Increased Tumor Necrosis Factor-alpha Research Articles

220 Litter performance, serum collagen, and hormone concentrations in prolapsed and non-prolapsed sows

Abstract Pelvic organ prolapse is one of the top leading causes of sow mortality today and widely considered a multifactorial issue. Previous reports observed prolapsed sows having decreased serum concentrations of various trace minerals and increased tumor necrosis factor-alpha compared with non-prolapsed sows. Additionally, collagen, hormones, and previous litter performance are other factors proposed to be associated with POP. A study was completed to determine differences in serum collagen type 1 (COL1), matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metalloproteinase 1 (TIMP-1), as well as relaxin and estradiol differences in the serum concentration between prolapsed and non-prolapsed sows. Furthermore, previous litter performance, lactation days, pigs born, stillborns, mummified, and pigs weaned on prolapse rate were evaluated. The study utilized 44 prolapsed sows and 44 non-prolapsed sows of similar parity, location, management, and stage of production. Blood was collected from the prolapsed and non-prolapsed sows upon discovery. Serum samples were analyzed using radioimmunoassay for estradiol content. Additionally, COL1, MMP-1, TIMP-1, and relaxin concentrations were determined from the serum using ELISA testing. Data were analyzed using the PROC GLIMMIX procedure in SAS. Prolapsed sows had decreased (P < 0.05) COL1 and TIMP-1 concentrations in the serum compared with the non-prolapsed sows. Prolapsed sows had marginally greater (P < 0.10) MMP-1 concentration compared with non-prolapsed sows. There were no differences (P > 0.10) between prolapsed and non-prolapsed serum concentraions of sows for estradiol and relaxin. Prolapsed sows had longer lactation days (P < 0.05) in the litter before prolapsing compared with non-prolapsed sows. Additionally, stillborns in the previous litter were marginally greater (P = 0.06) in prolapsed sows when compared with the non-prolapsed sows. There were no differences (P > 0.10) in pigs born, mummified, or pigs weaned between prolapsed and non-prolapsed sows. This study suggests that there is a reduced concentration of serum COL1 and TIMP-1 found in prolapsed sows compared with non-prolapsed sows and a marginally increased MMP-1 concentration in prolapsed sows. This could influence the structural integrity of the connective tissue that supports the pelvic organs. We found no differences in serum estradiol or relaxin levels. Additionally, lactation days and stillborn pigs in the litter prior to prolapsing could be contributing factors to prolapse. This work further supports the idea that prolapse is a multifactorial issue.

Characterizing MetALD in a Nonhuman Primate Model using High Fat and Sucrose Diet and Chronic Binge Alcohol Administration

Mechanisms leading to metabolic and alcohol associated liver disease (MetALD) are not clearly delineated. This study examined the differential regulation of markers of hepatic mitochondrial function in nonhuman primates fed a high fat/high sucrose (HFSD) and administered chronic binge alcohol (CBA) or vehicle as compared to control-fed animals. We hypothesized that markers of hepatic dysregulation due to HFSD will be further altered by the combination of CBA/HFSD. Eight rhesus macaques were fed HFSD (27% sucrose and 42% fat, by kcal) with n=4 receiving vehicle and n=4 receiving 13-14g/kg/wk of ethanol through a gastric catheter. Rhesus macaques fed standard primate chow were used as reference controls (n=4-6). Liver RNA was isolated for determining expression of genes regulating mitochondrial biogenesis and function using RT-qPCR. Results were analyzed using one-way ANOVA and post-hoc pairwise multiple comparisons were performed using Tukey’s method, with alpha set to 0.05. Expression of inflammatory genes was significantly altered across the groups (p<0.05). HFSD increased tumor necrosis factor alpha (p=0.01), interleukin 1-beta (p=0.04), cluster of differentiation 38 (p=0.01), and transforming growth factor beta (p=0.01) expression compared to control. Both HFSD and CBA/HFSD increased interleukin-10 compared to control (p=0.02, p=0.03). Gene expression of mitochondrial function and oxidative stress regulators were significantly altered across the groups (p<0.05). CBA/HFSD decreased expression of peroxisome proliferator-activated receptor-gamma coactivator-1 beta (p=0.04) and nuclear respiratory factor 2 (p=0.04) compared to control. Both HFSD and CBA/HFSD decreased peroxisome proliferator-activated receptor alpha expression compared to control (p=0.01, 0.01). HFSD decreased superoxide dismutase 2 (SOD2) expression compared to control (p=0.01) and increased uncoupling protein 2 (p=0.01). SOD2 expression was increased only in CBA/HFSD compared to HFSD (p=0.01). These results reveal marked HFSD-mediated increases in markers of inflammation and CBA/HFSD-mediated changes in markers of mitochondrial function regulation and oxidative stress regulation. These findings suggest a greater impact of calorie-dense diets than CBA on hepatic inflammation and a combined impact of CBA and HFSD on mitochondrial regulation. Ongoing studies will examine oxidative phosphorylation complex protein activities and expression to elucidate and integrate HFSD or CBA mediated changes in hepatic bioenergetic capacity. Supported by F30AA030910, P60AA009803, and T32AA007577. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of peripheral blood mononuclear cells preconditioned by activated platelet supernatant in managing gastric mucosal damage induced by zinc oxide nanoparticles in rats.

