Comparison of Neoadjuvant Chemotherapy Efficiency in Advanced Ovarian Cancer Patients Treated With Paclitaxel Plus Carboplatin and Intraperitoneal Bevacizumab vs. Paclitaxel With Carboplatin.

Objective: This study evaluated the role of neoadjuvant chemotherapy (NACT) with bevacizumab intraperitoneal perfusion in advanced ovarian cancer (AOC). Methods: In this study, 80 patients with advanced epithelial ovarian cancer (stage IIIc or IV) who received NACT at the Central Hospital of Zhuzhou between February 2019 and October 2020 were enrolled. Patients were randomized to receive paclitaxel plus carboplatin (TC) or TC plus intraperitoneal perfusion of bevacizumab (TCB). The effect of chemotherapy was assessed following two cycles of chemotherapy. Cancer antigen 125 (CA125), tumor size, ascites volume, bleeding volume, duration of operation, surgical satisfaction rate, complication rate, and residual tumor were assessed to monitor response to chemotherapy. Results: Treatment with TCB regimen significantly reduced serum levels of CA125 and ascites volume (p < 0.001). Meanwhile, the TCB group had significantly lower intraoperative blood loss and shorter operation time (p < 0.001). Most importantly, patients treated with TCB regimen had a higher surgical satisfaction rate (p < 0.01). Moreover, the incidence of postoperative wound infection, hypoproteinemia, abdominal distension, and fever was lower in the TCB group compared with the TC group. Assessment of adverse reactions during chemotherapy showed no severe complications between the two groups. Conclusions: The results demonstrated that the TCB regimen is superior to the TC regimen alone in the treatment of AOC. These findings could help improve the surgical satisfaction rate, provide more effective treatment strategies to prolong progression-free survival and reduce postoperative complications, and promote surgical recovery in AOC.

LncRNA Profile Study Reveals a Three-LncRNA Signature Associated With the Pathological Complete Response Following Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The purpose of this study is to develop an effective but concise long non-coding RNA (lncRNA) expression signature that can predict response to neoadjuvant chemotherapy for breast cancer (BC) patients. METHODS: lncRNA expression profiling in 1102 BC patients from Gene Expression Omnibus datasets was analyzed using lncRNA-mining approach. The association between lncRNA signature and pathological complete response (pCR) was analyzed using logistic regression model in the training set (GSE25066, n = 488). Validation was performed in independent testing datasets, GSE20194, GSE20271, GSE22093, and GSE23988 (n = 614). Bonferroni method was employed for multiple testing corrections. Cell proliferation assay and Western blot assay were performed to evaluate the cell viability and protein expression level, respectively. RESULTS: Three lncRNAs (AK291479, U79293, and BC032585) have been identified to be significantly associated with pCR in the training dataset (Bonferroni p-value < 0.05). Expression signature with these lncRNAs was predictive of pCR in the training (AUC = 0.74) and testing (AUC = 0.72) datasets. Weighted gene co-expression network analysis and gene functional annotation suggest that the three lncRNAs were involved in cell cycle process. To confirm the functional significance of the identified lncRNAs, BC032585 was selectively silenced using RNA interference. Knockdown of BC032585 lncRNA significantly promoted cell resistance to multiple anticancer-drugs through upregulating MDR1 expression in breast cancer cells. CONCLUSION: These results suggest that lncRNAs such as BC032585 might be involved in chemotherapeutic response in breast cancer patients, and the three-lncRNA signature identified in the present study may serve as a useful biomarker for the selection of responsive breast cancer patients in neoadjuvant chemotherapy.

ß­blockers inhibit the viability of breast cancer cells by regulating the ERK/COX­2 signaling pathway and the drug response is affected by ADRB2 single­nucleotide polymorphisms.

