Chimeric Small Molecules for Detouring Drugs into Mitochondria to Engender Apoptosis in Cancer Cells.

Mitochondrion has appeared as one of the important targets for anti-cancer therapy. Subsequently, small molecule anti-cancer drugs are directed to the mitochondria for improved therapeutic efficacy. However, simultaneous imaging and impairing mitochondria by a single probe remained a major challenge. To address this, herein Chimeric Small Molecules (CSMs) encompassing drugs, fluorophore and mitochondria homing moiety were designed and synthesized through a concise strategy. Screening of the CSMs in a panel of cancer cell lines (HeLa, MCF7, A549, and HCT-116) revealed that one of the CSMs comprising Indomethacin V exhibited remarkable cervical cancer cell (HeLa) killing (IC50 =0.97 µM). This lead CSM homed into the mitochondria of HeLa cells within 1 h followed by mitochondrial damage and reactive oxygen species (ROS) generation. This novel Indomethacin V-based CSM-mediated mitochondrial damage induced programmed cell death (apoptosis). We anticipate these CSMs can be used as tools to understand the drug effects in organelle chemical biology in diseased states.

Cyclooxygenase production of PGE2 promotes phagocyte control of A. fumigatus hyphal growth in larval zebrafish.

Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Increased germination and invasive hyphal growth is also observed in infected F0 crispant larvae with mutations in genes encoding for COX enzymes (ptgs2a/b). Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae.

Mycobacterium marinum mediates regulation of prostaglandin E2 expression on host immune response through cyclooxygenase pathway.

PURPOSE: Investigate the role of COX signaling in activating the PGE2-EP2 pathway. METHODS: Utilized a marine Mycobacterium infection model in zebrafish. Marine mycobacteria were stained with fluorescein isothiocyanate. The COX inhibitor indomethacin, EP2 receptor inhibitor AH6809, EP4 receptor inhibitor AH23848 and clodronate Liposomes were used to investigate the role of COX, EP2, EP4 and macrophage whether participating in combat marine mycobacterial infection. The expression level of the target gene was detected using real-time fluorescence quantitative PCR instrument. RESULTS: The findings revealed that larvae exposed to the COX inhibitor indomethacin or the EP2 receptor inhibitor AH6809 demonstrated a significantly higher mortality rate due to marine mycobacterium infection than those in the control group. Administration of exogenous prostaglandin E2 (PGE2) rescued the survival of zebrafish infected with marine mycobacteria and treated with indomethacin. Additionally, a significant reduction in survival rate was noted in macrophage-depleted zebrafish infected with marine mycobacteria. CONCLUSION: The host may combat marine mycobacterium infection via COX signaling, which activates the PGE2-EP2 pathway and mediates macrophage resistance.

Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and positively influences pain sensitivity and work capacity.

The aim of the study was to investigate the effects of rat housing conditions-standard conditions, social isolation, environmental enrichment-and the subsequent reversal of these conditions on the vulnerability of the gastric mucosa to ulcerogenic stimuli, somatic pain sensitivity, and treadmill work capacity. Rats, aged 30 days, were placed in standard conditions (SC), social isolation (Is), and environmental enrichment (EE) for 4 weeks. Then half of each group underwent a reversal of housing conditions: SC rats were moved to Is, Is rats were placed in EE, EE rats were moved to Is, for 2 weeks. The other half served as a control with no change in their initial housing. Two weeks after the reversal, vulnerability of the gastric mucosa to ulcerogenic action of indomethacin (IM, 35 mg/kg, sc), somatic pain sensitivity (hot plate test), and work capacity (measured by the running distance on a treadmill) were assessed in control and reversed groups. Social isolation induced a proulcerogenic effect, increasing IM-induced gastric erosions, which was effectively reversed when rats were transferred to an environmental enrichment. Conversely, transferring rats from an environmental enrichment to social isolation exacerbated ulcerogenic action of IM. Somatic pain sensitivity and treadmill work capacity were also influenced by housing conditions, with environmental enrichment showing positive effects. The present findings show that social isolation of rats induces a proulcerogenic effect. Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and increases resilience to pain stimuli and treadmill work capacity.

Endosomal TLR3 signaling in stromal osteoblasts induces prostaglandin E2-mediated inflammatory periodontal bone resorption.

