosphorylation, thereby abrogating the protective effects exerted by aloperine on the ipsilateral testis.

Aloperine has a strong testicular protective effect on the ipsilateral and contralateral testes after testicular torsion/detorsion. This aloperine-induced ipsilateral testicular protection is mediated via the STAT-3 signaling pathway.

Breast cancer is a major health issue among women, and doxorubicin (DOX) is a commonly used treatment. However, its clinical application is limited by its considerable toxicity. This study introduces an acidity-responsive magnetite nanoparticle-based nanocarrier for effective breast cancer treatment. The magnetite nanoparticles were initially coated with [3-(2,3-epoxypropoxy)-propyl]-trimethoxysilane, an epoxysilane cross-linker, to enhance their stability and functional properties. Subsequently, NH2-PEG-COOH was conjugated to epoxy-functionalized silica-coated magnetite nanoparticles to improve biocompatibility and introduce reactive carboxyl groups. These carboxyl groups were further modified with hydrazine via carbodiimide-mediated amidation to construct magnetic nanocarriers (MNC). DOX was loaded into the system via acid-sensitive hydrazone bonds, resulting in the final MNC-DOX formulation. The DOX loading process followed the Ho-McKay model, demonstrating chemical adsorption kinetics with a high loading capacity of 433.147 mg/g. The acid-sensitive hydrazone bond facilitated rapid DOX release in response to the acidic tumor microenvironment, with release kinetics following the Korsmeyer-Peppas model, indicative of Fickian diffusion. In vitro cytotoxicity assays revealed that MNC-DOX exhibited significant cytotoxicity against MCF-7 breast cancer cells. This novel MNC-DOX formulation holds great potential for enhancing cancer therapy, highlighting its responsiveness to subtle pH changes and its ability to improve the targeted delivery and controlled release of chemotherapeutic agents.

The p38 mitogen-activated protein kinase (p38 MAPK) is a key regulator of numerous cellular processes relevant to cancer therapy. Apart from reactive oxygen species (ROS)-mediated activation, the p38 pathway can also be activated through direct interactions between the p38 MAPK protein which stabilize an open conformation of the activation loop, exposing the phosphorylation sites. Therefore, assessing p38 MAPK expression and the direct binding of anticancer agents with p38 MAPK can provide critical insights for advancing the development of innovative anticancer therapies. In this research, following the incubation of A549 lung cancer cells with vernodalin (VN), a sesquiterpene lactone, several cellular assays were conducted. It was noted that VN suppressed the proliferation of A549 cells with IC50 values of 65.80 μM, 39,90 μM, and 25.85 μM at 24 h, 48 h, and 72 h, respectively, while, IC50 values were higher for VN in BEAS-2B human bronchial epithelial cells. Moreover, we discovered that VN leads to excessive ROS and MDA production by downregulating the activities of SOD/CAT/GPX, reducing GSH levels, and decreasing both HO-1 mRNA expression and activity, along with Nrft mRNA expression. We subsequently found that VN boosted the expression of p38 MAPK, Bax/Bcl-2 mRNA, and caspase-3/-9 mRNA and activity in A549 cells. Molecular docking analysis revealed strong binding affinity between VN and p38 MAPK (-9.97 kcal/mol) near the ATP-binding site (Asp-150 and Arg-149) and the activation loop (Gly-170 and Leu-171) facilitated by hydrophobic as well as hydrogen bond interactions. The fluorescence spectroscopy analysis demonstrated that the spontaneous interaction between p38 MAPK and one molecule VN occurred with logKb = 5.02 ± 0.18 and ΔG∘ = -28.49 ± 1.91 kJ/mol. Multi-spectroscopy measurements revealed minor alterations in the p38 MAPK conformation following interaction with VN. We hypothesize that the pro-apoptotic effect of VN on lung cancer cells may be mediated by two mechanisms: (1) ROS-dependent modulation of p38 pathway, and/or (2) direct ligand-receptor interaction between VN and critical residues near the ATP-binding pocket or activation loop of p38 MAPK, thereby stabilizing its catalytically active conformation. However, these preliminary findings necessitate further experimental validation and confirmation in subsequent studies.

Murine double minute 2 (MDM2), a key negative regulator of p53, forms a feedback loop with p53 to drive tumor progression, including colorectal cancer. Nutlin-3a, an MDM2 inhibitor, induces apoptosis in wild-type p53 tumors, but its effects on p53-mutated cancers and potential p53-independent apoptotic mechanisms remain unclear.

We investigated Nutlin-3a's effects on colon cancer cells with varying p53 phenotypes. Endoplasmic reticulum (ER) stress-associated CHOP was detected and knocked down to explore mechanisms. In vitro and in vivo experiments assessed Nutlin-3a's synergy with 5-fluorouracil and TRAIL.

Nutlin-3a activated caspase-8-dependent extrinsic apoptosis in colon cancer cells via DR5 upregulation, independent of p53 status. ER stress and CHOP activation mediated DR5 induction, driven by calcium release. Combined Nutlin-3a treatment enhanced sensitivity to 5-fluorouracil and TRAIL in vitro and in vivo through caspase-8 pathway activation.

These findings reveal a novel p53-independent apoptotic mechanism of Nutlin-3a involving ER stress and death receptor signaling. This pathway highlights Nutlin-3a's potential as an adjuvant therapy for colon cancer, even in p53-mutated tumors, by enhancing chemotherapeutic efficacy through extrinsic apoptosis.

