Novel FRET-Based Biosensors for Real-Time Monitoring of Estrogen Receptor Dimerization and Translocation Dynamics in Living Cells.

Estrogen receptors (ERs), comprising ER α and ER ß, are crucial for regulating cell growth and differentiation via homo- and hetero-dimer formation. However, accurately detecting ER dimerization with precise spatiotemporal resolution remains a significant challenge. In this study, fluorescence resonance energy transfer-based biosensors to monitor ER dynamics in real-time, are developed and optimized. This approach involves comprehensive structural analysis, linker comparison, and the selection of optimal fluorescent protein pairs, resulting in three distinct biosensors capable of detecting all ER homo- and hetero-dimerizations within the nucleus. These biosensors are utilized to reveal interactions between ER α/ß and calmodulin during dimer formation. Furthermore, by leveraging the ligand-binding domain (LBD) of ER ß, ER ßß LBD biosensor is designed for real-time analysis of ER ßß homodimerization in the cytoplasm, enhancing the ability to screen ER dimerization-related drugs. Additionally, we developed a novel ER ßß translocation biosensor, which enables real-time observation of ER ßß translocation to the nucleus-a capability previously unavailable, is developed. This spatiotemporal analysis demonstrates the relevance of ER translocation in response to drug binding efficacy and extracellular matrix changes. Our biosensors offertransformative tools for studying ER dynamics, providing valuable insights for drug screening and the investigation of ER-related cellular processes.

Enhanced endoplasmic reticulum stress signaling disrupts porcine sertoli cell function in response to Bisphenol A exposure.

Bisphenol A (BPA), a pervasive substance in our daily lives and livestock excreta, poses significant threats due to its infiltration into foods and water sources. BPA has adverse impacts on male reproductive function, particularly affecting the critical Sertoli (ST) cells that play a pivotal role in the process of spermatogonia differentiating into spermatozoa. In this study, we examined the prevalence of BPA within the pig industry and delved into the impact of BPA exposure on the motility of boar sperm, the function of pig ST cells, as well as the underlying molecular mechanisms involved. This study revealed spatial disparities in the global distribution of BPA and its analogue contamination, utilizing data compiled from 130 comprehensive studies. The average concentration of BPA found in pig feed ranges from 9.7 to 47.9 µg/kg, while in serum, it averages between 55.1 and 75.6 ng/L. The BPA concentration in feed exhibits a negative correlation with sperm viability and the percentage of progressive motile spermatozoa. Exposure to BPA reduced sperm motility in boar and ST cell activity at both 6 and 24 h. The transcriptome analysis revealed that, compared to untreated control cells, endoplasmic reticulum stress (ERS)-related genes were upregulated in ST cells exposed to BPA at 6 and 24 h. This activation of ERS in ST cells was mediated by receptor protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring protein-1α (IRE1α), and activating transcription factor 6 (ATF6). Additionally, BPA exposure triggered oxidative stress and a proinflammatory response mediated by the transcription factor NF-κB, accompanied by an increase in downstream proinflammatory cytokines. BPA exposure also led to apoptosis in ST cells and upregulated the expression levels of pro-apoptosis proteins. However, inhibiting ERS activity with 4-PBA attenuated the BPA-induced inflammatory response and apoptosis in ST cells. Our findings suggest that BPA induced apoptosis and inflammatory response in porcine ST cells through persistent activation of ERS, thereby compromising the normal function of these cells.

TRIM13 Reduces Damage to Alveolar Epithelial Cells in COPD by Inhibiting Endoplasmic Reticulum Stress-Induced ER-Phagy.

