NLRP3/1-mediated pyroptosis: beneficial clues for the development of novel therapies for Alzheimer's disease.

The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis, which is a lytic, inflammatory form of cell death. There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer's disease. In this review, we summarize the possible pathogenic mechanisms of Alzheimer's disease, focusing on neuroinflammation. We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer's disease. Finally, we examine the neuroprotective activity of small-molecule inhibitors, endogenous inhibitor proteins, microRNAs, and natural bioactive molecules that target NLRP3 and NLRP1, based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer's disease.

Thioredoxin-1 decreases alpha-synuclein induced by MPTP through promoting autophagy-lysosome pathway.

Parkinson's disease (PD) is characterized by the formation of Lewy body in dopaminergic neurons in the substantia nigra pars compacta (SNpc). Alpha-synuclein (α-syn) is a major component of Lewy body. Autophagy eliminates damaged organelles and abnormal aggregated proteins. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays roles in protecting dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the relationship between Trx-1 and α-syn in PD is still unknown. In the present study, the movement disorder and dopaminergic neurotoxicity in MPTP-treated mice were improved by Trx-1 overexpression and were aggravated by Trx-1 knockdown in the SNpc in mice. The expression of α-syn was increased in the SNpc of MPTP-treated mice, which was inhibited by Trx-1 overexpression and was exacerbated in Trx-1 knockdown mice. Autophagosomes was increased under electron microscope after MPTP treatment, which were recovered in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown in the SNpc in mice. The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase 1 (PINK1), Parkin, LC3 II and p62 were increased by MPTP, which were blocked in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown mice. Cathepsin D was decreased by MPTP, which was restored in Trx-1 overexpressing mice and was further decreased in Trx-1 knockdown mice. The mRFP-GFP-LC3 green fluorescent dots were increased by 1-methyl-4-phenylpyridinium (MPP+) and further increased in Trx-1 siRNA transfected PC12 cells, while mRFP-GFP-LC3 red fluorescent dots were increased in Trx-1 overexpressing cells. These results indicate that Trx-1 may eliminate α-syn in PD mice through potentiating autophagy-lysosome pathway.

Corrigendum: Advances in the roles of glycyrrhizic acid in cancer therapy.

[This corrects the article DOI: 10.3389/fphar.2023.1265172.].

Advances in the roles of glycyrrhizic acid in cancer therapy.

Since the first 70 years of reporting cancer chemotherapy, malignant tumors have been the second most common cause of death in children and adults. Currently, the commonly used anti-cancer methods include surgery, chemotherapy, radiotherapy, and immunotherapy. Although these treatment methods could alleviate cancer, they lead to different forms of side effects and have no particularly significant effect on prolonging the patients' life span. Glycyrrhizic acid (GL), a native Chinese herbal extract, has a wide range of pharmacological effects, such as anti-cancer, anti-inflammatory, antioxidant, and immune regulation. In this review, the anti-cancer effects and mechanisms of GL are summarized in various cancers. The inhibition of GL on chemotherapy-induced side effects, including hepatotoxicity, nephrotoxicity, genotoxicity, neurotoxicity and pulmonary toxicity, is highlighted. Therefore, GL may be a promising and ideal drug for cancer therapy.

Thioredoxin-1 inhibits the activation of IRE1 by targeting Hsp90/p-Cdc37 chaperone complex in Parkinson disease.

Endoplasmic reticulum stress is implicated in the etiopathogenesis of Parkinson disease (PD). Our previous study has revealed that thioredoxin-1 (Trx-1) attenuated IRE1 activation in 1-methyl-4-phenylpyridinium ion (MPP+)/1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models. However, its exact mechanism has been largely unclear. In this research, it was reported for the first time that the protein levels of heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) were significantly decreased and the interaction of Hsp90/p-Cdc37 complex with IRE1 was disturbed in MPP+/MPTP-induced PD models. Trx-1 overexpression reversed the expression of Hsp90 and p-Cdc37 in cultured cells and the substantia nigra pars compacta of mice. More importantly, Trx-1 overexpression enhanced the interaction of Hsp90/p-Cdc37 complex with IRE1. In conclusion, our data demonstrated that Trx-1 inhibited IRE1 activation in PD by elevating the expression of Hsp90 and p-Cdc37 and strengthening the interaction of Hsp90/p-Cdc37 complex and IRE1.

Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aß25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of ß-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aß deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aß25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Advances in the Functions of Thioredoxin System in Central Nervous System Diseases.

Significance: The thioredoxin system comprises thioredoxin (Trx), thioredoxin reductase (TrxR), and nicotinamide adenine dinucleotide phosphate, besides an endogenous Trx inhibitor, the thioredoxin-interacting protein (TXNIP). The Trx system plays critical roles in maintaining the redox homeostasis in the central nervous system (CNS), in which oxidative stress damage is prone to occurrence due to its high-energy demand. Recent Advances: Increasing studies have demonstrated that the expression or activity of Trx/TrxR is usually decreased and that TXNIP expression is increased in patients with CNS diseases, including neurodegenerative diseases, cerebral ischemia, traumatic brain injury, and depression, as well as in their cellular and animal models. The compromise of Trx/TrxR enhances the susceptibility of neurons to related pathological state. Increased TXNIP not only enhances the inhibition of Trx activity, but also activates the NOD-like receptor protein 3 inflammasome, resulting in neuroinflammation in the brain. Critical Issues: In this review, we highlight the sources of oxidative stress in the CNS. The expression and function of the Trx system are summarized in different CNS diseases. This review also mentions that some inducers of Trx show neuroprotection in CNS diseases. Future Directions: Accumulating evidence has demonstrated the important roles of the Trx system in CNS diseases, suggesting that the Trx system may be a promising therapeutic target for CNS diseases. Further study should aim to develop the most effective inducers of Trx and specific inhibitors of TXNIP and to apply them in the clinical trials for the treatment of CNS diseases. Antioxid. Redox Signal. 38, 425-441.

Estrogen Protects against Renal Ischemia-Reperfusion Injury by Regulating Th17/Treg Cell Immune Balance.

Inflammation is a critical mediator of renal ischemia-reperfusion (I/R) injury (IRI), and T lymphocytes exert a key role in the renal IRI-induced inflammation. Connexin 43 (Cx43) is related to the maintenance of T lymphocyte homeostasis. Various preclinical researches have reported that estrogen is a renoprotective agent based on its anti-inflammatory potential. The present research is aimed at studying the role of T lymphocytes activated by Cx43 in 17ß-estradiol-mediated protection against renal IRI. Female rats were classified into six groups: control rats, I/R rats, ovariectomized rats, ovariectomized I/R rats, and ovariectomized rats treated with 17ß-estradiol or gap27. Levels of serum creatinine (Scr) and blood urea nitrogen (BUN) and Paller scoring were dramatically increased in I/R rats, especially in ovariectomized rats. By contrast, these indicators were markedly decreased by administering estradiol or gap27. Immunofluorescence staining revealed that CD4+ T cells infiltrated kidney tissues in the early stage of IRI. In both peripheral blood and renal tissue, the proportion of CD3+CD4+ T cells and ratio of CD4+ to CD8+ were high in I/R rats, especially in ovariectomized rats. The proportion of CD3+CD8+ T cells was low in peripheral blood but high in renal tissues. Administration of estrogen or Gap27 reversed these effects. IL-17 levels in both serum and tissue homogenate were significantly increased in ovariectomized rats subjected to I/R but significantly decreased in estrogen or gap 27 treated rats. The opposite trend was observed for IL-10 levels. Correlation analysis demonstrated that IL-17 was correlated positively with BUN, Scr, and Paller scores, while IL-10 was negatively correlated with these indicators. Western blot showed that Cx43 expression was markedly increased in the peripheral blood T lymphocytes of I/R rats, especially ovariectomized rats. After intervention with estrogen and gap27, Cx43 expression was significantly downregulated. These findings indicate that Cx43 may participate in the regulation of Th17/Treg balance by estrogen against renal IRI.