Toll-like receptors (TLRs) are pattern recognition receptors that play a critical role in innate immune diseases. TLR3, which is localized in the endosomal compartments of hematopoietic immune cells, is able to recognize double-stranded RNA (dsRNA) derived from viruses and bacteria and thereby induce innate immune responses. Inflammatory periodontal bone resorption is caused by bacterial infections, which initially is regulated by innate immunity; however, the roles of TLR3 signaling in bone resorption are still not known. We examined the roles of TLR3 signaling in bone resorption using poly(I:C), a synthetic dsRNA analog. In cocultures of mouse bone marrow cells and stromal osteoblasts, poly(I:C) clearly induced osteoclast differentiation. In osteoblasts, poly(I:C) increased PGE2 production and upregulated the mRNA expression of PGE2-related genes, Ptgs2 and Ptges, as well as that of a gene related to osteoclast differentiation, Tnfsf11. In addition, we found that indomethacin (a COX-2 inhibitor) or an antagonist of the PGE2 receptor EP4 attenuated the poly(I:C)-induced PGE2 production and subsequent Tnfsf11 expression. Poly(I:C) also prolonged the survival of the mature osteoclasts associated with the increased mRNA expression of osteoclast marker genes, Nfatc1 and Ctsk. In ex vivo organ cultures of periodontal alveolar bone, poly(I:C) induced bone-resorbing activity in a dose-dependent manner, which was attenuated by the simultaneous administration of either indomethacin or an EP4 antagonist. These data suggest that TLR3 signaling in osteoblasts controls PGE2 production and induces the subsequent differentiation and survival of mature osteoclasts. Endogenous TLR3 in stromal osteoblasts and osteoclasts synergistically induces inflammatory alveolar bone resorption in periodontitis.

The ratio of M1 to M2 microglia in the striatum determines the severity of L-Dopa-induced dyskinesias.

L-Dopa, while treating motor symptoms of Parkinson's disease, can lead to debilitating L-Dopa-induced dyskinesias, limiting its use. To investigate the causative relationship between neuro-inflammation and dyskinesias, we assessed if striatal M1 and M2 microglia numbers correlated with dyskinesia severity and whether the anti-inflammatories, minocycline and indomethacin, reverse these numbers and mitigate against dyskinesia. In 6-OHDA lesioned mice, we used stereology to assess numbers of striatal M1 and M2 microglia populations in non-lesioned (naïve) and lesioned mice that either received no L-Dopa (PD), remained non-dyskinetic even after L-Dopa (non-LID) or became dyskinetic after L-Dopa treatment (LID). We also assessed the effect of minocycline/indomethacin treatment on striatal M1 and M2 microglia and its anti-dyskinetic potential via AIMs scoring. We report that L-Dopa treatment leading to LIDs exacerbates activated microglia numbers beyond that associated with the PD state; the severity of LIDs is strongly correlated to the ratio of the striatal M1 to M2 microglial numbers; in non-dyskinetic mice, there is no M1/M2 microglia ratio increase above that seen in PD mice; and reducing M1/M2 microglia ratio using anti-inflammatories is anti-dyskinetic. Parkinson's disease is associated with increased inflammation, but this is insufficient to underpin dyskinesia. Given that L-Dopa-treated non-LID mice show the same ratio of M1/M2 microglia as PD mice that received no L-Dopa, and, given minocycline/indomethacin reduces both the ratio of M1/M2 microglia and dyskinesia severity, our data suggest the increased microglial M1/M2 ratio that occurs following L-Dopa treatment is a contributing cause of dyskinesias.

Association between serum prostacyclin and cerebrovascular reactivity in healthy young and older adults.