Mounting evidence suggests that neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid β peptide (Aβ) could recruit and activate microglia, leading to the generation of pro-inflammatory factors, and ultimately neuroinflammation. Chitooligosaccharide (COS) is widely recognized as anti-inflammation bioactive substance, though whether it exerts beneficial effect on AD is unclear. In this study, we explored the effect of COS on AD prevention and treatment. We found that COS ameliorated cognitive deficiency, increased the expression of Nrf2 but decreased Aβ levels and the activation of NF-κB in APP/PS1 mice. In vitro, COS decreased the secretions of IL-6, IL-1β and TNF-α in Aβ25-35 + lipopolysaccharides (LPS) -exposed BV2 microglia. Meanwhile, COS down-regulated the expressions of iNOS, COX-2, NLRP3, caspase 1 and the nuclear translocation of NF-κB p65, while upregulated the expressions of Nrf2 and HO-1. Further, COS improved the viability of SK-N-SH cells that exposed to Aβ25-35 + LPS-stimulated microglial conditioned media, and the repressive effect of COS on NLRP3, iNOS, and phospho-NF-κB p65 expressions were markedly compromised upon Nrf2-siRNA transfection. Collectively, COS improved cognitive decline and suppressed neuroinflammation via the Nrf2/NF-κB signaling axis, suggesting COS might be a promising candidate in down-regulating inflammatory responses during AD progression.

The current study aimed to investigate the effect of isoegomaketone (IK) as a radiosensitizer for colon cancer and its effect on intestinal injury, and to verify its potential mechanism. A total of 40 BALB/c nude mice were selected to construct a HT‑29 tumor‑bearing mice model with T lymphocyte deficiency. Tumor size was measured every other day, and the survival of mice was counted. Intestinal and tumor tissues of mice were harvested when the experiment ended. The levels of inflammatory factors and markers of oxidative stress in intestinal tissues of different groups of mice were analyzed by ELISA. Western blotting was used to examine the expression of apoptosis‑ and autophagy‑related proteins, and the phosphorylation levels of the PI3K/AKT/mTOR signaling pathway in HT‑29 cells and tumor tissues. Radiotherapy (RT) combined with IK significantly reduced the viability of HT‑29 cells. The optimal dose proportion of RT combined with IK was 8 Gy and 100 µg/ml, and the combination index was <1, suggesting a strong combination effect. In addition, IK could further promote radiation DNA damage in HT‑29 cells by inhibiting the PI3K/AKT/hypoxia inducible factor 1α (HIF‑1α) signaling pathway, while upregulating the expression of proapoptotic and autophagy‑related proteins in HT‑29 cells. In HT‑29 tumor‑bearing mice, RT in combination with IK significantly inhibited the growth of xenografts and improved mouse survival. In addition, the combination of RT and IK significantly upregulated BAX and Beclin‑1 expression, downregulated BCL‑2 expression, and promoted the conversion of LC3 I to LC3 II. Radiation induced an increase in inflammatory cytokine levels as well as oxidative stress marker levels in intestinal tissue. Western blot analysis showed that the combination of RT and IK significantly inhibited the phosphorylation level of the PI3K/AKT/mTOR signaling pathway compared with the control and monotherapy groups. IK could significantly enhance the efficacy of RT by regulating the apoptosis and autophagy of colon cancer tumors, and alleviate inflammation and oxidative stress by regulating the PI3K/AKT/mTOR signaling pathway to alleviate intestinal injury. The present findings suggest that IK can be used as a promising sensitizer and has the potential to enhance the efficacy and safety of RT for colon cancer.

Cancer cells possess high proliferative ability and usually override apoptosis and metastasize to distant lesions. Autophagy in cancer cells is a double-edged weapon where a cross-regulation postulation between apoptosis and autophagy exists. The aim of the present study was to investigate the effect of adding Thymoquinone (TQ) to Imatinib (IM) in HCT116 human colorectal cancer cell line model on various apoptotic and autophagy markers. The combination doses of IM and TQ were selected according to our previous study concerned with cytotoxicity and uptake/efflux genes modulation. In the current study, the combination induced autophagy in HCT116 cell line which in turn enhanced apoptosis. Moreover, early apoptosis was evidenced. The induction of both autophagy and apoptosis resulted in programmed cell death. The assessment of AMPK, Par-4, apoptosis markers, colony formation assays, flow cytometry and autophagy detection by acridine orange proved this rapport.

Macromolecular glycopeptides are natural products derived from various sources, distinguished by their structural diversity, multifaceted biological activities, and low toxicity. These compounds exhibit a wide range of biological functions, such as immunomodulation, antitumor effects, anti-inflammatory properties, antioxidant activity, and more. However, limited understanding of natural glycopeptides has hindered their development and practical application. To promote their advancement and utilization, it is crucial to thoroughly investigate the pharmacological mechanisms of glycopeptides and address the challenges in natural glycopeptide research. This review uniquely focuses on the primary biological activities and potential molecular mechanisms of glycopeptides as reported in recent literature. Moreover, we emphasize the current challenges in glycopeptide research, including extraction and isolation difficulties, purification challenges, structural analysis complexities, elucidation of structure-activity relationships, characterization of biosynthetic pathways, and ensuring bioavailability and stability. The future prospects for glycopeptide research are also explored. We argue that ongoing research into glycopeptides will significantly contribute to drug development and provide more effective therapeutic options and disease treatment alternatives for human health.