The world has witnessed tremendous advancements in nano-base applications. Zinc oxide nanoparticles (ZON) are widely used in food industry and medicine. Although their application is of important value, they may cause toxicity to body tissues. Peripheral blood mononuclear cells (PBMCs) proved its efficacy in tissue regeneration especially when it is preconditioned by activated platelet supernatant (APS). The aim of this study is to evaluate the effect of ZON on the gastric mucosa and the therapeutic role of the PBMCs preconditioned by APS in rats. Ten rats were donors and fifty rats were recipients. The recipients were divided into; control group, ZON group (10 mg/kg/day orally for five days) and preconditioned PBMCs group (1×107 once intravenously 24 hours after ZON). Gastric specimens were processed for histological, immunohistochemical, biochemical and quantitative real-time polymerase chain reaction studies. ZON group showed marked structural changes in the gastric mucosa. There was desquamation or deep ulceration of the epithelium. Cytoplasmic vacuoles and pyknotic nuclei were in glandular cells. Reduced proliferating cell nuclear antigen and increased tumor necrosis factor-α were in epithelial cells. There were significant elevation in malondialdahyde and reduction in glutathione, superoxide dismutase, and catalase. Enhancement in mRNA expression of nuclear factor kappa-B and cyclooxygenase-2 was detected. The preconditioned PBMCs group showed significant improvement of all parameters. So, ZON had cytotoxic effects on the gastric mucosa and the preconditioned PBMCs had a therapeutic effect on gastric mucosal damage after ZON.

Evaluation of the relationship between serum BDNF concentration and indicators of oxidative stress and inflammation in COVID-19 patients with neurological disorders - a pilot study

ABSTRACTIntroductionThe aim of this study was to determine the effect of serum level of brain-derived neurotrophic factor (BDNF) on the development of neurological disorders in COVID-19 patients and the probable role of oxidative stress and inflammation in this phenomenon.MethodsThe present case-control study included 42 COVID-19 patients referring to Golestan and Sina hospitals of Ahvaz, Iran, for treatment. Patients with (n = 18) and without (n = 24) neurological disorders were allocated into test and control groups, respectively. Following blood sampling, serum isolation was done, and the serum was stored at −80°C until biochemical assessment for measuring BDNF, oxidative stress indices, and inflammatory factors.ResultsAlthough no significant brain damage was observed in the COVID-19 patients with neurological disorders, the results showed that the serum level of BDNF in the test group increased compared to that in the control group, and this increment was accompanied with increased Tumor Necrosis Factor-alpha (TNF-α) and decreased Interferon gamma (IFN-γ) levels in the serum. Moreover, compared to the control group, patients in the test group had a decreased level of Thiol and an increased level of Malondialdehyde (MDA) in the serum. Furthermore, there was a significant positive correlation between the serum concentration of BDNF and nitric oxide (NO) in the test group.ConclusionUsing over-the-counter (OTC) medicines which include thiol-group-related agents or any other antioxidants can alleviate oxidative stress and the associated increased inflammation in COVID-19 patients with neurological symptoms.