The ß2­adrenergic receptor (ß2­AR, encoded by the ADRB2 gene) is a member of the G­protein­coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that ß­blockers (ß­AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single­nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of ß2­AR, which may alter the ß­blocker drug response. The aim of the present study was to investigate the effect of ß­blockers on triple­negative breast cancer cells and determine whether ADRB2 SNPs affect the response to ß­blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA­MB­231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular­signal­regulated kinase (ERK)1/2 and the expression levels of cyclo­oxygenase 2 (COX­2) were significantly decreased following ß­blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild­type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX­2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA­MB­231 cells by downregulating the ERK/COX­2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.

Inhibition of ALDH2 protects PC12 cells against formaldehyde-induced cytotoxicity: involving the protection of hydrogen sulphide.

Formaldehyde (FA), a common environmental contaminant, has toxic effects on the central nervous system (CNS). We have previously found that hydrogen sulphide (H2 S), the third endogenous gaseous mediator, protects neuron against the toxicity of FA. However, the underlying mechanism is poor. Aldehyde-dehydrogenase-2 (ALDH2) plays a major role in detoxification of reactive aldehyde in a range of organs and cell types. Therefore, we speculated that H2 S antagonizes FA-induced neurotoxicity by modulating ALDH2. In the present study, we found that the exposure of PC12 cells to FA causes increase in ALDH2 expression and activity. Daidzin, an inhibitor of ALDH2, significantly antagonizes FA-exerted cytotoxicity and oxidative stress including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA), in PC12 cells. We also showed that daidzin markedly attenuated FA-induced apoptosis in PC12 cells. Furthermore, we found that H2 S reverses FA-elicited upregulation of ALDH2 in PC12 cells. Our results demonstrated the involvement of downregulation of ALDH2 in the protection of H2 S against FA neurotoxicity.

Long noncoding RNA expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients.

Dysregulated long noncoding RNAs (lncRNAs) are potential markers of several tumor prognoses. This study aimed to develop a lncRNA expression signature that can predict chemotherapeutic sensitivity for patients with advanced stage and high-grade serous ovarian cancer (HGS-OvCa) treated with platinum-based chemotherapy. The lncRNA expression profiles of 258 HGS-OvCa patients from The Cancer Genome Atlas were analyzed. Results revealed that an eight-lncRNA signature was significantly associated with chemosensitivity in the multivariate logistic regression model, which can accurately predict the chemosensitivity of patients [Area under curve (AUC) = 0.83]. The association of a chemosensitivity predictor with molecular subtypes indicated the excellent prognosis performance of this marker in differentiated, mesenchymal, and immunoreactive subtypes (AUC > 0.8). The significant correlation between ZFAS1 expression and chemosensitivity was confirmed in 233 HGS-OvCa patients from the Gene Expression Omnibus datasets (GSE9891, GSE63885, and GSE51373). In vitro experiments demonstrated that the ZFAS1 expression was upregulated by cisplatin in A2008, HeyA8, and HeyC2 cell lines. This finding suggested that ZFAS1 may participate in platinum resistance. Therefore, the evaluation of the eight-lncRNA signature may be clinically implicated in the selection of platinum-resistant HGS-OvCa patients. The role of ZFAS1 in platinum resistance should be further investigated.

BDNF-TrkB pathway mediates neuroprotection of hydrogen sulfide against formaldehyde-induced toxicity to PC12 cells.

Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity.

A novel mechanism of formaldehyde neurotoxicity: inhibition of hydrogen sulfide generation by promoting overproduction of nitric oxide.

BACKGROUND: Formaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H(2)S), an endogenous gastransmitter, protects nerve cells against oxidative stress by its antioxidant effect. It has been shown that overproduction of nitric oxide (NO) inhibits the activity of cystathionine-beta-synthase (CBS), the predominant H(2)S-generating enzyme in the central nervous system. OBJECTIVE: We hypothesize that FA-caused neurotoxicity involves the deficiency of this endogenous protective antioxidant gas, which results from excessive generation of NO. The aim of this study is to evaluate whether FA disturbs H(2)S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO. PRINCIPAL FINDINGS: We showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H(2)S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells. CONCLUSION/SIGNIFICANCE: Our data indicate that FA induces neurotoxicity by inhibiting the generation of H(2)S through excess of NO and suggest that strategies to manipulate endogenous H(2)S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity.