Thirty compounds including 13 new phenolic glycosides (1-6, 9-15) and 17 known aromatic compounds and aromatic glycosides (7-8, 16-30) were isolated from the roots of Wrightia pubescens. The structures of the new phenolic glycosides were established by extensive NMR spectroscopic data analysis as well as chemical derivatization method. The isolated compounds were evaluated for their hepatoprotective activities using cell model of acetaminophen (APAP)-induced HepG2 cells. The results indicated that phenolic glycosides (2, 4, 5, 7, 8, 11, 13) pretreatment enhanced the cells viability and reduced the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT). The hepatoprotective mechanism of a representative new compound, wrightioside D (4), was further investigated. Compound 4 exhibited hepatoprotective effects via reducing oxidative stress by attenuating ROS formation and inhibiting apoptosis in APAP-treated HepG2 cells.

Background and Objectives: Hind limb ischemia-reperfusion (I/R) injury is a serious clinical condition that requires urgent treatment and develops as a result of a sudden decrease in blood flow in the extremity. Antioxidant combinations are frequently used in diseases today. This study aimed to investigate and compare the effectiveness of ellagic acid (EA) and berberine (BER), which are important antioxidants, and the combination on hind limb I/R injury to evaluate their therapeutic power. Materials and Methods: Thirty-five male Sprague Dawley rats were randomly divided into five groups: sham, I/R, EA+I/R, BER+I/R, and EA/BER+I/R. In the I/R procedure, the infrarenal abdominal aorta was clamped and reperfused for 2 h. EA (100 mg/kg, ip) and BER (200 mg/kg, ip) were administered in the 75th minute of ischemia. Oxidative stress markers (MDA, GSH, SOD, and CAT) and TNF-α were measured. Apoptosis (Bax, Bcl-2, and Cleaved caspase-3) and pyroptosis (Nrf2, NLRP3, and Gasdermin D) pathways were evaluated via Western blot. Muscle tissue was examined histopathologically by hematoxylin eosin staining. One-way ANOVA and post hoc LSD tests were applied for statistical analyses (p < 0.05). Results: Bax levels increased in the ischemia group and decreased with EA and BER (p < 0.05). Bcl-2 levels decreased in the ischemia group but increased with EA and BER (p < 0.05). The highest level of the Bax/Bcl-2 ratio was in the I/R group (p < 0.05). Cleaved caspase 3 was higher in the other groups compared to the sham group (p < 0.05). While Nrf2 decreased in the I/R group, NLRP3 and Gasdermin D increased; EA and BER normalized these levels (p < 0.05). In the histopathological analysis, a combination of EA and BER reduced damage (p < 0.05). TNF-α levels were similar between groups (p > 0.05). MDA levels were reduced by EA and BER, but GSH, SOD, and CAT levels were increased (p < 0.05). Conclusions: It was concluded that TNF-α levels depend on the degree and duration of inflammation and that no difference was found in relation to duration in this study. As a result, EA, BER, and their combination could be potential treatment agents on hind limb I/R injury with these positive effects.

This study aimed to investigate the protective effect of adipose tissue-derived exosomes (AT-Exo) on rat nucleus pulposus cells (NPCs).

Ultracentrifugation was used to extract exosomes from rat adipose tissue. Transmission electron microscopy (TEM), Western blot, and nanoparticle tracking analysis (NTA) were used to characterize the exosomes. Tert-butyl hydrogen peroxide (TBHP) was used to induce apoptosis of rat NPCs. Cell viability was determined by CCK-8 assay. AT-Exo was administered to investigate its effect on rat NPCs using Western blot and immunofluorescence staining.

AT-Exo was successfully extracted and characterized by NTA, TEM, and Western blots. Uptake assay showed that AT-Exo can be taken up by the NPCs. TBHP (60 μM) resulted in decreased cell viability and increased apoptosis of NPCs. Interestingly, AT-Exo protected NPCs against TBHP, indicated by increased cell viability, decreased apoptosis, upregulated Aggrecan and type II collagen deposition, and downregulated matrix metalloproteinase 3/13.

In summary, rat adipose tissue-derived exosomes can increase the levels of Aggrecan, type II collagen, and Bcl2, and decrease the levels of matrix metalloproteinase 3/13, cleaved caspase3, and Bax. Therefore, rat adipose tissue-derived exosomes can maintain metabolic balance of extracellular matrix and protect against apoptosis in rat nucleus pulposus cells.