Abstract P200: Tnf-α Blockade During Pregnancy Does Not Impact Offspring Development In A Rat Model Of Preeclampsia

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with increased tumor necrosis factor alpha (TNF-α), agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA), and low birth weight babies. We have previously shown that Etanercept ( E ), a TNF-α inhibitor, improves PE features in the reduced uterine perfusion pressure (RUPP) rat. However, the long-term effect of E on offspring health and immune competency has not been studied. Therefore, we hypothesize that E will improve maternal health without affecting offspring outcomes in a rat model of PE. To test this hypothesis, E (0.4 mg/kg) was injected on gestation day 18 into sham and RUPP dams which were allowed to deliver. Weights were recorded at birth and 16 weeks of age when mean arterial pressure (MAP) was measured. Whole blood was collected to measure immune cells by flow cytometry. AT1-AA was measured using a cardiomyocyte bioassay. A student’s t-test was used to compare differences among male and female RUPP offspring with and without E . RUPP male and female offspring were smaller (5.21±0.19 g, n=7; 5.24±0.10 g, n=7) than sham offspring (5.94±0.14 g, n=7, p<0.05; 5.86±0.16 g, n=9, p<0.01) while RUPP male offspring were larger and female offspring were unchanged following perinatal E (6.01±0.29 g, n=9, p<0.05; 5.28±0.14, n=9). MAP was comparable between sham (133±4 mmHg) and RUPP (132±4 mmHg) male offspring with no change seen following perinatal E (133±4 mmHg). Perinatal E did not impact adult male circulating B cells. Circulating AT1-AA was elevated in male RUPP offspring (16±2 ΔBPM, p<0.01) compared to sham and was not improved with E (13±2 ΔBPM). MAP was comparable in sham (131±5 mmHg) and RUPP (130±5 mmHg) female offspring but trended downward with perinatal E (123±4 mmHg). RUPP female offspring had reduced circulating B cells (4.24±0.81 % gated, p=0.066) compared to sham females (9.56±2.07 % gated) which was normalized following perinatal E (9.04±1.42 % gated, p<0.05). AT1-AA trended lower following perinatal E (7±2 ΔBPM, p=0.0888) compared to RUPP female offspring (16±3 ΔBPM). Our findings indicate that E does not worsen fetal outcomes. Moreover, E improves male birth weight and reduces adult female AT1-AA without compromising offspring immune competency.

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats

Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.

Aspergillus fumigatus Extracellular Vesicles Display Increased Galleria mellonella Survival but Partial Pro-Inflammatory Response by Macrophages

Fungal extracellular vesicles (EVs) mediate intra- and interspecies communication and are critical in host-fungus interaction, modulating inflammation and immune responses. In this study, we evaluated the in vitro pro- and anti-inflammatory properties of Aspergillus fumigatus EVs over innate leukocytes. A. fumigatus EVs induced a partial proinflammatory response by macrophages, characterized by increased tumor necrosis factor-alpha production, and increased gene expression of induced nitric oxide synthase and adhesion molecules. EVs induce neither NETosis in human neutrophils nor cytokine secretion by peripheral mononuclear cells. However, prior inoculation of A. fumigatus EVs in Galleria mellonella larvae resulted in increased survival after the fungal challenge. Taken together, these findings show that A. fumigatus EVs play a role in protection against fungal infection, although they induce a partial pro-inflammatory response.

