Toll-like receptor 4 (Tlr4) is recognized due to its role in the immune response. Also, this protein can participate in the signaling pathway of events triggered by physical exercise such as ...apoptosis, inflammation, and endoplasmic reticulum (ER) stress. The main objective of this study was to evaluate the role of Tlr4 in the markers of these events in the myocardium of mice submitted to acute physical exercise (APE) protocols at different intensities.
Echocardiogram, RT-qPCR, and immunoblotting technique were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (Tlr4 KO) submitted to APE protocols at 45, 60, and 75% of their maximal velocity. Also, we performed the bioinformatics analysis to establish the connection of heart mRNA levels of Tlr4 with heart genes of inflammation and ER stress of several isogenic strains of BXD mice.
Under basal conditions, the Tlr4 deletion diminished the performance, and expression of inflammation and ER stress genes in the left ventricle, but increased the serum levels of CK, Il-17, and Tnf-alpha. Under the same exercise conditions, the Tlr4 deletion reduced the glycemia, serum levels of CK, Il-17, and Tnf-alpha, as well as genes and/or proteins related to apoptosis, inflammation and ER stress in the left ventricle, but increased the levels of CK-mb and LDH, as well as other genes related to apoptosis, inflammation, and ER stress in the left ventricle.
Altogether, the current findings highlighted the effects of different acute exercise intensities were attenuated in the heart of Tlr4 KO mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exhaustive and chronic physical exercise leads to peripheral inflammation, which is one of the molecular mechanisms responsible for the impairment of the insulin signaling pathway in the heart. ...Recently, 3 different running overtraining models performed downhill (OTR/down), uphill (OTR/up), and without inclination (OTR) increased the serum levels of proinflammatory cytokines. This proinflammatory status induced insulin signaling impairment in the skeletal muscle; however, the response of this signaling pathway in the cardiac muscle of overtrained mice was still unknown. Thus, we investigated the effects of OTR/down, OTR/up, and OTR protocols on the protein levels of phosphorylation of insulin receptor β (pIRβ) (Tyr), phosphorylation of protein kinase B (pAkt) (Ser473), plasma membrane glucose transporter‐1 (GLUT1) and GLUT4, phosphorylation of insulin receptor substrate‐1 (pIRS‐1) (Ser307), phosphorylation of IκB kinase α/β) (pIKKα/β (Ser180/181), phosphorylation of p38 mitogen‐activated protein kinase (p‐p38MAPK) (Thr180/Tyr182), phosphorylation of stress‐activated protein kinases‐Jun amino‐terminal kinases (pSAPK‐JNK) (Thr183/Tyr185), and glycogen content in mice hearts. The rodents were divided into naïve (N, sedentary mice), control (CT, sedentary mice submitted to performance evaluations), trained (TR, performed the training protocol), OTR/down, OTR/up, and OTR groups. After the grip force test, the cardiac muscles (ie, left ventricle) were removed and used for immunoblotting and histology. Although the OTR/up and OTR groups exhibited higher cardiac levels of pIRβ (Tyr), only the OTR group exhibited higher cardiac levels of pAkt (Ser473) and plasma membrane GLUT4. On the contrary, the OTR/down group exhibited higher cardiac levels of pIRS‐1 (Ser307). The OTR model enhanced the cardiac insulin signaling pathway. All overtraining models increased the left ventricle glycogen content, with this probably acting as a compensatory organ in response to skeletal muscle insulin signaling impairment.
Schematic representation summarizing the current data.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Acute exercise activates TLR4 and triggers transient negative responses in the heart.•Chronic exercise downregulates TLR4 and plays a protective effect in the heart.•Negative responses to acute ...exercise are necessary for chronic exercise adaptation.•TLR4 modulation by exercise may be involved in the cardiovascular diseases treatment.
