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Journal of Ethnopharmacology Sep 2024Long-term chronic inflammation often leads to chronic diseases. Although Sophora flavescens has been shown to have anti-inflammatory properties, its detailed molecular...
ETHNOPHARMACOLOGICAL RELEVANCE
Long-term chronic inflammation often leads to chronic diseases. Although Sophora flavescens has been shown to have anti-inflammatory properties, its detailed molecular mechanism is still unknown.
AIM OF STUDY
This study investigated the effect of Radix Sophorae Flavescentis on the LPS-induced inflammatory response in macrophages.
MATERIALS AND METHODS
LPS was used to induce the peritoneal macrophages to simulate the inflammatory environment in vitro. Different concentrations of Radix Sophorae Flavescentis-containing (medicated) serum were used for intervention. The peritoneal macrophages were identified by using hematoxylin-eosin and immunofluorescence staining. ELISA was used to measure the TNF-α and IL-6 expression to determine the concentration of LPS. ELISA and Western blot (WB) were used to detect the PGE2 and CFHR2 expression in each group, respectively. The lentiviral vector for interference and overexpression of the CFHR2 gene was constructed, packaged, and transfected into LPS-induced macrophages. The transfection efficiency was verified by WB. Then, ELISA was used to detect the TNF-α, PGE2, and IL-6 expression. WB was used to detect the CFHR2, iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression.
RESULTS
The primary isolated cells were identified as macrophages. The LPS-treated macrophages exhibited significantly higher expression of PGE2 and CFHR2, and the inflammatory factors TNF-α and IL-6, as well as iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression compared with the control group (P < 0.05). The TNF-α, PGE2, and IL-6 levels, as well as CFHR2, iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression were considerably lower in the LPS-induced+10% medicated-serum group, LPS-induced+20% medicated-serum group, and shCFHR interference group compared with the LPS group (P < 0.05).
CONCLUSION
Radix Sophorae Flavescentis might mediate CFHR2 expression and play an important role in inhibiting the LPS-induced pro-inflammatory response of macrophages. Radix Sophorae Flavescentis could be a potential treatment for LPS-induced related inflammatory diseases.
Topics: Animals; Lipopolysaccharides; Sophora; Anti-Inflammatory Agents; Mice; Macrophages, Peritoneal; Interleukin-6; Tumor Necrosis Factor-alpha; Dinoprostone; Plant Extracts; Inflammation; Toll-Like Receptor 2; Male; STAT1 Transcription Factor; Plant Roots; Cells, Cultured; Macrophages; Toll-Like Receptor 4; Sophora flavescens
PubMed: 38641074
DOI: 10.1016/j.jep.2024.118210 -
Revista Espanola de Enfermedades... Apr 2024A 62-year-old woman, originally from Peru, with rheumatoid arthritis under treatment with anti-tumor necrosis factor (anti-TNF) therapy, was admitted due to...
A 62-year-old woman, originally from Peru, with rheumatoid arthritis under treatment with anti-tumor necrosis factor (anti-TNF) therapy, was admitted due to constitutional syndrome and suspicion of neoplasia. Computed tomography (CT) scan revealed involvement of three segments of the colon, ascites, and likely peritoneal implants. Ascitic fluid analysis showed elevated adenosine deaminase (ADA) levels and lymphocytosis. The patient presented with hematemesis and hematochezia with hemodynamic instability. Upper gastrointestinal endoscopy identified an extensive ulcer in the middle esophagus with a granular base, elevated and defined edges, indeterminate for malignancy and without blood residues. Colonoscopy also revealed multiple extensive ulcers in the transverse colon, with whitish bases and thickened and necrotic-looking surrounding mucosal edges. Histology showed granulomas and yeast-like fungal structures with methenamine silver staining in both tissues, consistent with disseminated histoplasmosis. Antifungal treatment was initiated with good clinical evolution.
PubMed: 38634865
DOI: 10.17235/reed.2024.10432/2024 -
Veterinary Research Apr 2024Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development....
Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING‑deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.
Topics: Animals; Mice; Clostridium Infections; Clostridium perfringens; Interleukin-6; Lipopolysaccharides; TOR Serine-Threonine Kinases; Trained Immunity; Tumor Necrosis Factor-alpha
PubMed: 38622656
DOI: 10.1186/s13567-024-01301-1 -
International Journal of Molecular... Mar 2024KH-type splicing regulatory protein (KSRP) is a single-stranded nucleic acid-binding protein with multiple functions. It is known to bind AU-rich motifs within the...
KH-type splicing regulatory protein (KSRP) is a single-stranded nucleic acid-binding protein with multiple functions. It is known to bind AU-rich motifs within the 3'-untranslated region of mRNA species, which in many cases encode dynamically regulated proteins like cytokines. In the present study, we investigated the role of KSRP for the immunophenotype of macrophages using bone marrow-derived macrophages (BMDM) from wild-type (WT) and KSRP mice. RNA sequencing revealed that KSRP BMDM displayed significantly higher mRNA expression levels of genes involved in inflammatory and immune responses, particularly type I interferon responses, following LPS stimulation. In line, time kinetics studies revealed increased levels of interferon-γ (IFN-γ), interleukin (IL)-1β and IL-6 mRNA in KSRP macrophages after 6 h subsequent to LPS stimulation as compared to WT cultures. At the protein level, KSRP BMDM displayed higher levels of these cytokines after overnight stimulation. Matching results were observed for primary peritoneal macrophages of KSRP mice. These showed higher IL-6, tumor necrosis factor-α (TNF-α), C-X-C motif chemokine 1 (CXCL1) and CC-chemokine ligand 5 (CCL5) protein levels in response to LPS stimulation than the WT controls. As macrophages play a key role in sepsis, the in vivo relevance of KSRP deficiency for cytokine/chemokine production was analyzed in an acute inflammation model. In agreement with our in vitro findings, KSRP-deficient animals showed higher cytokine production upon LPS administration in comparison to WT mice. Taken together, these findings demonstrate that KSRP constitutes an important negative regulator of cytokine expression in macrophages.
Topics: Animals; Mice; Carrier Proteins; Interleukin-6; Lipopolysaccharides; Macrophages; Cytokines; 3' Untranslated Regions
PubMed: 38612694
DOI: 10.3390/ijms25073884 -
International Journal of Molecular... Mar 2024Endometriosis is a complex gynecological disease that affects more than 10% of women in their reproductive years. While surgery can provide temporary relief from women's...
Endometriosis is a complex gynecological disease that affects more than 10% of women in their reproductive years. While surgery can provide temporary relief from women's pain, symptoms often return in as many as 75% of cases within two years. Previous literature has contributed to theories about the development of endometriosis; however, the exact pathogenesis and etiology remain elusive. We conducted a preliminary investigation into the influence of primary endometrial cells (ECs) on the development and progression of endometriosis. In vitro studies, they were involved in inducing Lipopolysaccharide (LPS) in rat-isolated primary endometrial cells, which resulted in increased nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) mRNA gene expression (quantitative polymerase chain reaction analysis, qPCR) and protein expression (western blot analysis). Additionally, in vivo studies utilized autogenic and allogeneic transplantations (rat to rat) to investigate endometriosis-like lesion cyst size, body weight, protein levels (immunohistochemistry), and mRNA gene expression. These studies demonstrated that estrogen upregulates the gene and protein regulation of cytoskeletal (CK)-18, transforming growth factor-β (TGF-β), VEGF, and tumor necrosis factor (TNF)-α, particularly in the peritoneum. These findings may influence cell proliferation, angiogenesis, fibrosis, and inflammation markers. Consequently, this could exacerbate the occurrence and progression of endometriosis.