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction, oxidative stress, and neuroinflammation are recognized as critical pathological mechanisms driving neurodegeneration in PD. Exosome (Exo)-based therapies, particularly those derived from human neural stem cells (hNSCs), offer promising neuroprotective effects due to their ability to transfer bioactive molecules that modulate cellular processes. Resveratrol (RES), a polyphenolic compound with potent antioxidant and anti-inflammatory properties, has been shown to enhance the therapeutic potential of stem cell (SC)-derived Exos. This study investigated the neuroprotective effects of RES-treated hNSCs-derived Exos (RES-hNSCs-Exos) on SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin commonly used to model Parkinsonian neurotoxicity. Treating SH-SY5Y cells with MPP+ led to significant reductions in cell viability, mitochondrial dysfunction, increased oxidative stress, and the activation of inflammatory pathways. Treatment with RES-hNSCs-Exos rescued SH-SY5Y cells from MPP+-induced toxicity by improving cell viability, enhancing ATP production, increasing mitochondrial biogenesis, and reducing reactive oxygen species (ROS) generation. The findings also demonstrated the increased expression of essential genes involved in mitochondrial biogenesis, such as PGC1α, NRF1, and Tfam, indicating improved mitochondrial function in the presence of RES-hNSCs-Exos. Further analysis revealed that these protective effects were mediated by activating the AMP-activated protein kinase (AMPK) and Nrf2 signaling pathways, which promoted mitochondrial health and reduced oxidative stress. Moreover, RES-hNSCs-Exos treatment suppressed neuroinflammation by downregulating NLRP3 inflammasome activation and reducing the secretion of pro-inflammatory cytokines IL-1β and IL-18. In conclusion, the results suggest that RES-hNSCs-Exos exhibit potent neuroprotective effects against MPP+-induced neurotoxicity by enhancing mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation. These findings highlight the potential of hNSCs-Exos as a novel therapeutic strategy for neurodegenerative diseases like PD, with RES as a valuable enhancer of Exos efficacy.

Overexpression of epidermal growth factor receptor (EGFR) and thioredoxin reductase (TrxR) are commonly associated with an adverse prognosis in hepatocellular carcinoma (HCC). This makes them key targets for the treatment of HCC. Studies have shown that the clinical efficacy of the EGFR tyrosine kinase inhibitor gefitinib alone in treating HCC is limited. Herein, we developed a series of novel gold(I) complexes using a "dual-targeting strategy" by combining gold(I) complexes with different gefitinib derivatives. Among them, the best complex 6g exhibits significant antiproliferative activity against Huh7 cells and Huh7R (lenvatinib-resistant) cells. Remarkably, complex 6g inhibits the expression of phosphorylated EGFR while also effectively inhibiting intracellular TrxR activity. In addition, complex 6g causes a significant increase in the accumulation of reactive oxygen species (ROS), disrupts mitochondrial membrane potential (MMP), arrests the cell cycle in the G0/G1 phase, and induces apoptosis. Collectively, our findings demonstrate that complex 6g exhibits potential anti-HCC effects via dual-targeting of EGFR and TrxR.

Diverse liver diseases are characterised by late diagnosis and rapid progression and have become one of the major threats to human health. To delay the transition from benign tissue lesions to a substantial organ injury, scientists have gradually applied natural compounds derived from plants as a complementary therapy in the field of hepatology. Ginseng (Panax ginseng C. A. Meyer) is a tonic traditional Chinese herbal medicine, and natural products, including ginsenoside Rg1 (G-Rg1), which is a kind of 20(S)-protopanaxatriol saponin with a relatively high biological activity, can be isolated from the roots or stems of ginseng. Given these information, this review aimed to summarise and discuss the metabolic mechanisms of G-Rg1 in the regulation of diverse liver diseases and the measures to improve its bioavailability. As a kind of monomer in Chinese medicine with multitarget pharmacological effects, G-Rg1 can provide significant therapeutic benefits in the alleviation of alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, viral hepatitis, etc., which mainly rely on the inhibition of apoptosis, strengthening endogenous anti-inflammatory and antioxidant mechanisms, activation of immune responses and regulation of efflux transport signals, to improve pathological changes in the liver caused by lipid deposition, inflammation, oxidative stress, accumulation of hepatotoxic product, etc. However, the poor bioavailability of G-Rg1 must be overcome to improve its clinical application value. In summary, focusing on the hepatoprotective benefits of G-Rg1 will provide new insights into the development of natural Chinese medicine resources and their pharmaceutical products to target the treatment of liver diseases.

Genitourinary cancers affect over 480,000 patients in the United States annually. While promising therapeutic modalities continue to emerge, notably immune checkpoint inhibitors, molecular targeted therapies, antibody-drug conjugates, and radioligand therapies, these treatments are associated with a spectrum of adverse side-effects, including ophthalmologic toxicities. In this review, we cover the most commonly used antineoplastic agents for the kidneys, bladder, urinary tracts, prostate, testis, and penis, detailing mechanism, indication, and recent trials supporting their use. For each category of antineoplastic therapy, we describe the epidemiology, management, and clinical presentation, of common ophthalmologic toxicities stemming from these agents. This review serves to augment awareness and recognition of possible ophthalmologic manifestations resulting from the use of antineoplastic agents in genitourinary malignancy. Early identification of these side effects can hasten ophthalmology referral and ultimately improve visual outcomes in patients experiencing medication-induced ocular toxicities.

Lung cancer is the malignant tumor with the highest morbidity and mortality rate worldwide, of which non-small cell lung cancer (NSCLC) accounts for approximately 85%. KRAS mutations are one of the significant mechanisms underlying the occurrence, development, immune escape, and chemotherapy resistance of NSCLC. Two KRAS inhibitors are approved by Food and Drug Administration for the treatment of NSCLC in the past 3 years. However, they are only effective to KRAS G12C mutant, and moreover, innate and acquired drug resistance is already reported, leaving an urgent need to block KRAS pathways through novel targets. In this study, we focused on the discovery of ligands targeting the RNA G-quadruplexes in 5'-UTR of KRAS mRNA, and a novel tribenzophenazine analog (MBD) was identified as the lead compound. Further mechanisms were discussed in A549/DDP cells, a cisplatin-resistant and KRAS-mutant NSCLC cell line. Antitumor efficacy was verified both in vitro in A549/DDP cells, and in vivo in a nude mouse xenograft model implanted with A549/DDP cells. To sum up, our results suggest the potential of MBD as a prominent anti-KRAS-driven NSCLC agent and propose a new idea for the development of small molecule ligands targeting KRAS RNA G-quadruplexes.