Cardiovascular diseases are a leading cause of death for adults worldwide. Published articles have shown that toll-like receptor 4 (TLR4), a member of the toll-like receptor (TLR) family, is involved in several cardiovascular diseases and can be modulated by physical exercise. TLR4 is the most expressed TLR in cardiac tissue and is an essential mediator of the inflammatory and apoptosis processes in the heart, playing a pivotal role in the development of cardiovascular diseases. Physical exercise is recognized as a non-pharmacological strategy for the prevention and treatment of these diseases. In addition, physical exercise can modulate the TLR4 in the mice heart, and its absence attenuates apoptosis, endoplasmic reticulum stress, and inflammation. However, the relationship between TLR4 and physical exercise-induced cardiac adaptations has barely been explored. Thus, the objective of this brief review was to discuss studies describing how TLR4 influences cardiac responses to physical exercise and present a link between these responses and cardiovascular diseases, showing physical activity improves the cardiac function of individuals with cardiovascular diseases through the TLR4 modulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Many conditions, such as inflammation and physical exercise, can induce endoplasmic reticulum (ER) stress. Toll‐like Receptor 4 (TLR4) can trigger inflammation and ER stress events. However, there ...are still no data in the literature regarding the role of TLR4 in ER stress during exercise in skeletal muscle. Therefore, the current investigation aimed to verify the responses of ER stress markers in wild‐type (WT) and Tlr4 global knockout (KO) mice after acute and chronic physical exercise protocols. Eight‐week‐old male WT and KO mice were submitted to acute (moderate or high intensity) and chronic (4‐week protocol) treadmill exercises. Under basal conditions, KO mice showed lower performance in the rotarod test. Acute high‐intensity exercise increased eIF2α protein in the WT group. After the acute high‐intensity exercise, there was an increase in Casp3 and Ddit3 mRNA for the KO mice. Acute moderate exercise increased the cleaved Caspase‐3/Caspase‐3 in the KO group. In response to chronic exercise, the KO group showed no improvement in any performance evaluation. The 4‐week chronic protocol did not generate changes in ATF6, CHOP, p‐IRE1α, p‐eIF2α/eIF2α, and cleaved Caspase‐3/Caspase‐3 ratio but reduced BiP protein compared with the KO‐Sedentary group. These results demonstrate the global deletion of Tlr4 seems to have the same effects on UPR markers of WT animals after acute and chronic exercise protocols but decreased performance. The cleaved Caspase‐3/Caspase‐3 ratio may be activated by another pathway other than ER stress in Tlr4 KO animals.
Key points
While acute high‐intensity exercise increased the Casp3 and Ddit3 mRNA in KO mice, acute moderate‐intensity exercise increased the cleaved Caspase‐3/Caspase‐3 in the same group.
Under basal conditions, Tlr4 KO mice showed lower performance in the rotarod test. In response to chronic exercise, the Tlr4 KO group showed no improvement in any performance evaluation.
The global deletion of Tlr4 seems to have the same effects on UPR markers of WT animals after acute and chronic exercise protocols but decreased performance and seems to activate the apoptosis pathway.
Significance statement
The endoplasmic reticulum (ER) is responsible for translating and folding most proteins in our body. Protein homeostasis imbalance leads to malformed proteins in the ER lumen, and their accumulation leads to ER stress. Toll‐like Receptor 4 (TLR4) can trigger inflammation, and TLR4 global knockout (KO) mice are protected against ER stress. Furthermore, physical exercise can reduce the TLR4 in the cell. As inflammation seems to affect physical exercise‐related ER stress, the present study investigated the relationship between TLR4 and ER stress after physical exercise in skeletal muscle.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Strategies capable of attenuating TLR4 can attenuate metabolic processes such as inflammation, endoplasmic reticulum (ER) stress, and apoptosis in the body. Physical exercise has been a cornerstone ...in suppressing inflammation and dysmetabolic outcomes caused by TRL4 activation. Thus, the present study aimed to evaluate the effects of a chronic physical exercise protocol on the TLR4 expression and its repercussion in the inflammation, ER stress, and apoptosis pathways in mice hearts. Echocardiogram, RT-qPCR, immunoblotting, and histological techniques were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (TLR4 KO) mice submitted to a 4-week physical exercise protocol. Moreover, we performed a bioinformatics analysis to expand the relationship of Tlr4 mRNA in the heart with inflammation, ER stress, and apoptosis-related genes of several isogenic strains of BXD mice. The TLR4 KO mice had higher energy expenditure and heart rate in the control state but lower activation of apoptosis and ER stress pathways. The bioinformatics analysis reinforced these data. In the exercised state, the WT mice improved performance and cardiac function. However, these responses were blunted in the KO group. In conclusion, TLR4 has an essential role in the inhibition of apoptosis and ER stress pathways, as well as in the training-induced beneficial adaptations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The phloroglucinol eugenial C, eugenial D and eugenial E are the main active compounds in
fruits. This study aims to evaluate the extraction conditions of
, using ethanol as solvent, focusing on the ...phloroglucinol and antimicrobial activity. In order to optimize the extraction conditions, ethanol 50, 70 and 90
GL was used as a solvent in the proportions of 1:20 (w/v) of drug:solvent ratio (D:S), stirring (330 rpm) at room temperature during 4 h, monitored by LC-UV and antimicrobial assay. The LC-UV method developed was linear over a concentration range of 3.4-68.0, 5.3-106.0 and 5.0-100.8 μg.mL
of eugenial C, eugenial D and eugenial E, having LOQ of 1.68, 1.33 and 0.8 μg.mL
, respectively. The fruits showed the best herbal raw material and showed the highest phloroglucinol concentration and activity against
, when extracted with ethanol 90
GL, during 4 h, at 1:20 of D:S.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Recently, we demonstrated that different running overtraining (OT) protocols with the same external load, but performed downhill (OTR/down), uphill (OTR/up), and without inclination (OTR), led to ...hepatic fat accumulation. As the disruption of endoplasmic reticulum (ER) homeostasis is linked to animal models of fatty liver disease, we investigated the effects of these OT models on the proteins related to ER stress (i.e., BiP, inositol-requiring enzyme 1, protein kinase RNA-like endoplasmic reticulum kinase, eIF2alpha, ATF6beta, and glucose-regulated protein 94) and apoptosis (C/EBP-homologous protein, Caspase-3, 4, and 12, Bax, and tumor necrosis factor receptor-associated factor 2) in livers of C57BL/6 mice. Also, aerobic training can attenuate cardiac ER stress and improve exercise capacity. Therefore, we investigated whether the decrease in performance induced by our OT protocols is linked to ER stress and apoptosis in mouse hearts. The rodents were divided into six groups: naïve (N, sedentary mice), control (CT, sedentary mice submitted to the performance evaluations), trained (TR), OTR/down, OTR/up, and OTR groups. Rotarod, incremental load, exhaustive, and grip force tests were used to evaluate performance. After the grip force test, the livers and cardiac muscles (i.e., left ventricle) were removed and used for immunoblotting. All of the OT protocols led to similar responses in the performance parameters and displayed significantly lower hepatic ATF6beta values compared to the N group. The OTR/down group exhibited lower liver cleaved caspase-3 values compared to the CT group. However, the other proteins related to ER stress and apoptosis were not modulated. Also, the cardiac proteins related to ER stress and apoptosis were not modulated in the experimental groups. In conclusion, the OT protocols decreased the levels of hepatic ATF6beta, and the OTR/down group decreased the levels of hepatic cleaved caspase-3. Also, the decrease in performance induced by our OT models is not associated with ER stress and apoptosis in mice hearts.