Hepatoprotective Effect of Roselle (Hibiscus sabdariffa L.) in N-Diethylnitrosamine Induced Liver Damage in Rats

Introduction: Liver damage due N-diethylnitrosamine (DEN) is a global health challenge. The aim of this study was to assess the efficacy of roselle (Hibiscus sabdariffa L.) calyces’ water-extract as a Hepatoprotective material against liver damage induced by DEN in rats. Material and methods: Twenty-five (25) adult female albino Wistar rats were grouped randomly into five groups (Gs): G1, Normal healthy animals (act as control); G2, DEN; G3, Roselle extract; G4, DEN + roselle-extract; G5, DEN + nanoselenium. Tissue malondialdehyde (MDA) as oxidative stress marker, and antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) were measured. Also, caspase-3 as apoptotic marker and tumor necrosis factor-alpha (TNF-a) as inflammatory factor, were assessed. Results: The results revealed decrease in MAD level and significant increase in antioxidant markers, SOD and CAT in DEN-group compared with control group. Moreover high increase in apoptotic marker, caspase-3; and significant decrease in TNF-a in DEN-group were recorded compared with normal control. Administration of roselle-extract led to significant increase in MDA and decrease in SOD and CAT parameters. In addition, high decrease in caspase-3 and increase in TNF-a was noticed. These findings were ensured by histopathological results. Conclusion: The roselle-extract improve liver architecture, and might be involved in the hepatoprotective activity against DEN exposure. Further studies are needed for elucidation clinical applications of the plant bioactive materials and explore its mode of action in attenuating and preventing carcinogenesis.

Characterization of macrophage activation after treatment with polysaccharides from ginseng according to heat processing

The worldwide persistence of infectious diseases is a significant public health issue. Consequently, studying immunomodulatory ingredients present in natural products, such as ginseng, is important for developing new treatment options. Here, we extracted three different types of polysaccharides from white (P-WG), red (P-RG), and heat-processed (P-HPG) ginseng and analyzed their chemical properties and immunostimulatory activity against RAW 264.7 murine macrophages. Carbohydrates were the main components of all three polysaccharide types, while uronic acid and protein levels were relatively low. Chemical analysis indicated that the content of carbohydrates (total sugar) increased with processing temperature, while that of uronic acid decreased. Treatment with P-WG, P-RG or P-HPG stimulated nitric oxide (NO) production and increased tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 levels in RAW 264.7 macrophages, with P-WG showing the highest activity among the three polysaccharides. The expression of inducible NO synthase, which affects NO secretion, was highest in the macrophages treated with P-WG. Analysis of intracellular signaling pathways showed that mitogen-activated protein kinases (ERK, JNK, and p38) and NF-kB p65 were strongly phosphorylated by P-WG in macrophages but were only moderately phosphorylated by P-RG and P-HPG. Collectively, these results suggest that the polysaccharides isolated from ginseng undergo different changes in response to heat processing and display different chemical compositions and immune-enhancing activities.

The effect of alginate scaffolds on bone healing in defects formed with drilling model in rat femur diaphysis.

Alginate (ALG) is a biocompatible and biodegradable polymer. Mechanical weakness is one of the main problems for the alginate-based scaffolds. Various plasticizer additives or modifications tested to improve the mechanical properties. In the presented study, ALG plasticized with triacetin (TA), and tributyl citrate (TBC) than tested on bone healing. In the presented study, the alginate modified with triacetin or tributyl citrate. In-vitro, and in-vivo efficiency of the scaffolds tested on bone tissue regeneration. Scaffolds fabricated by solvent casting, and physicochemical characterizations performed. Monocytes (THP-1) cultured with scaffolds, and macrophage-released cytokines was determined. In-vivo efficacy of the scaffolds was tested in the rat drill hole model. Alginate and tributyl citrate-modified scaffolds have no cytotoxic effect on osteoblastic cells (MC-3T3). Tributyl citrate modification increased tumor necrosis factor-alpha (TNF-alpha) level but did not increase interleukin -1 beta (IL-1 beta) level. In vivo studies showed that osteoblastic growth was significant in alginate and triacetin-modified scaffolds. However, the best values for osteoclastic activity and osteoid tissue formation seen in the triacetin modification. The results demonstrated that the modified alginate scaffolds were more successful than non-modified alginate scaffolds and can used as long-term bone repairing treatments.