Topics: Female; Humans; Animals; Rats; Endometriosis; Vascular Endothelial Growth Factor A; Cell Proliferation; Cytoskeleton; RNA, Messenger
PubMed: 38612685
DOI: 10.3390/ijms25073873 -
Frontiers in Immunology 2024Excessive salt intake is a widespread health issue observed in almost every country around the world. A high salt diet (HSD) has a strong correlation with numerous...
Excessive salt intake is a widespread health issue observed in almost every country around the world. A high salt diet (HSD) has a strong correlation with numerous diseases, including hypertension, chronic kidney disease, and autoimmune disorders. However, the mechanisms underlying HSD-promotion of inflammation and exacerbation of these diseases are not fully understood. In this study, we observed that HSD consumption reduced the abundance of the gut microbial metabolite L-fucose, leading to a more substantial inflammatory response in mice. A HSD led to increased peritonitis incidence in mice, as evidenced by the increased accumulation of inflammatory cells and elevated levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein-1 (MCP-1, also known as C-C motif chemokine ligand 2 or CCL2), in peritoneal lavage fluid. Following the administration of broad-spectrum antibiotics, HSD-induced inflammation was abolished, indicating that the proinflammatory effects of HSD were not due to the direct effect of sodium, but rather to HSD-induced alterations in the composition of the gut microbiota. By using untargeted metabolomics techniques, we determined that the levels of the gut microbial metabolite L-fucose were reduced by a HSD. Moreover, the administration of L-fucose or fucoidan, a compound derived from brown that is rich in L-fucose, normalized the level of inflammation in mice following HSD induction. In addition, both L-fucose and fucoidan inhibited LPS-induced macrophage activation . In summary, our research showed that reduced L-fucose levels in the gut contributed to HSD-exacerbated acute inflammation in mice; these results indicate that L-fucose and fucoidan could interfere with HSD-promotion of the inflammatory response.
Topics: Mice; Animals; Sodium Chloride, Dietary; Fucose; Inflammation; Diet; Polysaccharides
PubMed: 38596683
DOI: 10.3389/fimmu.2024.1333848 -
Clinical Case Reports Apr 2024Gallbladder volvulus (GV) is a medical emergency and a rare cause of acute abdominal pain among the pediatric population. GV is more prominent usually in boys in...
Gallbladder volvulus (GV) is a medical emergency and a rare cause of acute abdominal pain among the pediatric population. GV is more prominent usually in boys in pediatric patients. If it is not diagnosed and surgically intervened promptly, GV will become a life-threating condition. Fortunately, a safe and effective laparoscopic cholecystectomy is now widely indicated. A 5 years old female patient with abdominal pain and heavy much vomiting was referred to the emergency room in our hospital. She was suspiciously diagnosed with acute inflammation of the gallbladder according to the results of abdominal ultrasound and computerized tomography (CT) scan already performed on admission. One day after the hospitalization, abdominal ultrasound, and CT scan were performed again because of intensification of her abdominal pain and revealed the clinical portrait of GV such as a "floating gallbladder" sign, an echogenic cone structure, an elongated axis displaced horizontally instead of vertically and a lack of intramural blood flow. The acute GV diagnosis was made and the patient was operated, using the laparoscopic cholecystectomy on time, the gallbladder was tightly twisted clockwise at approximately 720°. The operation and postoperative treatment went quite well and the patient was discharged from the hospital on postoperative Day 7. GV is very rare in children, easily omitted or misdiagnosed with cholecystitis. Imaging diagnosis such as ultrasound, CT with contrast helps make diagnosis promptly that avoids severe complications such as gallbladder perforation, necrosis, and biliary peritonitis.
PubMed: 38590331
DOI: 10.1002/ccr3.8743 -
Cureus Feb 2024An alarming number of zinc oxide nanoparticles (ZnO-NPs) have leaked into the environment, endangering the tissues of many living creatures, due to the recent surge in...
