•Pyroptosis involves in ischemic stroke via direct cell death and neuroinflammation.•Following ischemic stroke, pyroptosis happens in neurons, astrocytes and microglia.•Apoptotic caspases activation ...in pyroptotic cells update crosstalk of cell death.
Stroke is one of the leading causes of death worldwide with limited therapies. After ischemic stroke occurs, a robust sterile inflammatory response happens and lasts for days and determines neurological prognosis. Pyroptosis is an inflammatory programmed cell death characterized by cleavage of pore-forming proteins gasdermins as a result of activating caspases and inflammasomes. It has morphological characteristics of rapid plasma-membrane rupture and release of proinflammatory intracellular contents as well as cytokines. Recent researches implicate pyroptosis involvement in the pathogenesis of ischemic stroke and inhibition of pyroptosis attenuates ischemic brain injury. In this review, we discussed molecular mechanisms of pyroptosis, evidences for pyroptosis involvement in different kinds of the central nervous system cells, as well as potential inhibitors for intervention of pyroptosis. Based on the review, we hypothesize the feasibility of therapeutic strategies targeting pyroptosis in the context of ischemic stroke.
Antimicrotubulin chemotherapeutic agents, including plant-derived vincaalkaloids such as vincristine, can cause peripheral neuropathic pain. Exogenously activated heme oxygenase 1 (HO-1) is a ...potential therapy for chemotherapy-induced neuroinflammation. In this study, we investigated a role for Nrf2/HO-1/CO in mediating vincristine-induced neuroinflammation by inhibiting connexin 43 (Cx43) production in the spinal cord following the intrathecal application of the HO-1 inducer protoporphyrin IX cobalt chloride (CoPP) or inhibitor protoporphyrin IX zinc (ZnPP), and we analyzed the underlying mechanisms by which levo-corydalmine (
l
-CDL, a tetrahydroprotoberberine) attenuates vincristine-induced pain. Treatment with levo-corydalmine or oxycodone hydrochloride (a semisynthetic opioid analgesic, used as a positive control) attenuated vincristine-induced persistent pain hypersensitivity and degeneration of the sciatic nerve. In addition, the increased prevalence of atypical mitochondria induced by vincristine was ameliorated by
l
-CDL in both A-fibers and C-fibers. Next, we evaluated whether nuclear factor E2-related factor 2 (Nrf2), an upstream activator of HO-1, directly bound to the HO-1 promoter sequence and degraded heme to produce carbon monoxide (CO) following stimulation with vincristine. Notably,
l
-CDL dose-dependently increased HO-1/CO expression by activating Nrf2 to inhibit Cx43 expression in both the spinal cord and in cultured astrocytes stimulated with TNF-α, corresponding to decreased Cx43-mediated hemichannel. Furthermore,
l
-CDL had no effect on Cx43 following the silencing of the HO-1 gene. Taken together, our findings reveal a novel mechanism by which Nrf2/HO-1/CO mediates Cx43 expression in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely protects against nerve damage and attenuates vincristine-induced neuroinflammation by upregulating Nrf2/HO-1/CO to inhibit Cx43 expression.