NEW FINDINGS: What is the central question of this study? What is the relationship between prostacyclin and cerebrovascular reactivity to hypercapnia before and after administration of a cyclooxygenase inhibitor, indomethacin, in healthy young and older adults? What is the main finding and importance? Serum prostacyclin was not related to cerebrovascular reactivity to hypercapnia before or after administration of indomethacin. However, in older adults, serum prostacyclin was related to the magnitude of change in cerebrovascular reactivity from before to after indomethacin administration. This suggests that older adults with higher serum prostacyclin may rely more on cyclooxygenase products to mediate cerebrovascular reactivity. ABSTRACT: Platelet activation may contribute to age-related cerebrovascular dysfunction by interacting with the endothelial cells that regulate the response to vasodilatory stimuli. This study evaluated the relationship between a platelet inhibitor, prostacyclin, and cerebrovascular reactivity (CVR) in healthy young (n = 35; 25 ± 4 years; 17 women, 18 men) and older (n = 12; 62 ± 2 years; 8 women, 4 men) adults, who were not daily aspirin users, before and after cyclooxygenase inhibition. Prostacyclin was determined by levels of 6-keto-prostaglandin F1α (6-keto PGF1α) in the blood. CVR was assessed by measuring the middle cerebral artery blood velocity response to hypercapnia using transcranial Doppler ultrasound before (CON) and 90 min after cyclooxygenase inhibition with indomethacin (INDO). In young adults, there were no associations between prostacyclin and middle cerebral artery CVR during CON (r = -0.14, P = 0.415) or INDO (r = 0.27, P = 0.118). In older adults, associations between prostacyclin and middle cerebral artery CVR during CON (r = 0.53, P = 0.075) or INDO (r = -0.45, P = 0.136) did not reach the threshold for significance. We also evaluated the relationship between prostacyclin and the change in CVR between conditions (ΔCVR). We found no association between ΔCVR and prostacyclin in young adults (r = 0.27, P = 0.110); however, in older adults, those with higher baseline prostacyclin levels demonstrated significantly greater ΔCVR (r = -0.74, P = 0.005). In conclusion, older adults with higher serum prostacyclin, a platelet inhibitor, may rely more on cyclooxygenase products for cerebrovascular reactivity to hypercapnia.

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4.

Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.

Dark-purple rice extract modulates gut microbiota composition in acetic acid- and indomethacin-induced inflammatory bowel disease in rats.

Ulcerative colitis (UC) and Crohn's disease (CD) are two major forms of inflammatory bowel disease (IBD). The disease has been linked with gut microbiota dysbiosis in which the balance of commensal communities is disrupted. Accumulating evidence demonstrates that treatment with biologically active compounds can modulate gut microbiota composition in animal models. Our previous work has also shown the beneficial effect of Luem Pua (LP) rice extract, which is rich in anthocyanins, on inflammation. However, its effect on gut microbiota is yet to be explored. In this study, we profiled fecal microbiota of acetic acid (AA)-induced UC and indomethacin (ID)-induced CD rat models with and without pretreatment with LP rice extract by 16S rRNA gene sequencing. The results showed that gut microbiota communities of rats were altered by both AA-induced UC and ID-induced CD. The relative abundances of beneficial bacteria, especially the Lachnospiraceae NK4A136 group and Lactobacillus, were decreased in the AA-induced UC model, while some opportunistic pathogens (Bacteroides, Escherichia/Shigella, Fusobacterium, and Veillonella) were raised by ID-induced CD. Interestingly, pretreatment with LP rice extract before AA-inducing UC in rats increased the proportion of the butyrate-producing bacteria (Lachnospiraceae NK4A136 group). The abundances of these beneficial bacteria and other SCFA-producing bacteria were unaffected by the indomethacin treatment with LP. Overall, our study revealed different impacts of AA-induced UC and ID-induced CD on changes in community composition and hinted at how LP may protect against UC by modifying the gut microbiota.

TXA2 mediates LPA1-stimulated uterine contraction in late pregnant mouse.

Lysophosphatidic acid (LPA) is known to increase uterine contraction in the estrus cycle and early pregnancy, however, the effect of LPA in late pregnant uterus and its mechanisms are not clear. In the present study, we show the LPA receptor subtypes expressed and the mechanism of LPA-induced contractions in late pregnant mouse uterus. We determined the relative mRNA expression of LPA receptor genes by quantitative PCR and elicited log concentration-response curves to oleoyl-L-α-LPA by performing tension experiments in the presence and absence of nonselective and selective receptor antagonists and inhibitors of the TXA2 pathway. LPA1 was the most highly expressed receptor subtype in the late pregnant mouse uterus and LPA1/2/3 agonist (Oleoyl-L-α LPA) elicited increased contractions in this tissue that had lesser efficacy compared to oxytocin. LPA1/3 antagonist, Ki-16425, and a potent LPA1 antagonist (AM-095) significantly inhibited the LPA-induced contractions. Further, the nonselective COX inhibitor, indomethacin, and potent thromboxane A2 synthase inhibitor, furegrelate significantly impaired LPA-induced contractions. Moreover, selective thromboxane receptor (TP) antagonist, SQ-29548, and Rho kinase inhibitor, Y-27632 almost eliminated LPA-induced uterine contractions. LPA1 stimulation elicits contractions in the late pregnant mouse uterus using the contractile prostanoid, TXA2 and may be targeted to induce labor in uterine dysfunctions/ dystocia.