PURPOSE: Tripartite motif-containing protein 13 (TRIM13) directly or indirectly participates in autophagy and apoptosis. However, it remains unclear whether TRIM13 participates in chronic obstructive pulmonary disease (COPD) progression. This study aimed to reveal the molecular mechanisms through which TRIM13 regulates alveolar epithelial cell injury in COPD to provide new molecular targets for COPD treatment. METHODS: The TRIM13 expression levels were determined in clinical COPD patients and a rat emphysema model. A cigarette smoke-induced model of endoplasmic reticulum stress (ERS) and endoplasmic reticulum autophagy (ER-phagy) was developed using A549 cells, and the effects of TRIM13 gene overexpression/knockdown on ERS, ER-phagy, and cell apoptosis were assessed in these cells. RESULTS: TRIM13 expression was significantly decreased in the lung tissues of COPD patients and rats with emphysema. Moreover, the apoptosis level was significantly increased in the lung tissues of rats with emphysema. TRIM13 gene overexpression reduced the expression levels of ERS-related molecules (GRP78, GRP94, XBP-1, and eIF2a) in the COPD model; it also lowered the ER-phagy level, as evidenced by decreased number of autolysosomes observed by transmission electron microscopy, improved endoplasmic reticulum structure, reduced LC3-II/LC3-I and Beclin1 expression levels, and increased expression level of the autophagy inhibitory molecule Bcl-2. TRIM13 gene knockdown, however, led to opposite results. CONCLUSION: TRIM13 expression attenuated alveolar epithelial cell injury in COPD by inhibiting ERS-induced ER-phagy.

Brain and Muscle derived features to discriminate simple hand motor tasks for a rehabilitative BCI: comparative study on healthy and post-stroke individuals.

OBJECTIVE: Brain-Computer Interfaces targeting post-stroke recovery of the upper limb employ mainly electroencephalography to decode movement-related brain activation. Recently hybrid systems including muscular activity were introduced. We compared the motor task discrimination abilities of three different features, namely event-related desynchronization/synchronization (ERD/ERS) and movement-related cortical potential (MRCP) as brain-derived features and cortico-muscular coherence (CMC) as a hybrid brain-muscle derived feature, elicited in 13 healthy subjects and 13 stroke patients during the execution/attempt of two simple hand motor tasks (finger extension and grasping) commonly employed in upper limb rehabilitation protocols. Approach. We employed a three-way statistical design to investigate whether their ability to discriminate the two movements follows a specific temporal evolution along the movement execution and is eventually different among the three features and between the two groups. We also investigated the differences in performance at the single-subject level. Main results. The ERD/ERS and the CMC-based classification showed similar temporal evolutions of the performance with a significant increase in accuracy during the execution phase while MRCP-based accuracy peaked at movement onset. Such temporal dynamics were similar but slower in stroke patients when the movements were attempted with the affected hand. Moreover, CMC outperformed the two brain features in healthy subjects and stroke patients when performing the task with their unaffected hand, whereas a higher variability across subjects was observed in patients performing the tasks with their affected hand. Interestingly, brain features performed better in this latter condition with respect to healthy subjects. Significance. Our results provide hints to improve the design of Brain-Computer Interfaces for post-stroke rehabilitation, emphasizing the need for personalized approaches tailored to patients' characteristics and to the intended rehabilitative target.

A novel gene signature based on endoplasmic reticulum stress for predicting prognosis in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) remains one of the most common human cancers, the death cases induced by HCC are increasing these years. Endoplasmic reticulum stress (ERS) occurs when misfolded proteins cannot be disposed of properly. It is reported that ERS plays a crucial role in the pathogenesis of human malignant tumors. The aim of this study is to construct a novel gene signature based on ERS for predicting prognosis in HCC. Methods: The data of HCC patients were downloaded from public databases. The Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were performed to construct ERS-related gene signature. The cases were divided into high- and low-risk groups based on the ERS-related gene signature in The Cancer Genome Atlas (TCGA) cohort. Subsequently, the differences in messenger ribonucleic acid (mRNA) expression patterns, immune status, tumor mutation burden (TMB) and copy number variants (CNV) were investigated between high- and low-risk groups. Then, a predictive nomogram according to the ERS-related gene signature and clinicopathological variables was established. At last, we explored the biological functions of TMX1 which had the biggest coefficient and we investigated the effect of BRSK2 on apoptosis in HCC. Results: In our study, a 9-gene ERS-related gene signature was constructed. The results showed that patients in the low-risk group had a better prognosis than the high-risk group patients. The results of receiver operating characteristic (ROC) curves revealed that the area under the curve (AUC) was 0.784 at 1 year, 0.780 at 2 years, 0.793 at 3 years in the training set. While in validation cohort, this index was 0.694 at 1 year, 0.622 at 2 years, 0.613 at 3 years respectively. The analysis of immune status revealed an immunosuppressive microenvironment in the high-risk group. The analysis of TMB and CNV revealed that the high-risk group patients had a higher genomic mutation frequency. In Univariate Cox regression analysis, the hazard ratio of RiskScore was 2.718 [95% confidence interval (CI): 2.173-3.399]. In Multivariate Cox regression analysis, the hazard ratio of RiskScore was 2.422 (95% CI: 1.805-3.25). Then, we established a nomogram according to the RiskScore and Eastern Cooperative Oncology Group performance status. The AUCs of the nomogram were 0.851 at 1 year, 0.860 at 2 years, and 0.866 at 3 years. At last, we found that TMX1 knockdown can inhibit the proliferation and migration of Huh7 and HepG2 cells. In addition, BRSK2 knockdown could promote the apoptosis induced by ERS. Conclusions: In our study, a novel ERS-related gene signature was constructed to predict the prognosis of HCC patients. In addition, TMX1 and BRSK2 could promote the progression of HCC. This study may provide a new understanding for HCC.

