Repeated doses of captopril induce airway hyperresponsiveness by modulating the TRPV1 receptor in rats.

Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways.

Pharmacological potential of alkylamides from Acmella oleracea flowers and synthetic isobutylalkyl amide to treat inflammatory pain.

Acmella oleracea ("jambu") is an Amazonian plant rich in alkylamides. Its flowers are widely used in folk medicine to treat toothache due to tingling, numbness, and local anaesthesia caused in the mouth. Our group previously demonstrated that the intraplantar (i.pl.) injection of an alkylamide-rich hexane fraction (HF) obtained from jambu flowers and a synthetic isobutylalkyl amide (IBA) displayed antinociceptive and anesthetic effects in acute pain models. Thus, here we evaluated the effects of HF and IBA on carrageenan-induced acute inflammation. Mice were pretreated with HF or IBA (0.01, 0.1, and 1 µg/20 µL, i.pl.) 15 min before carrageenan injection (300 µg/20 µL, i.pl.). Mechanical allodynia and paw oedema were evaluated previously (basal) and at 0.5 until 6 h following carrageenan. Both HF and IBA at 0.1 µg promoted effective and long-lasting antiallodynic and anti-oedematogenic activities until 3 and 5 h, respectively, in comparison to the different doses evaluated. At the inflammatory peak, the plantar surfaces were excised for measurement of inflammatory and oxidative stress parameters. HF and IBA (0.1 µg) reduced the myeloperoxidase activity, TNF-α and IL-1ß levels, prevented the production of lipid hydroperoxides, and the decrease of antioxidant agents, namely superoxide dismutase and catalase activities, and glutathione contents. Furthermore, only HF maintained IL-10 levels and decreased PGE2 synthesis. On the basis of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, HF and IBA are devoid of antioxidant activity in vitro. Collectively, our results demonstrated the promising anti-inflammatory effect of local pretreatment with alkylamides, supporting the potential of these molecules to treat acute inflammatory pain conditions.

Effect of simvastatin on sensorial, motor, and morphological parameters in sciatic nerve crush induced-neuropathic pain in rats.

The present study compares the effects of a low and high doses of simvastatin in a model of peripheral neuropathy by evaluating sensorial, motor, and morphological parameters. First, male Wistar rats were orally treated with vehicle (saline, 1 mL/kg), simvastatin (2 and 80 mg/kg) or morphine (2 mg/kg, s.c.), 1 h before 2.5% formalin injection. Neuropathic pain was induced by crushing the sciatic nerve, and mechanical and cold allodynia, nerve function, histology, MPO and NAG concentrations, as well as mevalonate induced-nociception were evaluated. Animals were orally treated with vehicle, simvastatin, or gabapentin (30 mg/kg) for 18 days. Simvastatin (2 and 80 mg/kg) reduced the inflammatory pain induced by formalin, but failed to decrease the paw edema. Mechanical allodynia was reduced by the simvastatin (2 mg/kg) until the 12th day after injury and until the 18th day by gabapentin. However, both simvastatin and gabapentin treatments failed in attenuated cold allodynia or improved motor function. Interestingly, both doses of simvastatin showed a neuroprotective effect and inhibited MPO activity without altering kidney and hepatic parameters. Additionally, only the higher dose of simvastatin reduced the cholesterol levels and the nociception induced by mevalonate. Our results reinforce the antinociceptive, antiallodynic, and anti-inflammatory effects of oral simvastatin administration, which can strongly contribute to the sciatic nerve morphology preservation. Furthermore, our data suggest that lower and higher doses of simvastatin present beneficial effects that are dependent and independent of the mevalonate pathway, respectively, without causing signs of nerve damage.

Acid-gastric antisecretory effect of the ethanolic extract from Arctium lappa L. root: role of H+, K+-ATPase, Ca2+ influx and the cholinergic pathway.

BACKGROUND: Arctium lappa L., popularly known as burdock, is a medicinal plant used worldwide. The antiulcer and gastric-acid antisecretory effects of ethanolic extract from roots of Arctium lappa (EET) were already demonstrated. However, the mechanism by which the extract reduces the gastric acid secretion remains unclear. Therefore, this study was designed to evaluate the antisecretory mode of action of EET. MATERIALS AND METHODS: The effects of EET on H+, K+-ATPase activity were verified in vitro, whereas the effects of the extract on cholinergic-, histaminergic- or gastrinergic-acid gastric stimulation were assessed in vivo on stimulated pylorus ligated rats. Moreover, ex vivo contractility studies on gastric muscle strips from rats were also employed. RESULTS: The incubation with EET (1000 µg/ml) partially inhibited H+, K+-ATPase activity, and the intraduodenal administration of EET (10 mg/kg) decreased the volume and acidity of gastric secretion stimulated by bethanechol, histamine, and pentagastrin. EET (100-1000 µg/ml) did not alter the gastric relaxation induced by histamine but decreased acetylcholine-induced contraction in gastric fundus strips. Interestingly, EET also reduced the increase in the gastric muscle tone induced by 40 mM KCl depolarizing solution, as well as the maximum contractile responses evoked by CaCl2 in Ca2+-free depolarizing solution, without impairing the effect of acetylcholine on fundus strips maintained in Ca2+ -free nutritive solution. CONCLUSION: Our results reinforce the gastric antisecretory properties of preparations obtained from Arctium lappa, and indicate that the mechanisms involved in EET antisecretory effects include a moderate reduction of the H+, K+-ATPase activity associated with inhibitory effects on calcium influx and of cholinergic pathways in the stomach muscle.