Elabela relaxes rat pulmonary artery and trachea via BKCa, KV, and KATP channels.

OBJECTIVE: Elabela is a newly discovered peptide hormone. This study aimed to determine the functional effects and mechanisms of action of elabela in rat pulmonary artery and trachea. MATERIALS AND METHODS: Vascular rings isolated from the pulmonary arteries of male Wistar Albino rats were placed in chambers in the isolated tissue bath system. The resting tension was set to 1 g. After the equilibration period, the pulmonary artery rings were contracted with 10-6 M phenylephrine. Once a stable contraction was achieved, elabela was applied cumulatively (10-10-10-6 M) to the vascular rings. To determine the vasoactive effect mechanisms of elabela, the specified experimental protocol was repeated after the incubation of signaling pathway inhibitors and potassium channel blockers. The effect and mechanisms of action of elabela on tracheal smooth muscle were also determined by a similar protocol. RESULTS: Elabela exhibited a concentration-dependent relaxation in the precontracted rat pulmonary artery rings (p < .001). Maximal relaxation level was 83% (pEC50: 7.947 CI95(7.824-8.069)). Removal of the endothelium, indomethacin incubation, and dideoxyadenosine incubation significantly decreased the vasorelaxant effect levels of elabela (p < .001). Elabela-induced vasorelaxation levels were significantly reduced after iberiotoxin, glyburide, and 4-Aminopyridine administrations (p < .001). L-NAME, methylene blue, apamin, TRAM-34, anandamide, and BaCl2 administrations did not cause a significant change in the vasorelaxant effect level of elabela (p = 1.000). Elabela showed a relaxing effect on precontracted tracheal rings (p < .001). Maximal relaxation level was 73% (pEC50: 6.978 CI95(6.791-7.153)). The relaxant effect of elabela on tracheal smooth muscle was decreased significantly after indomethacin, dideoxyadenosine, iberiotoxin, glyburide, and 4-Aminopyridine incubations (p < .001). CONCLUSIONS: Elabela exerted a prominent relaxant effect in the rat pulmonary artery and trachea. Intact endothelium, prostaglandins, cAMP signaling pathway, and potassium channels (BKCa, KV, and KATP channels) are involved in the vasorelaxant effect of elabela. Prostaglandins, cAMP signaling pathway, BKCa channels, KV channels, and KATP channels also contribute to elabela-induced tracheal smooth muscle relaxant effect.

Antiulcer mechanisms of the hydroalcoholic extract from Aztec marigolds' medicinal and edible flowers (Tagetes erecta L.).

The antiulcer mechanisms of the dry extract of T. erecta flowers (DETe) were studied here. The acute ulcers induced by acidified ethanol or indomethacin were reproduced in mice pretreated with DETe (3 - 300 mg/kg). The antiulcer activity of DETe was also verified in mice pretreated with NEM, L-NAME, indomethacin, or yohimbine. The antisecretory effect of DETe was verified in rats, and its anti-Helicobacter pylori activity was determined in vitro. DETe (300 mg/kg, p.o) reduced the ethanol- or indomethacin-induced ulcer by 49 and 93%, respectively. The pre-treatment with L-NAME, NEM or yohimbine abolished the gastroprotective effect of DETe. However, DETe did not change the volume, acidity, or peptic activity in rats and did not affect H. pylori. This study expands knowledge about the antiulcerogenic potential of DETe, evidencing the role of nitric oxide, non-protein sulfhydryl groups, α2 adrenergic receptors, and prostaglandins, but not antisecretory or anti-H. pylori properties.

Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice.

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB1Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB1R knockout (CB1R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-ß) were performed. Conjugated E2 levels were higher in CB1R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB1R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB1R KO. Effects of indomethacin on E2-relaxation in CB1R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-ß density in CB1R KO than in WT mice. CB1R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB1Rs may have beneficial vascular effects.