trans-chalcone ameliorates CCl4-induced acute liver injury by suppressing endoplasmic reticulum stress, oxidative stress and inflammation.

BACKGROUND: Acute liver injury serves as a crucial marker for detecting liver damage due to toxic, viral, metabolic, and autoimmune exposures. Due to the response to adverse external stimuli and various cellular homeostasis, Endoplasmic reticulum stress (ERS), Oxidative stress, and Inflammation have great potential for treating liver injury. Trans-chalcones (TC) is a polyphenolic compound derived from a natural plant with anti-oxidative and anti-inflammatory abilities. Here, TC was aimed to attenuate liver injury by triggering ER stress, oxidative stress, inflammation, and apoptosis. A single dose of carbon tetrachloride (CCl4) 1 mL/kg was administered intraperitoneally into C57BL6 mice to construct an in vivo NAFLD model, whereas AML12 cells were treated with lipopolysaccharides (LPS) to construct an in vitro NAFLD model. The mice used in the experiment were randomly assigned to two groups: a 12-hour set and a 24-hour set. Forty-nine mice were randomly divided into seven groups, the control group (Group I), TC group (Group II) 10 mg/kg TC, negative control group (Group III) CCl4, TC + CCl4 groups (Groups IV-VI), mice were subcutaneously treated with (5, 10, and 20) mg/kg of TC for three consecutive days before the CCl4 injection and the positive control group (Group VII) received 10 mg/kg Silymarin. After the experiment, serum transaminase, liver histological pathology, hepatic expression levels ERS, oxidative stress, and inflammation-related markers were assessed. TC pre-treatment significantly alleviates the expression of ER stress, oxidative stress, inflammatory cytokines, and apoptosis in both in vivo and in vitro models of liver injury. TC treatment significantly reduced serum transaminase levels (ALT and AST), and improved liver histopathological scores. TC administration also led to a reduction in MDA levels and the suppression of ROS generated by CCl4 in hepatic tissue, which contributed to an increase in GSH levels. The protective effect of TC on the liver injury mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, TC pre-treatment dramatically decreased the protein levels of ER stress indicators such as CHOP, Bip, Ero-Lα, IRE1α, PERK, Calnexin, and PDI when compared to the CCl4-only treated group. TC exerts hepatoprotective effects against CCl4-induced acute liver injuries in mice by modulating ERS, oxidative stress, and inflammation. These results suggest that TC pre-treatment at a dose of (20 mg/kg BW) was as effective as silymarin (10 mg/kg) in preventing CCl4-induced acute liver injury. Further investigations are necessary to elucidate the precise molecular mechanisms underlying the hepatoprotective effects of TC and to explore its therapeutic potential in clinical trials.

CUMS induces depressive-like behaviors and cognition impairment by activating the ERS-NLRP3 signaling pathway in mice.