Sodium Propionate or Sodium Butyrate Promotes Fatty Acid Oxidation in HepG2 Cells Under Oxidative Stress.

The beneficial effects of sodium butyrate (NaB) and sodium propionate (NaP) on fatty acid oxidation (FAO) genes and production of proinflammatory cytokines related to nonalcoholic fatty liver disease (NAFLD) were evaluated using HepG2 human liver hepatocellular carcinoma cells exposed to palmitate/oleate or lipopolysaccharides (LPSs) as a model. The results showed that NaP or NaB was able to promote FAO, regulate lipolysis, and reduce reactive oxygen species production by significantly increasing the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 alpha (CPT1α), fibroblast growth factor 21 (FGF21), and uncoupling protein 2 (UCP2) in HepG2 cells. Together, NaP and NaB may produce greater effects by increasing CPT1α, PPARα, and UCP2 mRNA expression in LPS-treated HepG2 cells and by increasing CPT1α and ATGL mRNA expression in palmitate-/oleate-treated HepG2 cells. Only NaP treatment significantly increased FGF21 mRNA expression in palmitate-/oleate-treated HepG2 cells. The enzyme-linked immunosorbent assay results revealed that only pretreatment with LPSs and not palmitate/oleate significantly increased tumor necrosis factor alpha (TNF-α) expression in HepG2 cells. NaP alone or in combination with NaB significantly decreased TNF-α expression in LPS-induced HepG2 cells. The expression of interleukin-8 in both models showed no significant differences in all treatments. NaP and NaB show potential for in vivo studies on NAFLD.

Whey protein hydrolysate mitigates both inflammation and endotoxin tolerance in THP-1 human monocytic leukemia cells.

It is important to control both inflammation and immunosuppression after severe insults, such as sepsis, trauma, and surgery. Endotoxin tolerance is one of the immunosuppressive conditions and it has been known that endotoxin tolerance relates to poorer clinical outcomes in patients with severe insults. This study investigated whether whey protein hydrolysate (WPH) mitigates inflammation and endotoxin tolerance in THP-1 human monocytic leukemia cells. Endotoxin tolerance can be experimentally reproduced by two consecutive stimulations with lipopolysaccharide (LPS). THP-1 cells were incubated with LPS and WPH (first stimulation). After collecting the culture supernatant to evaluate the effect on inflammation, the cells were washed and restimulated by 100 ng/ml LPS (second stimulation). The culture supernatant was again collected to evaluate the effect on endotoxin tolerance. Concentrations of LPS and WPH in the first stimulation were adjusted to evaluate their dose dependency. Cytokine levels in the supernatant were determined by enzyme-linked immunosorbent assay. Statistical analysis was performed using the student's t-test or Dunnett's test. Five mg/ml WPH significantly decreased interleukin (IL)-6 (p = .006) and IL-10 (p < .001) levels after the first LPS stimulation (1000 ng/ml). WPH significantly increased tumor necrosis factor-alpha (p < .001) and IL-10 (p = .014) levels after the second LPS stimulation. The suppressive effect of WPH on inflammation and endotoxin tolerance was dependent on the concentrations of LPS and WPH. The effective dose of WPH for endotoxin tolerance was lower than its effective dose for inflammation. WPH mitigated both inflammation and endotoxin tolerance. Therefore, WPH might be a candidate for valuable food ingredients to control both inflammation and immunosuppression after severe insults.

Neohesperidin Alleviates the Neuropathic Pain Behavior of Rats by Downregulating the P2X4 Receptor.