Ginsenoside Rg5, a relatively uncommon secondary ginsenoside, exhibits notable pharmacological activity and is commonly hypothesized to originate from the dehydration of Rg3. In this work, we ...compared different conversion pathways using Rb1, R-Rg3 and S-Rg3 as the raw material under simple acid catalysis. Interestingly, the results indicate that the conversion follows this reaction activity order Rb1 > S-Rg3 > R-Rg3, which is contrary to the common understanding of Rg5 obtained from Rg3 by dehydration. Our experimental results have been fully confirmed by theoretical calculations and a NOESY analysis. The DFT analysis reveals that the free energies of S-Rg3 and R-Rg3 in generating carbocation are 7.56 mol/L and 7.57 mol/L, respectively, which are significantly higher than the free energy of 1.81 mol/L when Rb1 generates the same carbocation. This finding aligns with experimental evidence suggesting that Rb1 is more prone to generating Rg5 than Rg3. The findings from the nuclear magnetic resonance (NMR) analysis suggest that the fatty chains (C22–C27) in R-Rg3 and S-Rg3 adopt a Gauche conformation and an anti conformation with C16–C17 and C13–C17, respectively, due to the relatively weak repulsive van der Waals force. Therefore, the configuration of R-Rg3 is more conducive to the formation of intramolecular hydrogen bonds between 20C–OH and 12C–OH, whereas S-Rg3 lacks this capability. Consequently, this also explains the fact that S-Rg3 is more prone to dehydration to generate Rg5 than R-Rg3. Additionally, our research reveals that the synthetic route of Rg5 derived from protopanaxadiol (PPD)-type ginsenosides (including Rb1, Rb2, Rb3, Rc and Rd) exhibits notable advantages in terms of efficacy, purity and yield when compared to the pathway originating from Rg3. Moreover, this study presents a highly effective and practical approach for the extensive synthesis of Rg5, thereby facilitating the exploration of its pharmacological properties and potential application in drug discovery.
Although the efficacy and safety of mesenchymal stem cell therapy for liver cirrhosis have been demonstrated in several studies. Clinical cases of mesenchymal stem cell therapy for patients with ...liver cirrhosis are limited and these studies lack the consistency of treatment effects. This article aimed to systematically investigate the efficacy and safety of mesenchymal stem cells in the treatment of liver cirrhosis.
The data source included PubMed/Medline, Web of Science, EMBASE, and Cochrane Library, from inception to May 2023. Literature was screened by the PICOS principle, followed by literature quality evaluation to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Outcome indicators of the assessment included liver functions and adverse events. Statistical analysis was performed using Review Manager 5.4.
A total of 11 clinical trials met the selection criteria. The pooled analysis' findings demonstrated that both primary and secondary indicators had improved. Compared to the control group, infusion of mesenchymal stem cells significantly increased ALB levels in 2 weeks, 1 month, 3 months, and 6 months, and significantly decreased MELD score in 1 month, 2 months, and 6 months, according to a subgroup analysis using a random-effects model. Additionally, the hepatic arterial injection favored improvements in MELD score and ALB levels. Importantly, none of the included studies indicated any severe adverse effects.
The results showed that mesenchymal stem cell was effective and safe in the treatment of liver cirrhosis, improving liver function (such as a decrease in MELD score and an increase in ALB levels) in patients with liver cirrhosis and exerting protective effects on complications of liver cirrhosis and the incidence of hepatocellular carcinoma. Although the results of the subgroup analysis were informative for the selection of mesenchymal stem cells for clinical treatment, a large number of high-quality randomized controlled trials validations are still needed.
Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major ...chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system.
In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour.
By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.
Placenta accreta spectrum (PAS) disorder is a major cause of postpartum hemorrhage-associated maternal and fetal death, and novel methods for PAS screening are urgently needed for clinical ...application.
The purpose of this study was to develop new methods for PAS screening using serum biomarkers and clinical indicators. A total of 95 PAS cases and 137 controls were enrolled in a case-control study as cohort one, and 44 PAS cases and 35 controls in a prospective nested case-control study were enrolled as cohort two. All subjects were pregnant women of Chinese Han population. Biomarkers for PAS from maternal blood samples were screened based on high-throughput immunoassay and were further validated in three phases of cohort one. Screening models for PAS were generated using maternal serum biomarkers and clinical indicators, and were validated in two cohorts. The expression levels of biomarkers were analyzed using histopathological and immunohistochemical (IHC) techniques, and gene expression was examined by QPCR in the human placenta. Binary logistic regression models were built, and the area under the curve (AUC), sensitivity, specificity, and Youden index were calculated. Statistical analyses and model building were performed in SPSS and graphs were generated in GraphPad Prism. The independent-sample t test was used to compare numerical data between two groups. For nonparametric variables, a Mann-Whitney U test or a X
test was used.