BACKGROUND AND OBJECTIVE: Endoplasmic reticulum stress (ERS), as a primary defense mechanism against stress, is closely related to mental disorders, but its pathogenesis is still unclear. This research seeks to explore the influence of ERS-nucleotide-bound oligomerized domain-like receptor protein 3 (NLRP3) signaling on mice's depressive-like behaviors and cognitive impairment. DESIGN AND METHOD: We carried out a study on 32 male C57BL/6J mice to investigate how chronic unpredictable mild stress (CUMS) can give rise to depressive-like behaviors and cognitive dysfunction, randomly dividing them into control, model, inhibitor, and agonist groups. We utilized ELISA to quantify dopamine (DA) and 5-hydroxytryptamine (5-HT) levels. Using Nissl and hematoxylin and eosin (H&E) staining, we assessed the number and morphology of hippocampal neurons and cells. Western blot and immunofluorescence staining detected the changes in ERS and inflammation-related pathways in the hippocampus. RESULTS: CUMS could induce ERS and activate NLRP3 inflammasome, causing neuronal damage and histopathological changes, eventually leading to depressive-like behaviors and cognitive impairment in mice. The abnormal activation of NLRP3 inflammasome could be restored by ERS blocker 4-phenyl butyric acid (PBA), thus reducing neuronal damage, and ameliorating depressive-like behaviors and cognitive disorder in mice. CONCLUSION: Our study demonstrates a previously unknown link between ERS and NLRP3 inflammasome in CUMS mice. The ERS-NLRP3 signaling pathway may be activated by CUMS, potentially resulting in mice exhibiting depressive-like behaviors and cognitive dysfunction. Theoretical foundations for elucidating the pathogenesis of depression, as well as its prevention and treatment, will be established through the results.

Competition during verbal creative processes influences on ERS/ERD.

Humans are social creatures, and many tasks in our daily lives are solved together. The two main forms of social interaction in problem solving could be defined as competition and cooperation. In our study, we compared the ERS/ERD when performing a creative task (Alternative Uses Test, AUT) and a control task ("naming the objects from the presented category") under competitive conditions in dyads (22 dyads, m-m, f-f, 18-23 years old) compared to the performance of tasks individually. The number of answers given by subjects under competitive conditions was significantly lower than during the execution of the tasks individually. The solving of the creative task in competition versus individual performance was accompanied by EEG synchronization (9-30 hz) clusters: 140-1220 ms and 900-1780 ms after stimulus presentation; 13.5-30 hz (1800-1980 ms), reflecting the creative thinking mode, and expected cognitive, emotional answers' assessment. The control task under competitive conditions was accompanied by pronounced synchronization of low frequencies in the frontal areas (2-7 hz, 0-1980 ms), due to a greater working memory load; synchronization clusters in broadband (10-30 hz, 100-320 ms, 400-860 ms) and in the beta EEG band (17-30 hz, 1140-1980 ms). The competitive conditions significantly modulated the brain activity underlying creative and non-creative cognitive task performance, and resulted in greater induced EEG synchronization.

[Effects of wheat-grain moxibustion on autophagy and endoplasmic reticulum stress in rats with cervical spondylotic radiculopathy].

OBJECTIVE: To observe the effects of wheat-grain moxibustion on autophagy and endoplasmic reticulum stress (ERS) in the spinal cord and nerve root tissues of rats with cervical spondylotic radiculopathy (CSR), and to explore the potential mechanisms by which wheat-grain moxibustion alleviates neuropathic pain in CSR. METHODS: Forty-eight SPF-grade SD rats were randomly divided into a sham operation group, a model group, a wheat-grain moxibustion group, and a wheat-grain moxibustion + 3-methyladenine (3MA) group, with 12 rats in each group. The CSR model was established in the model group, the wheat-grain moxibustion group, and the wheat-grain moxibustion + 3MA group using the spinal canal insertion method. From the third day after successful modeling, the wheat-grain moxibustion group received wheat-grain moxibustion at "Dazhui" (GV 14), once daily, six cones each session. The wheat-grain moxibustion + 3MA group received intraperitoneal injection of 3MA (2.5 mg/kg), followed by the same wheat-grain moxibustion intervention as the wheat-grain moxibustion group. Interventions were performed once daily for seven consecutive days. The gait disturbance scores and peripheral nerve mechanical pain thresholds were observed before and after the intervention. Western blot was used to detect the expression of ERS apoptosis factors C/EBP-homologous protein (CHOP) and Caspase-12, as well as autophagy substrate P62 in spinal cord and nerve root tissues. Transmission electron microscopy was used to observe autophagosomes and cellular ultrastructure in spinal cord and nerve root tissues. RESULTS: After modeling, compared with the sham operation group, gait disturbance scores were increased (P<0.05) and peripheral nerve mechanical pain thresholds were decreased (P<0.05) in the model group, the wheat-grain moxibustion group, and the wheat-grain moxibustion + 3MA group. After intervention, compared with the sham operation group, gait disturbance scores were increased (P<0.05) and peripheral nerve mechanical pain thresholds were decreased (P<0.05) in the model group; compared with the model group, gait disturbance score was decreased (P<0.05) and peripheral nerve mechanical pain threshold was increased (P<0.05) in the wheat-grain moxibustion and the wheat-grain moxibustion + 3MA group; compared with the wheat-grain moxibustion + 3MA group, gait disturbance score was decreased (P<0.05) and peripheral nerve mechanical pain threshold was increased (P<0.05) in the wheat-grain moxibustion group. Compared with the sham operation group, the expression of CHOP and Caspase-12 proteins in spinal cord and nerve root tissues was increased in the model group (P<0.05); compared with the model group and the wheat-grain moxibustion + 3MA group, the expression of CHOP, Caspase-12, and P62 proteins in spinal cord and nerve root tissues was decreased in the wheat-grain moxibustion group (P<0.05). Compared with the model group and the wheat-grain moxibustion + 3MA group, the number of autophagosomes in spinal cord and nerve root tissues was increased in the wheat-grain moxibustion group, and the cellular ultrastructure was clear and intact, similar to the sham operation group. CONCLUSION: Wheat-grain moxibustion at "Dazhui" (GV 14) could effectively alleviate neuropathic pain in CSR model rats. The analgesic mechanism may be related to promoting autophagy, inhibiting ERS, reducing ERS-mediated apoptosis, and repairing damaged nerves.