Vitamin C Improves Gastroparesis in Diabetic Rats: Effects on Gastric Contractile Responses and Oxidative Stress.

BACKGROUND: Diabetic gastroparesis is a common complication of diabetes mellitus, which mainly affects women. Previous studies have demonstrated that oxidative stress is involved in its onset and development. AIMS: This study evaluated the role of vitamin C on diabetes-associated gastric dysmotility. METHODS: Female rats with streptozotocin-induced diabetes were treated with vehicle (water, 1 mL/kg, p.o.), vitamin C (300 mg/kg/day, p.o.), or insulin (6 IU/day, s.c.). Gastric emptying, in vitro gastric contractility, and biochemistry parameters were analyzed at the end of the treatment (i.e. 8 weeks after the diabetes induction). RESULTS: Vitamin C reversed the delayed gastric emptying of diabetic rats to normal levels, and avoided the changes in the contractile responses to acetylcholine (0.1 nM-1 µM), but not to 5-hydroxytryptamine (0.1 nM-1 µM), in the pylorus and fundus from diabetic rats. Moreover, the contraction evoked by KCl (40 mM) in the fundus, but not in the pylorus, was intensely increased in diabetic rats treated with vitamin C. Notably, the vitamin C reestablished the reduced glutathione levels by 77% and decreased the reactive oxygen species content by 60% in the gastric tissue from diabetic rats. Despite the effects on gastric motility, vitamin C treatment did not change the fasting glycaemia or the glycated hemoglobin of diabetic rats. Unsurprisingly, insulin treatment normalized all parameters evaluated. CONCLUSIONS: Vitamin C exhibited a remarkable beneficial effect on gastric emptying dysfunction in diabetic rats, which was mediated by attenuation of oxidative stress and maintenance of the cholinergic contractile responses in fundus and pylorus.

Anti-inflammatory effect of laser acupuncture in ST36 (Zusanli) acupoint in mouse paw edema.

Low-level laser therapy (LLLT) in acupuncture is a low-power laser applied to acupoints for providing luminous energy, capable to produce photobiological induction that results in biochemical, bioelectric, and bioenergetic effects. ST36 (Zusanli) is a point of acupuncture commonly used for treatment of several pathological alterations, such as inflammation, acute pain, and gastrointestinal disorders. In this study, we evaluated the anti-inflammatory effect of LLLT (830 nm, 4 J/cm(2)) in ST36 acupoint through the model of carrageenan-induced paw edema in mice and the possible mechanisms involved. Female Swiss mice were treated with LLLT in ST36 before the paw edema induction, which was measured by means of a digital micrometer and the temperature through a high-resolution digital thermograph. After this, the levels of reactive oxygen species (ROS), lipid hydroperoxides (LOOH), and reduced glutathione (GSH) were quantified. In another set of experiments, the paw edema was induced by bradykinin, histamine, and prostaglandin E2 (PGE2). LLLT in ST36 acupoint significantly inhibited the edema formation for 4 h after the carrageenan injection and reduced the paw temperature in 10 %. Furthermore, LLLT also reduced the levels of ROS (55 %) and LOOH (50 %) but, however, did not alter the GSH levels. LLLT in ST36 reduced the paw edema induced by bradykinin (30 min, 6 %, 60 min, 7 %), histamine (30 min, 11 %), and PGE2 (90 min, 10 %, 120 min, 16 %). In conclusion, these results prove that LLLT in ST36 acupoint produces a relevant anti-inflammatory effect, reducing edema, temperature, and free radicals levels in mice paw.

Dietary Marine n-3 PUFAs Do Not Affect Stress-Induced Visceral Hypersensitivity in a Rat Maternal Separation Model.

BACKGROUND: Although never evaluated for efficacy, n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS). OBJECTIVE: This study was designed to investigate, in a mast cell-dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment via peroxisome proliferator-activated receptor γ (PPARG) activation. METHODS: Maternally separated rats were subjected to hypersensitivity-inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil-supplemented diets [4% soy oil (SO) and 3% tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg · kg⁻¹ · d⁻¹). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor α (TNF-α) and ß-hexosaminidase release. RESULTS: Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO-T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 ± 4 vs. 128 ± 12 (P < 0.05) vs. 115 ± 14 and 82 ± 5 vs. 127 ± 16 (P < 0.01) vs. 113 ± 19, respectively]. Comparison of SO-T7 with its control showed similar results [74 ± 6 vs. 103 ± 13 (P < 0.05) vs. 115 ± 17 and 66 ± 3 vs. 103 ± 10 (P < 0.05) vs. 117 ± 11, respectively]. Erythrocytes showed significant LCPUFA uptake in the absence of colonic PPARG activation. Rosiglitazone induced increased PPARG target gene expression, but did not prevent hypersensitivity. Mast cell degranulation never differed between groups. Rosiglitazone and LCPUFAs significantly reduced PMA/calcium ionophore-induced TNF-α release but not degranulation of HMC-1 cells. CONCLUSION: Dietary LCPUFAs did not reverse stress-induced visceral hypersensitivity in maternally separated rats. Although further research is needed, claims concerning LCPUFAs as a treatment option in IBS cannot be confirmed at this point and should be regarded with caution.