Genistein (4',5,7-trihydroxyisoflavone) is a phytoestrogen belonging to a subclass of natural flavonoids that exhibits a wide range of pharmacological functions, including antioxidant and anti-inflammatory properties. These characteristics make genistein a valuable phytochemical compound for the prevention and/or treatment of cancer. Genistein effectively inhibits tumor growth and dissemination by modulating key cellular mechanisms. This includes the suppression of angiogenesis, the inhibition of epithelial-mesenchymal transition, and the regulation of cancer stem cell proliferation. These effects are mediated through pivotal signaling pathways such as JAK/STAT, PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and Wnt/β-catenin. Moreover, genistein interferes with the function of specific cyclin/CDK complexes and modulates the activation of Bcl-2/Bax and caspases, playing a critical role in halting tumor cell division and promoting apoptosis. The aim of this review is to discuss in detail the key cellular and molecular mechanisms underlying the pleiotropic anticancer effects of this flavonoid.

The work is aimed to investigate whether midazolam functions in thyroid cancer and reveal the potential mechanism of action. Cell viability was detected by CCK-8 method when treated by varying doses of midazolam to detect the cytotoxicity of midazolam on human thyroid follicular epithelial cell line and thyroid cancer cell lines. In thyroid cancer cells, EDU staining, wound healing and transwell assays were respectively used to detect cell proliferation, migration and invasion. Western blot was used to detect the expressions of matrix metalloproteinases (MMPs). Flow cytometry assay, western blot and immunofluorescence staining were used to detect cell apoptosis. CB-Dock2 server predicted midazolam-tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) interaction and western blot was also used to detect YWHAH expression. Midazolam dose-dependently decreased the viability of thyroid cancer cells and demonstrated no cytotoxicity on Nthy-ori-3-1 cells. In addition, increasing concentrations of midazolam or silencing of YWHAH significantly inhibited thyroid cancer cell proliferation, migration and invasion and induced cell apoptosis. Midazolam had a molecular binding with YWHAH and midazolam downregulated YWHAH expression. YWHAH partially reversed the impacts of midazolam on the cellular events in thyroid cancer. Collectively, midazolam may act as an anti-thyroid cancer agent via its interrelation with YWHAH.

Chlorogenic acid (CGA) has strong antioxidant properties. In order to improve the low maturation rate and poor vitrification freezing effect of sheep oocytes caused by oxidative stress. In this study, oocytes from 200 2-3-year-old Kazakh sheep were collected, and different concentrations of CGA were added to the maturation medium and vitrification freezing solution to study the effects of CGA on the maturation rate, cleavage rate, blastocyst rate, reactive oxygen species (ROS) and glutathione (GSH) levels, mitochondrial membrane potential, and the expression levels of oxidation and apoptosis-related genes in sheep oocytes. The results showed that adding 40 μmol/L CGA to the oocyte in vitro maturation solution significantly increased the maturation rate of oocytes, adding 50 μmol/L CGA to the vitrification cryopreservative solution significantly increased the cleavage and blastocyst rates of mature oocytes activated by parthenogenetic activation after freezing. During in vitro maturation and vitrification freezing in sheep oocytes, CGA significantly reduced the level of ROS and the expression of apoptosis-related genes (Caspase-3 and Bax/Bcl-2), and significantly increased the level of glutathione (GSH), mitochondrial membrane potential, and the expression of antioxidant and anti-apoptosis-related genes (SOD-2 and GPX-3). In addition, CGA significantly increased the expression of the anti-apoptotic gene (AKT) and anti-stress gene (FOXO) during vitrification freezing of sheep oocytes. In conclusion, 40 μmol/L CGA improves the maturation rate of sheep oocytes, and 50 μmol/L CGA improves the quality of parthenogenetic activation embryos after vitrification freezing of mature oocytes in sheep. These results provide a basis for the production of sheep in vitro embryos and the establishment of a germplasm resource bank.

The current study explores the impact of CLL on γδ T cells and, in an attempt to better understand the sources of immunosuppression, assesses the impact of M-MDSCs on γδ T cells in vitro.

The study included 163 CLL patients and 34 healthy volunteers. γδ T cells were screened with flow cytometry, including NKG2D, Fas, FasL, and TRAIL staining. Additionally, to deepen understanding of the immunosuppressive impact of CLL on γδ T, a set of in vitro co-cultures of γδ T and M-MDSCs was performed.

RNAseq revealed significant, though relatively minor, changes in the transcriptome. Functional analyses showed a minor drop in cytotoxic potential against CLL cells. Finally, depletion of M-MDSCs from CLL-derived peripheral blood mononuclear cells did not restore γδ T cells' proliferative response.

Altogether, this suggests a minor impact of M-MDSCs on activated γδ T. Thus, it seems probable that other mechanisms than M-MDSCs mediate the negative impact of CLL on circulating γδ T cells.