Low-molecular-weight estrogenic phytoprotein suppresses osteoporosis development through positive modulation of skeletal estrogen receptors.

Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal women. Prolonged use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators (SERMs) has been associated with various clinical drawbacks. We recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein, called HKUOT-S2 protein (32 kDa), from Dioscorea opposita Thunb that can accelerate bone defect healing. Here, we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors (ERs) ERα, ERß, and GPR30 expressions in vivo. Also, HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers, ALP, and RUNX2 expressions, ALP activity, and osteoblast biomineralization in vitro. Fulvestrant treatment impaired the HKUOT-S2 protein-induced ERs expressions, osteoblasts differentiation, and functions. Finally, we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic properties. Our results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress osteoporosis. Currently, there is no or limited data if any, on osteoanabolic SERMs. The HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

The roles and mechanisms of endoplasmic reticulum stress-mediated autophagy in animal viral infections.

The endoplasmic reticulum (ER) is a unique organelle responsible for protein synthesis and processing, lipid synthesis in eukaryotic cells, and the replication of many animal viruses is closely related to ER. A considerable number of viral proteins are synthesised during viral infection, resulting in the accumulation of unfolded and misfolded proteins in ER, which in turn induces endoplasmic reticulum stress (ERS). ERS further drives three signalling pathways (PERK, IRE1, and ATF6) of the cellular unfolded protein response (UPR) to respond to the ERS. In numerous studies, ERS has been shown to mediate autophagy, a highly conserved cellular degradation mechanism to maintain cellular homeostasis in eukaryotic cells, through the UPR to restore ER homeostasis. ERS-mediated autophagy is closely linked to the occurrence and development of numerous viral diseases in animals. Host cells can inhibit viral replication by regulating ERS-mediated autophagy, restoring the ER's normal physiological process. Conversely, many viruses have evolved strategies to exploit ERS-mediated autophagy to achieve immune escape. These strategies include the regulation of PERK-eIF2α-Beclin1, PERK-eIF2α-ATF4-ATG12, IRE1α-JNK-Beclin1, and other signalling pathways, which provide favourable conditions for the replication of animal viruses in host cells. The ERS-mediated autophagy pathway has become a hot topic in animal virological research. This article reviews the most recent research regarding the regulatory functions of ERS-mediated autophagy pathways in animal viral infections, emphasising the underlying mechanisms in the context of different viral infections. Furthermore, it considers the future direction and challenges in the development of ERS-mediated autophagy targeting strategies for combating animal viral diseases, which will contribute to unveiling their pathogenic mechanism from a new perspective and provide a scientific reference for the discovery and development of new antiviral drugs and preventive strategies.

Naringin attenuates inflammatory injury to the bovine endometrium by regulating the endoplasmic reticulum stress-PI3K/AKT-autophagy axis.