Neuropathic pain (NP) is a type of chronic pain affecting 6-8% of human health as no effective drug exists. The purinergic 2X4 receptor (P2X4R) is involved in NP. Neohesperidin (NH) is a dihydroflavonoside compound, which has anti-inflammatory and antioxidative properties. This study aimed to investigate whether NH has an effect on P2X4R-mediated NP induced by chronic constriction injury (CCI) of the sciatic nerve in rats. In this study, the CCI rat model was established to observe the changes of pain behaviors, P2X4R, and satellite glial cells (SGCs) activation in dorsal root ganglion (DRG) after NH treatment by using RT-PCR, immunofluorescence double labeling and Western blotting. Our results showed CCI rats had mechanical and thermal hyperalgesia with an increased level of P2X4R. Furthermore, SGCs were activated as indicated by increased expression of glial fibrillary acidic protein and increased tumor necrosis factor-alpha receptor 1and interleukin-1β. In addition, phosphorylated extracellular regulated protein kinases and interferon regulatory factor 5 in CCI rats increased. After NH treatment in CCI rats, the levels of above protein decreased, and the pain reduced. Overall, NH can markedly alleviate NP by reducing P2X4R expression and SGCs activation in DRG.

Complementary Approaches for Military Women with Chronic Pelvic Pain: A Randomized Trial.

Introduction: Active duty (AD) women suffer with chronic pelvic pain (CPP) while providers tackle diagnoses and treatments to keep them functional without contributing to the opioid epidemic. The purpose of this randomized trial was to determine the effectiveness of noninvasive, self-explanatory mindfulness-based stress reduction (MBSR) or self-paced healthy lifestyle (HL) interventions on CPP in AD women. Methods: A 6-week, interventional prospective study with AD women aged 21-55 years at Mountain Home (MTHM), Idaho, was conducted. Women were randomly assigned to MBSR (N = 21) or HL (N = 20) interventions. The primary outcome was pain perception. The secondary outcomes were depression and circulating cytokine levels. Results: Women in the MBSR group exhibited reduced pain interference (p < 0.01) and depression (p < 0.05) alongside decreased interleukin (IL)-4 (p < 0.05), IL-6 (p < 0.05), eotaxin (p < 0.05), monocyte chemoattractant protein-1 (p = 0.06), and interleukin-1 receptor antagonist (IL-1ra) (p < 0.01) and increased vascular endothelial growth factor (p < 0.05). Women in the HL group did not have changes in pain; however, they did exhibit reduced depression (p < 0.05) alongside decreased granulocyte-macrophage colony-stimulating factor (p < 0.05) and increased tumor necrosis factor alpha (p < 0.05), stromal cell-derived factor-1 (p < 0.01), and IL-1ra (p < 0.01). Conclusions: AD women receiving MBSR or HL had reduced depression scores and altered circulating cytokine levels; however, only those receiving MBSR had reduced pain perception. Findings support MBSR as an effective and viable behavioral treatment for AD women suffering from CPP and provide premise for larger randomized controlled studies. Clinical Trial Registration: MOCHI-An RCT of mindfulness as a treatment for CPP in AD Women NCT04104542 (September 26, 2019).

Exercise and Gotu Kola Extract to Ameliorate Tumor Necrosis Factor - Alpha, Quality of Life, and Executive Function in Cognitive Impairment Women

Increasing tumor necrosis factor-alpha (TNF-alpha) and decreasing quality of life (QoL) are associated with cognitive deterioration. Exercise and Gotu kola (Centella Asiatica) can improve memory and antiinflammation, but their combination has not yet been revealed. This study aimed to see how exercise and Gotu kola extract affected TNF-alpha, quality of life, and executive functions in women with cognitive impairment. This study used an experimental design with a control group with a 12-week pre and post-test in women with cognitive impairment. The Montreal Cognitive Assessment (MoCA) was used to screen for cognitive impairment. The participants in the study were 64 women with a mean age of 53.3 (4.8) years. The subjects were divided into four groups: Gotu kola/GK extract capsule (1x500 mg/day), exercises (2x75 minutes per week), a GK-exercise combination, and the control group. The WHO-QoL questionnaire was used to assess the quality of life. The Trail Making Test-B (TMT-B) was used to assess executive functions. The study found that Gotu kola might increase QoL in the physical domain (p=0.028) and environmental domain (p=0.016). Exercise and a GK-exercise combination could improve QoL: physical, psychological, social, and environmental domain (p<0.05). According to the Mann-Whitney test, the GK-exercise combination was the most helpful in enhancing TNF-alpha (Δ=-10.5; p=0.003), MoCA (∆= 4.6; p=<0.001), and TMT-B (Δ=-21.4; p=0.023). Discussion: Physical activity is one of the factors that can play a role in cognitive function through several mechanisms. To conclude, exercise, Gotu Kola, and their combination can effectively decrease inflammation and increase the quality of life and cognitive function in women with cognitive impairment. This study expected that exercise and Gotu Kola could be priority interventions in treating cognitive impairment.