Neuroprotective Mechanisms of Ginsenoside Rb1 in Central Nervous System Diseases.

Panax ginseng and Panax notoginseng, two well-known herbs with enormous medical value in Asian countries, have a long usage history in China for the therapy of some diseases, such as stroke. Ginsenoside Rb1 is one of most important active ingredients in Panax ginseng and Panax notoginseng. In the last two decades, more attention has focused on ginsenoside Rb1 as an antioxidative, anti-apoptotic and anti-inflammatory agent that can protect the nervous system. In the review, we summarize the neuroprotective roles of ginsenoside Rb1 and its potential mechanisms in central nervous system diseases (CNSDs), including neurodegenerative diseases, cerebral ischemia injury, depression and spinal cord injury. In conclusion, ginsenoside Rb1 has a potential neuroprotection due to its inhibition of oxidative stress, apoptosis, neuroinflammation and autophagy in CNSDs and may be a promising candidate agent for clinical therapy of CNSDs in the future.

Thioredoxin-1 inhibits amyloid-ß25-35-induced activation of NLRP1/caspase-1/GSDMD pyroptotic pathway in PC12 cells.

BACKGROUND: Alzheimer's disease (AD), the most common neurodegenerative disease, is charactered by these accepted pathological features, such as ß-amyloid (Aß) plaques outside the neurons and neurofibrillary tangles inside the neurons. In recent years, several studies have demonstrated that pyroptosis is associated with the development of AD process. However, whether Aß25-35 induces pyroptosis is still unclear. Thioredoxin-1 (Trx-1), an intracellular multifunctional protein, showed neuroprotective roles by inhibiting the neurotoxicity of Aß, attenuating the apoptosis of brain neurons and improving the spatial learning and memory ability in AD models. Whether Trx-1 could inhibit pyroptosis in AD needs to be further investigated. METHODS AND RESULTS: In the present study, MTT assay was employed to detected the viability. Western blotting was employed to detect the protein levels. Enzyme linked immunosorbent assay was used to examine the intracellular and extracellular levels of IL-18 and IL-1ß. Chronic Aß25-35 treatment remarkedly compromised the viability of PC12 cells, increased the expression of NOD-like receptor pyrin domain containing 1 (NLRP-1), caspase-1 and gasdermin D (GSDMD), and promoted the extracellular release of interleukin (IL)-18 and IL-1ß. Simultaneously, Aß25-35 treatment also significantly reduced the intracellular protein levels of Trx-1. Pharmacological inhibition of Trx-1 activity further decreased the cell viability, activated the NLRP-1/caspase-1/GSDMD pyroptotic pathway, and exacerbated the extracellular release of IL-18 and IL-1ß. CONCLUSIONS: These data suggest that Trx-1 may play a potential inhibitory effect on Aß25-35-induced pyroptosis.

Advances in forensic diagnosis of electric shock death in the absence of typical electrical marks.

Electrical injury is a relatively uncommon but potentially devastating form of multi-system injury with high morbidity and mortality. In common electric injury cases, it is usually difficult to find characteristic changes of electric injury in major organs by using routine histopathological test methods unless there are landmark traces of electric injury, known as electric marks. How to determine electric shock death, especially in the absence of typical electrical marks on the body surface in some cases (which account for about two-thirds of electric injury cases), remains a challenging problem in forensic practice. Our summary shows that many current related studies have focused their efforts to find characteristic histopathological changes in major organs of the body caused by electric injury. Based on the results obtained through comparison of the literature, we find that it may be more urgent and important to find the optimal autopsy or sampling sites in cases with no typical electric marks, knowing that these sites may often reflect the most significant histopathological changes of electric injury, for instance anatomy and sampling of the anterior wrist and the medial malleolus in cases involving the hand-to-foot electric circuit pathway. In this article, we make a summary of advances in identification methods of electric injury, hoping that it could provide some new insights for further research in this field.

Liver extracellular matrix hydrogel-based three-dimensional culture system of HepG2 cells to enhance cancer stem cell properties.