Background: Endometritis seriously affects maternal reproductive health and fertility. Natural compounds have the characteristics of high efficiency and low residue in disease treatment. We aimed to discover and reveal the pharmacological effects of naringin, which is widely present in food and plants, on endometritis. Methods: Based on network pharmacology, the potential targets and pathways of naringin's actions on endometritis were predicted. Animal in vivo experiments were conducted to examine the inflammatory response of lipopolysaccharides (LPSs) in uterine tissue and the therapeutic effect of naringin. An in vitro primary bovine endometrial epithelial cell inflammation and drug treatment model was constructed. The production of reactive oxygen species (ROS) was measured using DCFH-DA, and the effect of naringin on LPS-induced endometritis was evaluated using HE staining, real-time quantitative PCR, Western blot, and immunofluorescence staining methods. Results: Naringin alleviated LPS-induced inflammatory injury and oxidative stress in the endometrium of mice and bovine endometrial epithelial cells (bEECs). Furthermore, in vitro studies were carried out to reveal the potential anti-inflammatory mechanisms of naringin based on network pharmacology. We found that naringin significantly inhibited LPS-stimulated endoplasmic reticulum stress (ERS)-related gene and protein expression, thus reducing the unfolded protein response (UPR). Furthermore, treatment of naringin attenuated the autophagic flux induced by ERS. In a further study, we observed that PI3K/AKT pathway inhibitors or ERS inducers partially reverse naringin's inhibition of autophagy and cell apoptosis. Conclusion: It is demonstrated that naringin suppresses autophagy by directly inhibiting the ERS-PI3K/AKT axis and exerting anti-inflammatory and antioxidant effects in endometritis. These findings provide novel insights into the pathogenesis of endometritis, highlighting potential therapeutic targets of traditional herbs and compounds.

Cardioprotective effect of Robinin ameliorates Endoplasmic Reticulum Stress and Apoptosis in H9c2 cells.

Robinin is one of the glycosyloxyflavones that has been less explored for its therapeutic application, especially in the field of CVD. Herein, we explored the cardioprotective efficacy of Robinin by using H2O2 and Doxorubicin (DOX) - treated H9c2 cells as an in vitro model. H2O2 and DOX treatment resulted in severe cellular damage to the cardiomyocytes, which was followed by apoptosis. Apoptosis and nuclear morphology were analysed through Hoechst 33342 and AO/EB staining. qPCR was employed to detect the expression of apoptosis as well as ERS-related markers. Reactive oxygen species (ROS) generation was observed using DCFH-DA staining and FACS analysis. Signaling pathways involved were analysed using Western blot. Robinin pre-treatment considerably decreased the apoptotic rate by boosting the endogenous anti-oxidative activity and lowering the activity of Malonaldehyde and Lactate dehydrogenase enzyme. Robinin also inhibited the generation of ROS. Robinin reduced the expression of ERS-associated genes and proteins, thereby decreasing apoptosis-related proteins. Upon comparing the cardioprotective effect of Robinin with a known cardioprotective agent Dexrazoxane (DEX) it was revealed that DEX has more cardioprotective effect against DOX than H2O2-induced stress, while Robinin showed a significant protective effect against both H2O2 and DOX induced stress.

Study on different brain activation rearrangement during cognitive workload from ERD/ERS and coherence analysis.

The functional activities of the brain during any task like imaginary, motor, or cognitive are different in pattern as well as their area of activation in the brain is also different. This variation in pattern is also found in the brain's electrical variations that can be measured from the scalp of the brain using an electroencephalogram (EEG). This work exclusively studied a group of subjects' EEG data (available at: https://archive.physionet.org/physiobank/database/eegmat/) to unravel the activation pattern of the human brain during a mental arithmetic task. Since any cognitive task creates variations in EEG signal pattern, the relative changes in the signal power also occur which is also known as event-related desynchronization/synchronization (ERD/ERS). In this work, ERD/ERS have calculated the band-wise power spectral density (PSD) using Welch's method from the EEG signals. Besides, the coherence analysis was also performed to verify the results of ERD/ERS analysis from several randomly chosen subjects' EEG data. Here, subjects performing mental arithmetic tasks were grouped based on their performances: good (subtraction solved > 10 on average) and bad (subtraction solved ≤ 10 on average) to conduct group-specific ERD/ERS analysis regarding their performance in cognitive tasks. It was found that when the brain is on count condition, the variations found in the band power of theta and beta. The amounts of ERS in the left hemisphere are increased. When the task complexity increases, it contributes to an increase in relative ERD/ERS amounts and durations. The left and right hemispheres were asymmetrically distributed by both the pre-stimulus stages of the corresponding band power and relative ERD/ERS.