Quinolinic Acid Induces Alterations in Neuronal Subcellular Compartments, Blocks Autophagy Flux and Activates Necroptosis and Apoptosis in Rat Striatum.

Quinolinic acid (QUIN) is an agonist of N-methyl-D-aspartate receptor (NMDAr) used to study the underlying mechanism of excitotoxicity in animal models. There is evidence indicating that impairment in autophagy at early times contributes to cellular damage in excitotoxicity; however, the status of autophagy in QUIN model on day 7 remains unexplored. In this study, the ultrastructural analysis of subcellular compartments and the status of autophagy, necroptosis, and apoptosis in the striatum of rats administered with QUIN (120nmol and 240nmol) was performed on day 7. QUIN induced circling behavior, neurodegeneration, and cellular damage; also, it promoted swollen mitochondrial crests, spherical-like morphology, and mitochondrial fragmentation; decreased ribosomal density in the rough endoplasmic reticulum; and altered the continuity of myelin sheaths in axons with separation of the compact lamellae. Furthermore, QUIN induced an increase and a decrease in ULK1 and p-70-S6K phosphorylation, respectively, suggesting autophagy activation; however, the increased microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and sequestosome-1/p62 (SQSTM1/p62), the coexistence of p62 and LC3 in the same structures, and the decrease in Beclin 1 and mature cathepsin D also indicates a blockage in autophagy flux. Additionally, QUIN administration increased tumor necrosis factor alpha (TNFα) and receptor-interacting protein kinase 3 (RIPK3) levels and its phosphorylation (p-RIPK3), as well as decreased B-cell lymphoma 2 (Bcl-2) and increased Bcl-2-associated X protein (Bax) levels and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting an activation of necroptosis and apoptosis, respectively. These results suggest that QUIN activates the autophagy, but on day 7, it is blocked and organelle and cellular damage, neurodegeneration, and behavior alterations could be caused by necroptosis and apoptosis activation.

The effect of tropisetron on peripheral diabetic neuropathy: possible protective actions against inflammation and apoptosis.

Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-β (TNFα and IL-1β) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.

Protective effects of dexpanthenol in carbon tetrachloride-induced myocardial toxicity in rats

Exposure to various organic compounds including several environmental pollutants and drugs can cause cellular damage through the generation of lipid peroxidation products. Carbon tetrachloride (CCl4) is a potent toxic agent that causes peroxidative degeneration in many tissues. Dexpanthenol (Dxp) is a member of the B complex vitamins that exhibits antioxidant effects against lipid peroxidation products. This study was designed to evaluate the cardioprotective effect of Dxp against CCl4-induced myocardial toxicity in rats. Administration of a single dose of CCl4 caused cardiotoxicity by the increase in lipid peroxidation and histopathological changes (cardiomyocytes degeneration, interstitial edema) in the myocardial tissue. Moreover, CCl4 caused a decrease in lactate dehydrogenase (LDH) and troponin-I immunoreactivities, while significantly increasing tumor necrosis factor-alpha (TNF-α) and caspase-3 immunoreactivities. On the other hand, administration of Dxp improved biochemical, histopathological, and immunohistochemical parameters compared to the CCl4 treated group. Overall, this study suggests that Dxp is effective in inhibiting CCl4-induced lipid peroxidation, and that administration of Dxp may help prevent CCl4 related inflammation, necrosis, and apoptosis on the cardiac tissue.

Nonalcoholic Fatty Liver Disease Patients Exhibit Reduced CD47 and Increased Sphingosine, Cholesterol, and Monocyte Chemoattractant Protein-1 Levels in the Erythrocyte Membranes.