In the tissue regeneration field, stem cell transplantation represents a promising therapeutic strategy. To favor their implantation, proliferation and differentiation need to be controlled. Several studies have demonstrated that stem cell fate can be controlled by applying continuous electric field stimulation. This study aims to characterize the effect of a specific microsecond electric pulse stimulation (bipolar pulses of 100 µs + 100 µs, delivered for 30 min at an intensity of 250 V/cm) to induce an increase in cell proliferation on mesenchymal stem cells (MSCs) and induced neural stem cells (iNSCs). The effect was evaluated in terms of (i) cell counting, (ii) cell cycle, (iii) gene expression, and (iv) apoptosis. The results show that 24 h after the stimulation, cell proliferation, cell cycle, and apoptosis are not affected, but variation in the expression of specific genes involved in these processes is observed. These results led us to investigate cell proliferation until 72 h from the stimulation, observing an increase in the iNSCs number at this time point. The main outcome of this study is that the microsecond electric pulses can modulate stem cell proliferation.

CLP36 is also known as PDZ and LIM Domain 1 (PDLIM1) that is a ubiquitously-expressed α-actinin-binding cytoskeletal protein involved in carcinogenesis, and our current study aims to explore its involvement in lymphoma.

Accordingly, the CLP36 expression pattern in lymphoma and its association with the overall survival was predicted. Then, qPCR was applied to gauge CLP36 expression in lymphoma cells and determine the knockdown efficiency. The survival, proliferation and apoptosis of CLP36-silencing lymphoma cells were tested. Cell viability, proliferation and apoptosis were assessed based on cell counting kit-8 (CCK-8) assay, colony formation assay, EdU staining, and flow cytometry, respectively. Additionally, qPCR was used to calculate the expressions of proteins associated with metastasis and apoptosis, while immunoblotting was employed to determine the phosphorylation status of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/cAMP-response element binding protein (CREB).

CLP36 expression was relatively higher in lymphoma, which was associated with a poor prognosis. Also, CLP36 was highly-expressed in lymphoma cells and the silencing of CLP36 contributed to the suppressed survival and proliferation as well as the enhanced apoptosis of lymphoma cells. Further, CLP36 silencing repressed the expressions of Cadherin 2 (CDH2) and Vimentin (VIM) yet promoted those of Bax and Caspase 3 in lymphoma cells, concurrent with the reduction on the phosphorylation of PI3K, AKT and CREB, all of which were confirmed to be positively correlated with CLP36.

This study, so far as we are concerned, provided evidence on the involvement of CLP36/PI3K/AKT/CREB axis in lymphoma, which may be contributive for the identification on the relevant molecular targets of lymphoma.

This review assesses the diverse health risk factors associated with microplastic (MP) exposure and their impact on cellular signaling pathways. MPs induce chronic inflammation, oxidative stress, endocrine disruption, apoptosis, and immune dysregulation. They activate signaling pathways such as NF-κB, MAPK, and Nrf2, exacerbating inflammatory responses, oxidative damage, and hormonal imbalances. Understanding the interplay between MPs and signaling pathways is crucial for elucidating the mechanisms underlying MP-induced health effects. Effective risk assessment and management strategies are essential to mitigate the adverse health impacts of MPs on human populations. This research underscores the urgent need for interdisciplinary collaboration to safeguard human health and environmental sustainability in the face of rising MP pollution. In this paper, we also assess the risk factors caused by the microplastics in the pregnant women and the development of the fetus. This review explores the potential risks and challenges associated with MP exposure in newborn babies. It is quite concerning that microplastic particles were recently found in the placental tissue of newborn children for the first time. Although it is unclear how these tiny particles affect different organs, researchers believe that these tiny particles could potentially carry harmful chemicals or disrupt the developing immune system of the fetus. This review overall focuses on the impact of microplastic disrupting different signaling including reproductive health in humans.

The intricate cooperation between cancer cells and nontumor stromal cells within melanoma microenvironment (MME) enables tumor progression and metastasis. We previously demonstrated that the interplay between tumor-associated macrophages (TAMs) and melanoma cells can be disrupted by using long-circulating liposomes (LCLs) encapsulating prednisolone phosphate (PLP) (LCL-PLP) that inhibited tumor angiogenesis coordinated by TAMs. In this study, our goal was to improve LCL specificity for protumor macrophages (M2-like (i.e., TAMs) macrophages) and to induce a more precise accumulation at tumor site by loading PLP into IL-13-conjugated liposomes (IL-13-LCL-PLP), since IL-13 receptor is overexpressed in this type of macrophages. The IL-13-LCL-PLP liposomal formulation was obtained by covalent attachment of thiolated IL-13 to maleimide-functionalized LCL-PLP. C57BL/6 mice bearing B16.F10 s.c melanoma tumors were used to investigate the antitumor action of LCL-PLP and IL-13-LCL-PLP. Our results showed that IL-13-LCL-PLP formulation remained stable in biological fluids after 24h and it was preferentially taken up by M2 polarized macrophages. IL-13-LCL-PLP induced strong tumor growth inhibition compared to nonfunctionalized LCL-PLP at the same dose, by altering TAMs-mediated angiogenesis and oxidative stress, limiting resistance to apoptosis and invasive features in MME. These findings suggest IL-13-LCL-PLP might become a promising delivery platform for chemotherapeutic agents in melanoma.

Histone deacetylases (HDACs) are validated drug targets for various therapeutic applications. A series of Tetrahydro-β-carboline-based hydroxamate derivatives, designed as HDAC inhibitors (HDACis), were synthesized. Compound 11g exhibited strong inhibitory activity against HDAC1 and the A549 cancer cell line. Additionally, this compound increased the levels of acetylated histone H3 and H4. Notably, 11g effectively arrested A549 cells in the G2/M phase and also increased ROS production and DNA damage, thereby inducing apoptosis. Further molecular docking experiments illustrated the potential interactions between compound 11g and HDAC1. These findings suggested that the novel Tetrahydro-β-carboline-based HDACis could serve as a promising framework for further optimization as anticancer agents.