In vitro and in vivo evaluation of thapsigargin as an antiviral agent against transmissible gastroenteritis virus.

Swine enteric coronaviruses (SeCoVs) pose a significant threat to the global pig industry, but no effective drugs are available for treatment. Previous research has demonstrated that thapsigargin (TG), an ER stress inducer, has broad-spectrum antiviral effects on human coronaviruses. In this study, we investigated the impact of TG on transmissible gastroenteritis virus (TGEV) infection using cell lines, porcine intestinal organoid models, and piglets. The results showed that TG effectively inhibited TGEV replication both in vitro and ex vivo. Furthermore, animal experiments demonstrated that oral administration of TG inhibited TGEV infection in neonatal piglets and relieved TGEV-associated tissue injury. Transcriptome analyses revealed that TG improved the expression of the ER-associated protein degradation (ERAD) component and influenced the biological processes related to secretion, nutrient responses, and epithelial cell differentiation in the intestinal epithelium. Collectively, these results suggest that TG is a potential novel oral antiviral drug for the clinical treatment of TGEV infection, even for infections caused by other SeCoVs.

Tributyltin induces apoptosis in mammalian cells in vivo: a scoping review.

The present review aimed to evaluate the apoptotic effect of tributyltin (TBT) exposure on mammalian tissues and cells in vivo. A search was conducted in specialized literature databases including Embase, Medline, Pubmed, Scholar Google, and Scopus for all manuscripts using the following keywords: "tributyltin", "apoptosis", "mammals", "mammalian cells', "eukaryotic cells", 'rodents', "rats", "mice" and "in vivo" for all data published until September 2023. A total of 16 studies were included. The studies have demonstrated that TBT exposure induces apoptosis in cells from various mammalian organs or tissues in vivo. TBT is capable to increase apoptotic cells, to activate proapoptotic proteins such as calpain, caspases, bax and beclin-1 and to inhibit antiapoptotic protein bcl-2. Additionally, TBT alters the ratio of bcl-2/bax which favor apoptosis. Therefore, the activation of enzymes such as calpain induces apoptosis mediated by ERS and caspases through the intrinsic apoptosis pathway. This review has demonstrated that TBT exposure induces apoptosis in mammalian tissues and cells in vivo.

Identification and validation of endoplasmic reticulum stress-related genes that enhance immunotherapy in colon cancer.

Background: Endoplasmic reticulum stress (ERS)-related genes are related to tumor growth, metastasis, and immunotherapy response. In this paper, we tried to identify ERS-related genes related to immunotherapy in colon cancer. Methods: ERS-related genes were downloaded from the Molecular Signatures Database (MSigDB) and GeneCards websites. Normal and tumor samples of the colon were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), and Gene Expression Omnibus (GEO) databases. A risk model based on gene coefficients was constructed by using the least absolute shrinkage and selection operator (LASSO) regression. The inherent biological process differences between risk groups were explored by Gene Ontology (GO) and gene set enrichment analysis (GSEA). ESTIMATE and single-sample GSEA (ssGSEA) algorithms were used to analyze the correlation between tumor microenvironment (TME) and immune checkpoint and risk score. The semi-inhibitory concentration (IC50) values of chemotherapeutic drugs between risk groups were calculated to evaluate the sensitivity of immunotherapy. Results: The pathway analysis showed that the ERS risk model was relevant to biosynthesis and metabolism. Consistent clustering based on the ERS-related differentially expressed genes (DEGs) demonstrated that the samples divided into three clusters had significant clinicopathological differences. A risk model consisting of six ERS-related genes was established. The model was verified on GSE39582 and GSE17536 testing datasets. The results showed that ERS risk model was significantly related to TME and immune checkpoint, and these genes enhanced the immunotherapy ability of colon cancer. Conclusions: We established a risk model with ERS-related genes (PMM2, STC2, EIF2AK1, HSPA1A, SLC8A1, KCNQ1), which enhance the sensitivity of immunotherapy for colon cancer. These may provide a new perspective for the treatment of colon cancer.