The results demonstrated that the serum levels of matrix metalloproteinase-1 (MMP-1), epidermal growth factor (EGF), and vascular endothelial growth factor-A (VEGF-A) were consistently higher, while the level of tissue-type plasminogen activator (tPA) was significantly lower in PAS patients compared with normal term controls and patients with pre-eclampsia (PE) and placenta previa (PP). IHC and QPCR analysis confirmed that the expression of the identified biomarkers significantly changed during the third trimester in human placenta. The generated screening model combining serum biomarkers and clinical indicators detected 87% of PAS cases with AUC of 0.94.
Serum biomarkers can be used for PAS screening with low expense and high clinical performance; therefore, it may help to develop a practicable method for clinical prenatal PAS screening.
Hypoxic conditions at high altitudes severely affect cognitive functions such as vigilance, attention, and memory and reduce cognitive ability. Hence, there is a critical need to investigate methods ...and associated mechanisms for improving the cognitive ability of workers at high altitudes. This study aimed to use transcranial direct current stimulation (tDCS) to modulate thalamic network functional connectivity to enhance cognitive ability. We recruited 20 healthy participants that underwent hypoxia exposure in a hypoxic chamber at atmospheric pressure to simulate a hypoxic environment at 4,000 m. Participants received both sham and real stimulation. tDCS significantly improved the participants’ emotional status, including depression, fatigue, and energy level. These effects were sustained for more than 6 h (
P
< 0.05 at the second to fifth measurements). In addition, tDCS enhanced vigilance, but this was only effective within 2 h (
P
< 0.05 at the second and third measurements). Central fatigue was significantly ameliorated, and cerebral blood oxygen saturation was increased within 4 h (
P
< 0.05 at the second, third, and fourth measurements). Furthermore, functional connectivity results using the thalamus as a seed revealed enhanced connectivity between the thalamus and hippocampus, cingulate gyrus, and amygdala after tDCS. These results indicated that tDCS increased local cerebral blood oxygen saturation and enhanced thalamic network connectivity in a hypoxic environment, thereby improving vigilance, depression, fatigue, and energy levels. These findings suggest that tDCS may partially rescue the cognitive decline caused by hypoxia within a short period. This approach affords a safe and effective cognitive enhancement method for all types of high-altitude workers with a large mental load.
Abstract
Background
Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. ...DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity.
Methods
We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro.
Results
The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed.
Conclusion
The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.
As the poverty of conventional energy and the abundance of renewable energy coincide in Tibetan plateau, the on-site renewable energy supply is essential for alleviating energy poverty and ...decarbonizing buildings. For the on-site supply, a prominent issue is the daily and seasonal mismatch between energy supply and demand. To formulate the mismatch issue and achieve near-zero energy in Tibetan plateau, the on-site energy supply and demand characteristics of an office building are investigated based on modelled photovoltaic (PV) power generation with PVsyst software and electricity consumption data from on-site research, and the impact of energy storage on mismatch alleviation is examined in terms of both short-term and trans-seasonal storage. The results reveal that, without energy storage, the carbon emission reduction rate (α) is limited to 58% due to temporal mismatch, when PV generation equals electricity demand. Energy storage can effectively alleviate the daily mismatch, and α can be increased to 93% by short-term storage. Moreover, the seasonal mismatch is pronounced in the plateau as the enormous heating energy consumption occurs in winter while cooling is not required in summer. It is demonstrated in this study that trans-seasonal hydrogen storage could eliminate the seasonal mismatch and further achieve near-zero energy buildings.
Discursive strategies are often used in cosmetic advertisements to construct different discursive identities in order to enter larger markets. Based on the graphic advertisements, the article reveals ...the dynamic selection and construction of discursive identities and their dynamic adaptation in the foundation advertisements of international brands and national brands. It is found that the cosmetic advertisements employ textual features to construct three discursive identities: one explicit identity for marketing purposes and two implicit identities: friend identity and expert identity. Based on the theories of discursive identity and linguistic adaptation, the article explores the dynamic discursive identities in this kind of advertisement discourse and analyzes the ways to dynamically adapt to the psychological, social and physical worlds of the discourse receivers.
PDF