BACKGROUND
An alarming number of zinc oxide nanoparticles (ZnO-NPs) have leaked into the environment, endangering the tissues of many living creatures, due to the recent surge in their use in several items. Through intra-peritoneal injection, this research intends to examine the impact of ZnO-NPs on the hepatic and gastrointestinal structures of male albino mice.
METHOD
For seven and 14 days, animals were given 0.1 ml of 100 and 200 mg kg-1 of 50 nm-size ZnO-NPs, respectively. In contrast, those in the control group were given only water and food.
RESULT
The results demonstrated that the treated mice's livers underwent functional changes and histological damage. After seven and 14 days, there was a notable rise in the average levels of the glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase enzymes in comparison to the control group (p≤0.05). Concentration time determines the magnitude of this impact. When enzyme levels vary, it means the liver isn't working properly. Histological changes in the liver, such as necrosis, destruction of hepatocyte membranes, widening of sinusoidal spaces and vacuolation of their cytoplasm, vascular congestion, and an increased number of Kupffer cells, were induced in mice treated with ZnO-NPs at two studied concentrations (100 and 200 mg/kg) for seven and 14 days, respectively. These effects were time-dose-dependent, according to the results of hematoxylin-eosin staining of liver tissue images.
PubMed: 38529423
DOI: 10.7759/cureus.54822 -
PloS One 2024Stroke is a leading cause of death and long-term disability which can cause oxidative damage and inflammation of the neuronal cells. Retinoic acid is an active...
Stroke is a leading cause of death and long-term disability which can cause oxidative damage and inflammation of the neuronal cells. Retinoic acid is an active metabolite of vitamin A that has various beneficial effects including antioxidant and anti-inflammatory effects. In this study, we investigated whether retinoic acid modulates oxidative stress and inflammatory factors in a stroke animal model. A middle cerebral artery occlusion (MCAO) was performed on adult male rats to induce focal cerebral ischemia. Retinoic acid (5 mg/kg) or vehicle was injected into the peritoneal cavity for four days before MCAO surgery. The neurobehavioral tests were carried out 24 h after MCAO and cerebral cortex tissues were collected. The cortical damage was assessed by hematoxylin-eosin staining and reactive oxygen species assay. In addition, Western blot and immunohistochemical staining were performed to investigate the activation of glial cells and inflammatory cytokines in MCAO animals. Ionized calcium-binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) were used as markers of microglial and astrocyte activation, respectively. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were used as representative pro-inflammatory cytokines. Results showed that MCAO damage caused neurobehavioral defects and histopathological changes in the ischemic region and increased oxidative stress. Retinoic acid treatment reduced these changes caused by MCAO damage. We detected increases in Iba-1 and GFAP in MCAO animals treated with vehicle. However, retinoic acid alleviated increases in Iba-1 and GFAP caused by MCAO damage. Moreover, MCAO increased levels of nuclear factor-κB and pro-inflammatory cytokines, including TNF-α and IL-1β. Retinoic acid alleviated the expression of these inflammatory proteins. These findings elucidate that retinoic acid regulates microglia and astrocyte activation and modulates pro-inflammatory cytokines. Therefore, this study suggests that retinoic acid exhibits strong antioxidant and anti-inflammatory properties by reducing oxidative stress, inhibiting neuroglia cell activation, and preventing the increase of pro-inflammatory cytokines in a cerebral ischemia.
Topics: Rats; Male; Animals; Tumor Necrosis Factor-alpha; Tretinoin; Antioxidants; Stroke; Brain Ischemia; Neuroglia; Cytokines; Anti-Inflammatory Agents; Infarction, Middle Cerebral Artery; Neuroprotective Agents
PubMed: 38527023
DOI: 10.1371/journal.pone.0300072 -
EClinicalMedicine Apr 2024Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations...
Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial.
BACKGROUND
Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries.
METHODS
We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381).
FINDINGS
Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms.
INTERPRETATION
Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients.
FUNDING
Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.
PubMed: 38516100
DOI: 10.1016/j.eclinm.2024.102517