Neurophysiological Oscillatory Mechanisms Underlying the Effect of Mirror Visual Feedback-Induced Illusion of Hand Movements on Nociception and Cortical Activation.

Mirror Visual Feedback (MVF)-induced illusion of hand movements produces beneficial effects in patients with chronic pain. However, neurophysiological mechanisms underlying these effects are poorly known. In this preliminary study, we test the novel hypothesis that such an MVF-induced movement illusion may exert its effects by changing the activity in midline cortical areas associated with pain processing. Electrical stimuli with individually fixed intensity were applied to the left hand of healthy adults to produce painful and non-painful sensations during unilateral right-hand movements with such an MVF illusion and right and bilateral hand movements without MVF. During these events, electroencephalographic (EEG) activity was recorded from 64 scalp electrodes. Event-related desynchronization (ERD) of EEG alpha rhythms (8-12 Hz) indexed the neurophysiological oscillatory mechanisms inducing cortical activation. Compared to the painful sensations, the non-painful sensations were specifically characterized by (1) lower alpha ERD estimated in the cortical midline, angular gyrus, and lateral parietal regions during the experimental condition with MVF and (2) higher alpha ERD estimated in the lateral prefrontal and parietal regions during the control conditions without MVF. These preliminary results suggest that the MVF-induced movement illusion may affect nociception and neurophysiological oscillatory mechanisms, reducing the activation in cortical limbic and default mode regions.

AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment.

The anterior gradient protein 2 (AGR2) plays a crucial role in facilitating the formation of protein disulfide bonds within the endoplasmic reticulum (ER). Research suggests that AGR2 can function as an oncogene, with its heightened expression linked to the advancement of hepatobiliary and pancreatic cancers through invasion and metastasis. Notably, AGR2 not only serves as a pro-oncogenic agent but also as a downstream targeting protein, indirectly fostering cancer progression. This comprehensive review delves into the established functions and expression patterns of AGR2, emphasizing its pivotal role in cancer progression, particularly in hepatobiliary and pancreatic malignancies. Furthermore, AGR2 emerges as a potential cancer prognostic marker and a promising target for immunotherapy, offering novel avenues for the treatment of hepatobiliary and pancreatic cancers and enhancing patient outcomes.

Prevalence of Bronchodilator Responsiveness: A Comparison of Old Versus New Criteria.

BACKGROUND: In 2021, the European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines issued a new definition of bronchodilator responsiveness, which is now defined as an increase in FEV1 or FVC by ≥ 10% of the predicted FEV1 or FVC. The impact of this revised definition on bronchodilator responsiveness prevalence has been relatively understudied. METHODS: We retrospectively analyzed data from 2,696 subjects who performed pulmonary function testing at the University of Iowa from 1997 to 2018. We compared the prevalence of bronchodilator responsiveness by using the 2005 (FEV1 or FVC increase ≥ 12% baseline value and ≥ 200 mL) and 2021 (FEV1 or FVC increase ≥ 200 mL and ≥ 12% of baseline value) ERS/ATS definitions, across several different respiratory diagnosis categories. We compared the prevalence of bronchodilator responsiveness using the 2 definitions by applying the McNemar test and assessed concordance of bronchodilator responsiveness by calculating kappa coefficients for the whole study population and within each diagnosis category. RESULTS: The prevalence of bronchodilator responsiveness increased from 9% when using the 2005 ERS/ATS definition to 16% when using the 2021 definition within the entire cohort and also within each respiratory diagnosis category. In the subjects with normal pre-bronchodilator spirometry, there was a low prevalence of bronchodilator responsiveness (3%) when using the 2005 definition, and the prevalence increased (8%) when using the 2021 definition. In the subjects with normal pre-bronchodilator spirometry and FEV1 Z score ≥ 0, 2% had bronchodilator responsivness according to the 2005 guidelines, whereas 7% had bronchodilator responsiveness according to the 2021 guidelines. CONCLUSIONS: The prevalence of bronchodilator responsiveness increased when using the new 2021 ERS/ATS definition compared with the 2005 definition. In the subjects with normal pre-bronchodilator spirometry, the prevalence of bronchodilator responsiveness increased when using the 2021 definition, in particular, among those with an FEV1 Z score ≥ 0, which raises concerns for overdiagnosis. Future investigations should examine the correlation of bronchodilator responsiveness with clinical outcomes in this group of subjects.