Accumulating evidence suggests that the nuclear envelope (NE) is not just a target, but also a mediator of apoptosis. We showed recently that the NE protein nesprin-2 has pro-apoptotic activity, which involves its subcellular redistribution and Bcl-2 proteins. Here we further characterize the pro-apoptotic activity of nesprin-2 focusing on its redistribution. We assessed the redistribution kinetics of endogenous nesprin-2 tagged with GFP relative to apoptosis-associated mitochondrial dysfunction. The results show apoptosis-induced GFP-nesprin-2G redistribution occurred by two different modes - complete and partial, both lead to appearance of nesprin-2G near the mitochondria. Moreover, GFP-nesprin-2 redistribution is associated with reduction in mitochondrial membrane potential and mitochondrial outer membrane permeabilization and precedes the appearance of morphological features of apoptosis. Our results show that nesprin-2G redistribution and translocation near mitochondria is an early apoptotic effect associated with mitochondrial dysfunction, which may be responsible for the pro-apoptotic function of nesprin-2.

In order to study the mechanisms of ginsenoside Rb3 (G-Rb3) against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in HT22 cells based on metabolomics and PCR array, HT22 cells were randomly divided into control group, model group, G-Rb3 high-dose group (10 µmol/l) and G-Rb3 low-dose group (5 µmol/l). Except for the control group, which was left untreated, the remaining groups were incubated with 10 mmol/l Na2S2O4 in sugar-free DMEM medium for 2 h and then replaced with serum-free high-sugar DMEM medium for 2 h in order to replicate in vitro OGD/R model. Trypan blue staining was used to detect the cell viability; flow cytometry was used to detect apoptosis; western blotting was used to detect the protein expression levels of Bax, Bcl-2 and caspase-3. The metabolomics were used to analyze the differential metabolites of G-Rb3 affecting OGD/R in order to find the relevant metabolic pathways. PCR array assay was performed to identify the expression of the differential genes. G-Rb3 could inhibit HT22 apoptosis according to the result of cell morphology, trypan blue staining and flow cytometry. The levels of Bax and caspase-3 protein expression were decreased, whereas the level of Bcl-2 protein expression was increased after the treatment of G-Rb3. Metabolomics results showed that a total of 31 differential metabolites between OGD/R group and G-Rb3 group, such as guanosine level, was downregulated, the levels of enalaprilat and sorbitol were upregulated, affecting ABC transporters, galactose metabolism, citrate cycle and other related metabolic pathways; according to the result of PCR array, it was observed that G-Rb3 significantly downregulated Trp63, Trp73, Dapk1, Casp14 and Cd70 pro-apoptotic genes. In conclusion, G-Rb3 has a significant protective effect on the OGD/R model simulated in vitro, and the mechanism may be related to the inhibition of apoptosis by affecting metabolites.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.

In recent years, spheroids (tridimensional cell cultures) have emerged as a more physiologically relevant replacement for monolayer models. Their distinctive advantage is the formation of an extracellular matrix that facilitates enhanced cellular interaction and communication, approximating the conditions observed in vivo. Therefore, the potential for conducting intricate cellular and molecular techniques in these models could offer a more precise assessment of pivotal proteins within various cellular pathways of interest. Amitraz (AMZ), an acaricide classified as a formamidine chemical, has been detected in honey at concentrations exceeding legal limits. The objective of this study was to characterize a spheroid model of SH-SY5Y cells and determine the cytotoxic effect of AMZ and its mechanisms of action on this spheroid. The formation of mature spheroids was observed on the seventh day following seeding. The results obtained with SH-SY5Y spheroids were an IC50 of 238.8 ± 17 µM and 224.3 ± 19 µM, respectively, after 24 and 48 h of exposure by the MTT assay. The findings revealed that AMZ did not exhibit any indications of inflammatory over-expression markers in the spheroids. Nevertheless, at 238.8 µM of AMZ, an increase incidence of late apoptosis within spheroid cells and Bcl-2 protein expression in peripheral spheroid cells were observed through annexin V and propidium iodide probe and immunofluorescence analysis. In conclusion, the results demonstrated that spheroids could be useful for an accurate assessment of toxicity, representing a viable alternative method for determining the mechanisms of action of AMZ and related compounds.

Vitamin D receptor (VDR) can prevent myocardial ischemia reperfusion injury (MIRI). Hence, we aimed to illuminate the effect of VDR on cerebral ischemia/reperfusion injury (CIRI).

C57BL/6 mice and SK-N-SH cells were utilized to establish CIRI and cellular oxygen deprivation/reoxygenation (OGD/R) models. Mice were injected with 1 μg/kg Calcitriol or 1 μg/kg Paricalcitol (PC) and adenovirus-mediated VDR overexpression or knockdown plasmids. 2,3,5-triphenyl-tetrazolium chloride (TTC) and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed to measure the brain infarct volume and the apoptosis of cerebral cells. SK-N-SH cells were treated with 5 mM N-acetyl-L-cysteine (NAC) and transfected with VDR knockdown plasmid. Flow cytometry and Cell Counting Kit-8 (CCK-8) assays were employed to assess the apoptosis and cell viability. Enzyme-Linked Immunosorbent Assay (ELISA), quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) and Western blot were exploited to quantify the levels of reactive species oxygen (ROS), other oxidative stress-related factors, VDR and apoptosis-related factors.