Exploring the Effect of Deep-Sea Water on the Therapeutic Potential of the Anti-Inflammatory Response in an Indomethacin-Induced Gastric Ulcer Rat Model.

Gastric ulcers are often exacerbated by factors such as nonsteroidal anti-inflammatory drugs (NSAIDs) and inflammation, and they have a substantial impact on a significant portion of the population. Notably, indomethacin is recognized as a prominent contributor to ulcers. This study investigated this potential method, with normalization to the anti-inflammatory and antiulcer properties of deep-sea water (DSW)-derived mineral water, using an indomethacin-induced gastric ulcer model in rats. The study involved four groups (n = 6 rats/group): normal control group (CON), indomethacin-only group (IND), indomethacin with trace mineral water group (TM), and indomethacin with high magnesium low sodium water group (HMLS). For three weeks, the CON and IND groups consumed tap water, while the TM and HMLS groups had access to mineral water. Gastric ulcers were induced on the final day using indomethacin, for all groups except the CON group. The results demonstrated that HMLS intake significantly improved gastric mucosal damage, preserved mucin stability, and increased gastric thickness, indicating its potential to prevent and alleviate indomethacin-induced gastric ulcers. Furthermore, HMLS consumption led to the upregulation of key genes associated with inflammation and a reduction in inflammatory cytokines. These findings suggest that DSW-derived mineral water, and particularly its high Mg2+ content, may offer promising health benefits including anti-inflammatory and anti-ulcer properties.

Gintonin Alleviates HCl/Ethanol- and Indomethacin-Induced Gastric Ulcers in Mice.

Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in vivo preventive effects of gintonin on gastric damage. ICR mice were randomly assigned to five groups: a normal group (received saline, 0.1 mL/10 g, p.o.); a control group (administered 0.3 M HCl/ethanol, 0.1 mL/10 g, p.o.) or indomethacin (30 mg/kg, p.o.); gintonin at two different doses (50 mg/kg or 100 mg/kg, p.o.) with either 0.3 M HCl/ethanol or indomethacin; and a positive control (Ranitidine, 40 mg/kg, p.o.). After gastric ulcer induction, the gastric tissue was examined to calculate the ulcer index. The expression of gastric damage markers, such as tumor necrosis factor (TNF)-α, cyclooxygenase 2 (COX-2), and LPA2 and LPA5 receptors, were measured by Western blotting. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay. The platelet endothelial cell adhesion molecule (PECAM-1), Evans blue, and occludin levels in gastric tissues were measured using immunofluorescence analysis. Both HCl/ethanol- and indomethacin-induced gastric ulcers showed increased TNF-α, IL-6, Evans blue permeation, and PECAM-1, and decreased COX-2, PGE2, occludin, and LPA5 receptor expression levels. However, oral administration of gintonin alleviated the gastric ulcer index induced by HCl/ethanol and indomethacin in a dose-dependent manner. Gintonin suppressed TNF-α and IL-6 expression, but increased COX-2 expression and PGE2 levels in mouse gastric tissues. Gintonin intake also increased LPA5 receptor expression in mouse gastric tissues. These results indicate that gintonin can play a role in gastric protection against gastric damage induced by HCl/ethanol or indomethacin.

Potential effects of carbon monoxide donor and its nanoparticles on experimentally induced gastric ulcer in rats.

The prevalence of gastric ulcers is increasing worldwide, especially those brought on by non-steroidal anti-inflammatory drugs (NSAIDS), so prevention is extremely crucial. The protective potential of carbon monoxide (CO) in several inflammatory disorders has been clarified. The goal of the current study was to investigate the gastroprotective effect of CO produced by its pharmacological donor (CORM2) and its nanoparticles (NPs) against indomethacin (INDO)-induced ulcers. Investigations on CORM2's dose-dependent effects were also conducted. For induction of gastric ulcer, 100 mg kg-1 of INDO was given orally. Before ulcer induction, CORM2 (5, 10, and 15 mg kg-1), CORM2 nanoparticles (5 mg kg-1), or ranitidine (30 mg kg-1) were given intraperitoneally for 7 days. Ulcer score, gastric acidity, gastric contents of malondialdehyde (MDA), nitric oxide (NO), heme oxygenase-1 (HO-1), and carboxyhemoglobin (COHb) blood content were estimated. Additionally, gene expression of nuclear factor erythroid 2-related factor 2 (NRF2) and immunohistochemical staining of cyclooxygenase-1 (COX-1) as well as cyclooxygenase-2 (COX-2) were analyzed. Results demonstrated a substantial dose-dependent decrease in ulcer score, pro-inflammatory indicators, and oxidative stress markers with CORM2 and its NPs. Furthermore, CORM2 and its NPs markedly increased NRF2, COX-1, and HO-1, but CORM2 NPs outperformed CORM2 in this regard. In conclusion, the CO released by CORM2 can protect against INDO-induced gastric ulcers dose dependently, and the highest used dose had no effect on COHb concentration.