Both extracellular matrix (ECM) components and three-dimensional (3D) structure play important roles in the expression and maintenance of cancer stem cell (CSC) properties. Considering the excellent biophysical and biochemical properties of hydrogels, the objective of this study was to develop a 3D cell culture system based on liver ECM hydrogel (LEMH) to enhance CSC properties. Results showed that LEMH was devoid of cellular materials but contained the main components of the liver ECM. HepG2 hepatocellular carcinoma cells cultured in LEMH displayed cluster growth and formed multilayer 3D cell structures with increased expression of hepatocyte-specific genes compared to two-dimensional (2D) cells. In addition, enhanced CSC characteristics, including migration, self-renewal and drug-resistance, were observed in 3D cells. More importantly, inhibitory effects of epigallocatechin gallate on CSC self-renewal and metastatic characteristics were observed, confirming the applicability of the LEMH-based 3D model for the research and development of CSC-specific drugs. These findings suggest that LEMH-based 3D culture offers a simple and efficient platform to enhance CSC properties in vitro, thereby providing a novel approach for exploring CSC-specific agents and chemotherapeutic drugs.

Ovarian dysgerminoma with pseudo-Meigs syndrome: A case report.

RATIONALE: Dysgerminoma is a rare malignant tumor of the ovary, more frequently occurring in young women. The main signs of pseudo-Meigs syndrome (PMS) are ascites and hydrothorax accompanying benign or malignant ovarian tumors (no fibroma or fibroma-like tumor). PATIENT CONCERNS: A 19-year-old woman with fever and chest tightness for 2 days. DIAGNOSES: Pectoral-abdominal computed tomography (CT) scan and contrast-enhanced magnetic resonance imaging revealed a large amount of right pleural effusion, a small amount of ascites, and a huge abdominopelvic mass measuring about 29.2cm × 11.8cm × 8.4 cm in the left ovary. The result of hydrothorax examination was consistent with the diagnosis of exudative pleural effusion. In addition, Rivalta-test showed a positive result and lactate dehydrogenase was elevated. The histopathological diagnosis was a giant germ cell tumor, which was consistent with dysgerminoma in terms of both morphology and immunophenotype. Based on these findings, a diagnosis of malignant ovarian neoplasm with PMS was made. INTERVENTIONS: Surgical resection of the tumor was performed. OUTCOMES: The patient recovered well after operation, and the pleural effusion and abdominal ascites vanished. No recurrence was observed during the 1-year follow-up period. LESSONS: Ovarian dysgerminoma with PMS is a rare malignant tumor of the ovary, which often occurs in young women. It should be considered in differential diagnosis of patients with a pelvic mass, ascites and pleural effusion. Early diagnosis and surgical treatment are beneficial to prolonged survival.

Advances in Stem Cells Transplantation for the Therapy of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease and is a major culprit that harms the health of elderly people. The main pathological feature is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The current mainstream therapeutic strategies include surgical treatment and medicine substitute therapy. However, these treatment methods sometimes have limitations. Subsequently, the treatment with stem cells (SCs) transplantation has been gradually established. SCs is a kind of cell with self-renewal ability and multi-directional differentiation potential. Transplantation of SCs, including embryonic stem cells, adult stem cells (neural stem cells and mesenchymal stem cells) and induced pluripotent stem cells, have the ability to mediate nerve regeneration and restoration within the lesioned midbrain tissue, bringing hope for the treatment of PD. In this paper, we summarize the progress in therapeutic strategies of different types of SCs in PD treatment, with an emphasis on the advantages and limitations.

The Potential Roles of Redox Enzymes in Alzheimer's Disease: Focus on Thioredoxin.

Alzheimer's disease (AD) is the most common neurodegenerative diseases. Increasing studies have demonstrated the critical importance for redox proteins mediating neuronal protection in models of AD. This review briefly describes some of the risk factors contributing to AD, specifically highlighting the important roles of oxidative stress in the pathology of AD. Then this article concisely introduces the dysregulation and functions of two main redox enzymes, peroxiredoxins and glutaredoxins, in AD models. This review emphasizes the neuroprotective role of the third redox enzyme thioredoxin (Trx), an important multifunctional protein regulating cellular redox status. This commentary not only summarizes the alterations of Trx expression in AD patients and models, but also reviews the potential effects and mechanisms of Trx, Trx-related molecules and Trx-inducing compounds against AD. In conclusion, Trx has a potential neuroprotection in AD and may be very promising for clinical therapy of AD in the future.

Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors.

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.

Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1.

Long-term administration of morphine for the management of chronic pain will result in tolerance to its analgesic effect and could even cause drug dependence. Numerous studies have demonstrated significant redox alteration in morphine dependence and addiction. Thioredoxin-1 (Trx-1) play important roles in controlling the cellular redox balance. In recent years, several recent studies have demonstrated that Trx-1 may be a promising novel therapeutic target for morphine addiction. In this article, we firstly review the redox alteration in morphine addiction. We also summarize the expression and the protective roles of Trx-1 in morphine dependence. We further highlight the protection of geranylgeranylacetone (GGA), a noncytotoxic pharmacological inducer of Trx-1, in morphine-induced conditioned place preference. In conclusion, Trx-1 may be very promising for clinical therapy of morphine addiction in the future.

The role of thioredoxin system in cancer: strategy for cancer therapy.

PURPOSE: Cancer, a major public health problem, exhibits significant redox alteration. Thioredoxin (Trx) system, including Trx and Trx reductase (TrxR), as well as Trx-interacting protein (TXNIP) play important roles in controlling the cellular redox balance in cancer cells. In most cancers, Trx and TrxR are usually overexpressed and TXNIP is underexpressed. In recent years, some agents targeting Trx, TrxR, and TXNIP were used to explore a therapy approach for cancer patients. METHODS: A systematic search of PMC and the PubMed Database was conducted to summarize the potential of Trx system inhibitors for cancer treatment. RESULTS: In this article, we first summarize the functions of Trx, TrxR, and TXNIP in cancers. We also review some small molecule inhibitors of Trx/TrxR and D-allose (TXNIP inducer) and discuss their antitumor mechanisms. We highlight the combined inhibition of Trx system and GSH system in cancer therapy. We expect that a highly specific and selective antitumor agent with no cytotoxicity on human normal cells could be developed in the future. CONCLUSION: In conclusion, Trx system may be very promising for clinical therapy of cancer in the future.

Thioredoxin as a Therapeutic Target in Cerebral Ischemia.

BACKGROUND: Cerebral ischemia is a common cause of disability and death. Ischemic brain injury results from complex pathological processes, including oxidative stress, inflammation, and apoptosis. Thioredoxin( Trx) is an important multifunctional protein, which regulates cellular redox status. Increasing studies have demonstrated that Trx provides a neuroprotective role against cerebral ischemia-induced injury. METHODS: A systematic search of PMC and the PubMed Database was conducted to summarize the protective effects of Trx against cerebral ischemia. RESULTS: This article reviews the understanding of potential effects and mechanisms of Trx against cerebral ischemia, including the anti-oxidant, anti-apoptotic and anti-inflammatory effects, as well as the activation of prosurvival pathway. We also summarize that some natural compounds induce the expression of Trx, which is involved in their anti-ischemic effects. CONCLUSION: In conclusion, Trx has a potential neuroprotection in cerebral ischemia and may be very promising for clinical therapy of ischemic stroke in the future.

Neurotoxin-Induced Animal Models of Parkinson Disease: Pathogenic Mechanism and Assessment.

Parkinson disease (PD) is the second most common neurodegenerative movement disorder. Pharmacological animal models are invaluable tools to study the pathological mechanisms of PD. Currently, invertebrate and vertebrate animal models have been developed by using several main neurotoxins, such as 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, paraquat, and rotenone. These models achieve to some extent to reproduce the key features of PD, including motor defects, progressive loss of dopaminergic neurons in substantia nigra pars compacta, and the formation of Lewy bodies. In this review, we will highlight the pathogenic mechanisms of those neurotoxins and summarize different neurotoxic animal models with the hope to help researchers choose among them accurately and to promote the development of modeling PD.