The association between excessive training sessions (i.e., overtraining/OT) and periods of inadequate recovery is linked to the nonfunctional overreaching (NFOR) state, which is defined as an ...unexplained decrement or stagnation of performance. The cytokine hypothesis of OT considers that pro-inflammatory cytokines are responsible by the NFOR state-induced performance decrement. Investigations using rodent models of OT verified increased levels of pro-inflammatory cytokines in hypothalamus, liver, serum and skeletal muscle samples. Recently, our research group observed that a 2-week total recovery period was not able to re-establish the NFOR state-induced performance decrement. As the responses of anti- and pro-inflammatory cytokines were not measured, we aimed to investigate the effects of 2-week total recovery period on the protein contents of IL-1beta, IL-6, IL-10, IL-15, TNF-alpha and SOCS-3 in serum and skeletal muscle samples of overtrained mice. Also, a bioinformatics analysis was performed to investigate the correlations of IL-1beta, IL-6, IL-10, IL-15, TNF-alpha and SOCS-3 in skeletal muscle with locomotor activity. In summary, the 2-week total recovery period upregulated the anti-inflammatory cytokines and normalized the pro-inflammatory cytokines without a concomitant re-establishment of performance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The phloroglucinol eugenial C, eugenial D and eugenial E are the main active compounds in Eugenia umbelliflora fruits. This study aims to evaluate the extraction conditions of E. umbelliflora, using ...ethanol as solvent, focusing on the phloroglucinol and antimicrobial activity. In order to optimize the extraction conditions, ethanol 50, 70 and 90
o
GL was used as a solvent in the proportions of 1:20 (w/v) of drug:solvent ratio (D:S), stirring (330 rpm) at room temperature during 4 h, monitored by LC-UV and antimicrobial assay. The LC-UV method developed was linear over a concentration range of 3.4-68.0, 5.3-106.0 and 5.0-100.8 μg.mL
−1
of eugenial C, eugenial D and eugenial E, having LOQ of 1.68, 1.33 and 0.8 μg.mL
−1
, respectively. The fruits showed the best herbal raw material and showed the highest phloroglucinol concentration and activity against S. aureus, when extracted with ethanol 90
o
GL, during 4 h, at 1:20 of D:S.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Fusarium is considered an emerging pathogen, and there are few reports of fusariosis in children. The objective of this study was to describe an outbreak of invasive fusariosis in a children's cancer ...hospital. A neutropenic 17-year-old male patient hospitalized for 10 days for a relapse of acute myeloid leukaemia, under chemotherapy, presented fever without any other symptoms; a thoracic computerized tomography showed bilateral pulmonary nodules. During voriconazole treatment, 1-cm reddened and painful subcutaneous nodules appeared on arms and legs and the culture of a skin biopsy revealed F. solani. Another case occurred 11 days later and started an outbreak investigation. Water samples for cultures were collected from taps, showers and water reservoirs. Air from all patient rooms was sampled. Faucets and the drains of sinks and showers were swabbed and cultured. Environmental and clinical isolates were typed. There were 10 confirmed cases of infection caused by Fusarium spp. F. oxysporum and F. solani were isolated from water, swabs and air in patient rooms. Many control measures were instituted, but the outbreak was only controlled 1 year after the first case, when water filters filtering 0.2 μm were installed at the exit of all faucets and showers in all patient rooms (points-of-use). Typing demonstrated that clinical isolates of F. oxysporum were similar to those of the environment. In conclusion, to our knowledge this is the first reported outbreak of invasive fusariosis in children with oncohaematologic disease. It was controlled using 0.2-μm filters in all tap faucets and showers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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