Background: Nonalcoholic fatty liver disease (NAFLD) constitutes a significant cause of deaths, liver transplantations, and economic costs worldwide. Despite extended research, investigations on the role of erythrocytes are scarce. Red blood cells from experimental animals and human patients with NAFLD present phosphatidylserine exposure, which is then recognized by Kupffer cells. This event leads to erythrophagocytosis and amplification of inflammation through iron disposition. In addition, it has been shown that erythrocytes from NAFLD patients release the chemokine monocyte chemoattractant protein-1 (MCP1), leading to increased tumor necrosis factor alpha release from macrophages RAW 264.7. However, erythrophagocytosis can also be caused by reduced CD47 levels. Moreover, increased MCP1 release could be either signal-induced or caused by higher MCP1 levels on the erythrocyte membrane. Finally, erythrocyte efferocytosis could provide additional inflammatory metabolites. Methods: In this study, we measured the erythrocyte membrane levels of CD47 and MCP1 by enzyme-linked immunosorbent assay, and cholesterol and sphingosine with thin-layer chromatography. Eighteen patients (8 men and 10 women, aged 56.7 ± 11.5 years) and 14 healthy controls (7 men and 7 women, aged 39.3 ± 15.6 years) participated in our study. Results: The erythrocyte CD47 levels were decreased in the erythrocyte membranes of NAFLD patients (844 ± 409 pg/mL) compared with healthy controls (2969 ± 1936 pg/mL) with P = 0.012. Levels of MCP1 increased in NAFLD patients (389 ± 255 pg/mL) compared with healthy controls (230 ± 117 pg/mL) with P = 0.0274, but low statistical power. Moreover, in erythrocyte membranes, there was a statistically significant accumulation of sphingosine and cholesterol in NAFLD patients compared with healthy controls. Conclusions: Our results imply that erythrocytes release chemotactic "find me" signals (MCP1) while containing reduced "do not eat me" signals (CD47). These molecules can lead to erythrophagocytosis. Next, increased "goodbye" signals (sphingosine and cholesterol) could augment inflammation by metabolic reprogramming.

Ornipural® Mitigates Malathion-Induced Hepato-Renal Damage in Rats via Amelioration of Oxidative Stress Biomarkers, Restoration of Antioxidant Activity, and Attenuation of Inflammatory Response.

The current study was instigated by investigating the ameliorative potential of Ornipural® solution against the hepato-renal toxicity of malathion. A total number of 35 male Wistar albino rats were divided equally into five groups. Group 1 served as control and received normal saline intraperitoneally. Group 2, the sham group, were administered only corn oil (vehicle of malathion) orally. Group 3 was orally intoxicated by malathion in corn oil at a dose of 135 mg/kg BW via intra-gastric gavage. Group 4 received malathion orally concomitantly with Ornipural® intraperitoneally. Group 5 was given Ornipural® solution in saline via intraperitoneal injection at a dose of (1 mL/kg BW). Animals received the treatment regime for 30 days. Histopathological examination revealed the harmful effect of malathion on hepatic and renal tissue. The results showed that malathion induced a significant decrease in body weight and marked elevation in the activity of liver enzymes, LDH, and ACP. In contrast, the activity of AchE and Paraoxonase was markedly decreased. Moreover, there was a significant increase in the serum content of bilirubin, cholesterol, and kidney injury markers. A significant elevation in malondialdehyde, nitric oxide (nitrite), and 8-hydroxy-2-deoxyguanosine was observed, along with a substantial reduction in antioxidant activity. Furthermore, malathion increased tumor necrosis factor-alpha, the upregulation of IL-1B, BAX, and IFN-β genes, and the downregulation of Nrf2, Bcl2, and HO-1 genes. Concurrent administration of Ornipural® with malathion attenuated the detrimental impact of malathion through ameliorating metabolic biomarkers, restoring antioxidant activity, reducing the inflammatory response, and improving pathologic microscopic alterations. It could be concluded that Ornipural® solution demonstrates hepatorenal defensive impacts against malathion toxicity at biochemical, antioxidants, molecular, and cellular levels.