Formaldehyde impairs learning and memory involving the disturbance of hydrogen sulfide generation in the hippocampus of rats.

Formaldehyde (FA), a well-known indoor and outdoor pollutant, has been implicated as the responsible agent in the development of neurocognitive disorders. Hydrogen sulfide (H(2)S), the third gasotransimitter, is an endogenous neuromodulator, which facilitates the induction of hippocampal long-term potentiation, involving the functions of learning and memory. In the present study, we analyzed the effects of intracerebroventricular injection of FA on the formation of learning and memory and the generation of endogenous H(2)S in the hippocampus of rats. We found that the intracerebroventricular injection of FA in rats impairs the function of learning and memory in the Morris water maze and novel object recognition test and increases the formation of apoptosis and lipid peroxidation in the hippocampus. We also showed that FA exposure inhibits the expression of cystathionine ß-synthase, the major enzyme responsible for endogenous H(2)S generation in hippocampus and decreases the production of endogenous H(2)S in hippocampus in rats. These results suggested that FA-disturbed generation of endogenous H(2)S in hippocampus leads to the oxidative stress-mediated neuron damage, ultimately impairing the function of learning and memory. Our findings imply that the disturbance of endogenous H(2)S generation in hippocampus is a potential contributing mechanism underling FA-caused learning and memory impairment.

Hydrogen sulfide prevents formaldehyde-induced neurotoxicity to PC12 cells by attenuation of mitochondrial dysfunction and pro-apoptotic potential.

Hydrogen sulfide (H(2)S) has been shown to act as a neuroprotectant and antioxidant. Numerous studies have demonstrated that exposure to formaldehyde (FA) causes neuronal damage and that oxidative stress is one of the most critical effects of FA exposure. Accumulation of FA is involved in the pathogenesis of Alzheimer's disease (AD). The aim of present study is to explore the inhibitory effects of H(2)S on FA-induced cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. We show that sodium hydrosulfide (NaHS), a H(2)S donor, protects PC12 cells against FA-mediated cytotoxicity and apoptosis and that NaHS preserves the function of mitochondria by preventing FA-induced loss of mitochondrial membrane potential and release of cytochrome c in PC12 cells. Furthermore, NaHS blocks FA-exerted accumulation of intracellular reactive oxygen species (ROS), down-regulation of Bcl-2 expression, and up-regulation of Bax expression. These results indicate that H(2)S protects neuronal cells against neurotoxicity of FA by preserving mitochondrial function through attenuation of ROS accumulation, up-regulation of Bcl-2 level, and down-regulation of Bax expression. Our study suggests a promising future of H(2)S-based preventions and therapies for neuronal damage after FA exposure.

Involvement of K(ATP)/PI (3)K/AKT/Bcl-2 pathway in hydrogen sulfide-induced neuroprotection against the toxicity of 1-methy-4-phenylpyridinium ion.

We previously reported that hydrogen sulfide (H(2)S) produces protection in PC12 cells during 1-methy-4-phenylpyridinium ion (MPP(+)) challenge. The present study aims to clarify the mechanisms underlying the neuroprotective effects of H(2)S. We showed that both glybenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker, and LY294002, a specific PI(3)K-AKT pathway inhibitor, reversed the neuroprotective effect of NaHS (a H(2)S donor) against MPP(+)-induced cytotoxicity to PC12 cells and that NaHS up-regulated the activity of AKT in PC12 cells, which was abolished by blockade of K(ATP) channels with glybenclamide. In addition, NaHS up-regulated the expression of Bcl-2 and blocked MPP(+)-induced down-regulation of Bcl-2, and this augmentation of Bcl-2 expression was prevented by both glybenclamide and LY294002. These data provided the evidence that the neuroprotective action of H(2)S against MPP(+) toxicity to PC12 cells is via the K(ATP)/PI(3)K/AKT/Bcl-2 pathway. We also demonstrated that NaHS attenuated the inhibitory effect of MPP(+) ERK1/2 activation in PC12 cells, whereas U0126, a specific MEK inhibitor, did not reverse the neuroprotective effect of NaHS, which indicated that attenuating MPP(+)-triggered down-regulation of ERK1/2 activation is involved in the protection of H(2)S against MPP(+) neurotoxicity, but ERK1/2 is not an essential effector mediating the neuroprotective effect of H(2)S. In conclusion, the present observations identify a crucial role of the K(ATP)/PI(3)K/AKT/Bcl-2 pathway in H(2)S-exerted neuroprotection against the toxicity of MPP(+). Findings from the present study will help shed light on the mechanisms of H(2)S-elicited neuroprotective effects on MPP(+) toxicity.