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Anti-Inflammatory Effect of Technologically Processed Antibodies to the Molecules of the Major Histocompatibility Complex in a Model of Acute Inflammation In Vivo.

The anti-inflammatory effect of technologically processed antibodies (TPA) to immune targets (MHC I and MHC II) was assessed in the carrageenan-induced rat paw edema model. The parameters "increase in edema" and "suppression of edema" significantly decreased (p<0.05) against the background of treatment with TPA and the reference drug indomethacin compared to the placebo group. The tested TPA produced an anti-inflammatory effect.

Sex differences in rat renal arterial responses following exercise training.

During aerobic exercise, hemodynamic alterations occur. Although blood flow in skeletal muscle arteries increases, it decreases in visceral vessels because of mesenterial vasoconstriction. However, maintaining renal blood flow during intensive sport is also a priority. Our aim was to investigate the changes of vascular reactivity and histology of isolated renal artery of male and female rats in response to swim training. Wistar rats were distributed into four groups: male sedentary (MSed), male trained (MTr), female sedentary (FSed), and female trained (FTr). Trained animals underwent a 12-wk-long intensive swimming program. Vascular function of isolated renal artery segments was examined by wire myography. Phenylephrine-induced contraction was lower in FSed than in MSed animals, and it was decreased by training in male but not in female animals. Inhibition of cyclooxygenases by indomethacin reduced contraction in both sedentary groups, and in MTr but not in FTr animals. Inhibition of nitric oxide production increased contraction in both trained groups. Acetylcholine induced relaxation was similar in all experimental groups showing predominant NO-dependency. Elastin and smooth muscle cell actin density was reduced in female rats after aerobic training. This study shows that, as a result of a 12-wk-long training, there are sex differences in renal arterial responses following exercise training. Swimming moderates renal artery vasoconstriction in male animals, whereas it depresses elastic fiber and smooth muscle actin density in females.NEW & NOTEWORTHY We provided the first detailed analysis of the adaptation of the renal artery after aerobic training in male and female rats. As a result of a 12-wk-long training program, the pharmacological responses of renal arteries changed only in male animals. In phenylephrine-induced contraction, cyclooxygenase-mediated vasoconstriction mechanisms lost their significance in female rats, whereas NO-dependent relaxation became a significant contraction reducing factor in both sexes. Early structural changes, such as reduced elastin and smooth muscle cell actin evolves in females.

Indomethacin has no effect on trigeminally provoked parasympathetic output.

BACKGROUND: Unlike other non-steroidal anti-inflammatory drugs, indomethacin has been shown to be highly effective in two forms of trigeminal autonomic cephalalgias, hemicrania continua and paroxysmal hemicrania and in some forms of idiopathic stabbing headaches. This specificity is unique in the headache field. Previous findings suggest the involvement of the trigeminal autonomic reflex to play an important role in the pathophysiology of these diseases. METHODS: 22 healthy participants were enrolled in a double-blind, three-day within-subject design. The participants received indomethacin, ibuprofen or placebo in a randomized order. After an incubation period of 65 min the baseline lacrimation and the lacrimation during intranasal stimulation evoked by kinetic oscillation stimulation were assessed using Schirmer II lacrimation tests. The lacrimation difference in mm was calculated and compared in a repeated measures ANOVA. RESULTS: No significant differences were found between the three conditions. CONCLUSION: In our study, neither indomethacin nor ibuprofen had an inhibitory effect on the trigeminal autonomic reflex. We suggest that blocking this reflex may not be the treatment mechanism of indomethacin.