The level of VDR in mouse cerebral tissue was elevated by CIRI (p < 0.001). CIRI-induced cerebral infarction (p < 0.001) and the apoptosis of cerebral cells (p < 0.001) in mice were mitigated by the activation of VDR. VDR overexpression abrogated while VDR silencing enhanced CIRI-induced infarction, oxidative stress and apoptosis of cerebral cells (p < 0.05). Furthermore, VDR silencing aggravated the oxidative stress and apoptosis in OGD/R-treated SK-N-SH cells (p < 0.05). NAC, a scavenger of oxidative stress, could reverse the effects of VDR silencing on apoptosis and oxidative stress in OGD/R-treated SK-N-SH cells (p < 0.01).

VDR alleviates the oxidative stress to protect against CIRI.

The natural compounds PSK and PSP have antitumor and immunostimulant properties. These pharmacological benefits have been documented in vitro and in vivo, although there is no information in silico which describes the action mechanisms at the molecular level. In this study, the inverse docking method was used to identify the interactions of PSK and PSP with two local databases: BPAT with 66 antitumor proteins, and BPSIC with 138 surfaces and intracellular proteins. This led to the identification interactions and similarities of PSK and the AB680 inhibitor in the active site of CD73. It was also found that PSK binds to CD59, interacting with the amino acids APS22 and PHE23, which coincide with the rlLYd4 internalization inhibitor. With the isoform of the K-RAS protein, PSK bonded to the TYR32 amino acid at switch 1, while with BAK it bonded to the region of the α1 helix, while PSP bonded to the activation site and the C-terminal and N-terminal ends of that helix. In Bcl-2, PSK interacted at the binding site of the Venetoclax inhibitor, showing similarities with the amino acids ASP111, VAL133, LEU137, MET115, PHE112, and TYR108, while PSP had similarities with THR132, VAL133, LEU137, GLN118, MET115, APS111, PHE112, and PHE104.

The accumulation of misfolded proteins is a common pathological characteristic shared by many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. The disruption of proteostasis triggers endoplasmic reticulum (ER) stress, during which the unfolded protein response (UPR) is initiated by the activation of protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6). These three branches of UPR signals act in concert to reduce the levels of abnormal proteins and restore ER homeostasis. However, the overactivation of UPR impairs cell function and induces apoptosis, which has been implicated in neurodegeneration. Astaxanthin is a xanthophyll carotenoid which has been shown to have neuroprotective effects in both cell and animal models; however, its effects on ER stress and UPR induced by disrupted proteostasis remain unclear. In this study, the effects of astaxanthin on ER stress and cytotoxicity were investigated in N2a cells stably expressing the pro-aggregant tau repeat domain carrying FTDP-17 mutation ΔK280 (Tau4RDΔK280). The results demonstrated that astaxanthin significantly inhibited Tau4RDΔK280-induced loss of cell viability and apoptosis, attenuating Tau4RDΔK280-induced caspase-3 activation and decrease of Bcl-2. Further studies revealed that astaxanthin treatment alleviated Tau4RDΔK280-induced ER stress and suppressed the activation of PERK, IRE1 and ATF6 signaling pathways. These findings suggested that astaxanthin might inhibit Tau4RDΔK280-induced cytotoxicity by attenuating UPR and ER stress. In addition, astaxanthin treatment resulted in a great reduction in the production of intracellular reactive oxygen species and a significant decrease in calcium influx induced by Tau4RDΔK280, which also contributed to the protective effects of astaxanthin against Tau4RDΔK280-induced cytotoxicity.

Kidney disease has emerged as a significant global health issue, projected to become the fifth-leading cause of years of life lost by 2040. The kidneys, being highly radiosensitive, are vulnerable to damage from various forms of radiation, including gamma (γ) and X-rays. However, the effects of electron radiation on renal tissues remain poorly understood. Given the localized energy deposition of electron beams, this study seeks to investigate the dose-dependent morphological and molecular changes in the kidneys following electron irradiation, aiming to address the gap in knowledge regarding its impact on renal structures. The primary aim of this study is to conduct a detailed morphological and molecular analysis of the kidneys following localized electron irradiation at different doses, to better understand the dose-dependent effects on renal tissue structure and function in an experimental model. Male Wistar rats (n = 75) were divided into five groups, including a control group and four experimental groups receiving 2, 4, 6, or 8 Gray (Gy) of localized electron irradiation to the kidneys. Biochemical markers of inflammation (interleukin-1 beta [IL-1β], interleukin-6 [IL-6], interleukin-10 [IL-10], tumor necrosis factor-alpha [TNF-α]) and oxidative stress (malondialdehyde [MDA], superoxide dismutase [SOD], glutathione [GSH]) were measured, and morphological changes were assessed using histological and immunohistochemical techniques (TUNEL assay, caspase-3). The study revealed a significant dose-dependent increase in oxidative stress, inflammation, and renal tissue damage. Higher doses of irradiation resulted in increased apoptosis, early stages of fibrosis (at high doses), and morphological changes in renal tissue. This study highlights the dose-dependent effects of electrons on renal structures, emphasizing the need for careful consideration of the dosage in clinical use to minimize adverse effects on renal function.