Endogenous hydrogen sulfide is involved in asymmetric dimethylarginine-induced protection against neurotoxicity of 1-methyl-4-phenyl-pyridinium ion.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is profoundly protective against 1-methy-4-phenylpyridinium ion (MPP+)-induced neurotoxicity. Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of MPP+; while hydrogen sulfide (H2S) is a pivotal endogenous antioxidant. This study is to assess the potential role of endogenous H2S in the neuroprotection of ADMA against MPP+-induced toxicity in PC12 cells. We showed that ADMA prevented MPP+-induced inhibition of endogenous H2S generation through inhibiting the down-regulation of cystathionine-ß-synthetase (CBS, the major enzyme responsible for endogenous H2S generation in PC12 cells) expression and activity elicited by MPP+. ADMA obviously attenuated MPP+-triggered accumulation of intracellular ROS, dissipation of mitochondrial membrane potential (MMP), release of cytochrome c (Cyt-c), and downregulation of Bcl-2 protein expression in PC12 cells. Inhibition of CBS activity by amino-oxyacetate and CBS silencing with a short hairpin RNA vector targeting rat CBS gene reversed the protective action of ADMA against MPP+-caused cytotoxicity, ROS overproduction, and MMP loss in PC12 cells. These results indicate that the protection of ADMA against MPP+-mediated neurotoxicity involves the melioration of MPP+-induced inhibition of endogenous H2S generation. Our findings suggest that modulation of H2S production provide new therapeutic targets for the treatment of neurodegenerative disease, such as Parkinson's disease.

Hydrogen sulfide and nervous system regulation.

OBJECTIVE: This review discusses the current status and progress in studies on the roles of hydrogen sulfide (H(2)S) in regulation of neurotoxicity, neuroprotection, and neuromodulator, as well as its therapeutic potential for neurodegenerative disorders. DATA SOURCES: The data used in this review were mainly from Medline and PubMed published in English from 2001 to August 2011. The search terms were "hydrogen sulfide", "neuron", and "neurodegenerative disorders". STUDY SELECTION: Articles regarding the regulation of neuronal function, the protection against neuronal damage and neurological diseases, and their possible cellular and molecular mechanisms associated with H(2)S were selected. RESULTS: The inhibited generation of endogenous H(2)S is implicated in 1-methy-4-phenylpyridinium ion, 6-OHDA, and homocysteine-triggered neurotoxicity. H(2)S elicits neuroprotection in Alzheimer's disease and Parkinson's disease models as well as protecting neurons against oxidative stress, ischemia, and hypoxia-induced neuronal death. H(2)S offers anti-oxidant, anti-inflammatory and anti-apoptotic effects, as well as activates ATP-sensitive potassium channels and cystic fibrosis transmembrane conductance regulator Cl- channels. H(2)S regulates the long-term potentiation (LTP) and GABAB receptors in the hippocampus, as well as intracellular calcium and pH homeostasis in neurons and glia cells. CONCLUSIONS: These articles suggest that endogenous H(2)S may regulate the toxicity of neurotoxin. H(2)S not only acts as a neuroprotectant but also serves as a novel neuromodulator.