Antidepressant-like effect of celecoxib piroxicam in rat models of depression.

Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.

Arabinan-rich pectic polysaccharide fraction from Malpighia emarginata fruits alleviates inflammatory pain in mice.

Malpighia emarginata (Malpighiaceae), popularly known as "acerola", is a tropical and subtropical fruit native to the Americas. Despite its high vitamin C content, which gives it a high antioxidant property, soluble dietary fibers, such as polysaccharides, are also abundant constituents of acerola (10% of the dried fruit). The acerola cold-water soluble (ACWS) fraction presented anti-fatigue and antioxidant effects in vivo and in vitro. To infer further systemic effects of ACWS, this study aimed to investigate the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS in murine models of pain. In formalin-induced nociception, ACWS (0.1, 1, and 10 mg/kg) reduced only the inflammatory phase, and also (10 and 30 mg/kg) attenuated the acetic acid-induced writhing and leukocyte migration in the peritoneal cavity. The mechanical allodynia and paw edema induced by intraplantar injection of carrageenan were greatly reduced by ACWS (10 mg/kg). At the inflammatory pick induced by carrageenan (4 h), ACWS significantly reduced myeloperoxidase activity, TNF-α, IL-1ß, and PGE2 levels, and restored IL-10 levels. ACWS also exhibited antioxidant properties by decreasing lipid hydroperoxides content, increasing GSH levels, and restoring superoxide dismutase and catalase activities in the carrageenan model and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. Collectively, these results support the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS and reveal a promising candidate for the treatment of inflammatory pain conditions.

Rational use of aminoglycosides--review and recommendations by the Swedish Reference Group for Antibiotics (SRGA).

The Swedish Reference Group for Antibiotics (SRGA) has carried out a risk-benefit analysis of aminoglycoside treatment based on clinical efficacy, antibacterial spectrum, and synergistic effect with beta-lactam antibiotics, endotoxin release, toxicity, and side effects. In addition, SRGA has considered optimal dosage schedules and advice on serum concentration monitoring, with respect to variability in volume of drug distribution and renal clearance. SRGA recommends that aminoglycoside therapy should be considered in the following situations: (1) progressive severe sepsis and septic shock, in combination with broad-spectrum beta-lactam antibiotics, (2) sepsis without shock, in combination with broad-spectrum beta-lactam antibiotics if the infection is suspected to be caused by multi-resistant Gram-negative pathogens, (3) pyelonephritis, in combination with a beta-lactam or quinolone until culture and susceptibility results are obtained, or as monotherapy if a serious allergy to beta-lactam or quinolone antibiotics exists, (4) serious infections caused by multi-resistant Gram-negative bacteria when other alternatives are lacking, and (5) endocarditis caused by difficult-to-treat pathogens when monotherapy with beta-lactam antibiotics is not sufficient. Amikacin is generally more active against extended-spectrum beta-lactamase (ESBL)-producing and quinolone-resistant Escherichia coli than other aminoglycosides, making it a better option in cases of suspected infection caused by multidrug-resistant Enterobacteriaceae. Based on their resistance data, local drug committees should decide on the choice of first-line aminoglycoside. Unfortunately, aminoglycoside use is rarely followed up with audiometry, and in Sweden we currently have no systematic surveillance of adverse events after aminoglycoside treatment. We recommend routine assessment of adverse effects, including hearing loss and impairment of renal function, if possible at the start and after treatment with aminoglycosides, and that these data should be included in hospital patient safety surveillance and national quality registries.

2'-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family.

The 5' cap of human messenger RNA consists of an inverted 7-methylguanosine linked to the first transcribed nucleotide by a unique 5'-5' triphosphate bond followed by 2'-O-ribose methylation of the first and often the second transcribed nucleotides, likely serving to modify efficiency of transcript processing, translation and stability. We report the validation of a human enzyme that methylates the ribose of the second transcribed nucleotide encoded by FTSJD1, henceforth renamed HMTR2 to reflect function. Purified recombinant hMTr2 protein transfers a methyl group from S-adenosylmethionine to the 2'-O-ribose of the second nucleotide of messenger RNA and small nuclear RNA. Neither N(7) methylation of the guanosine cap nor 2'-O-ribose methylation of the first transcribed nucleotide are required for hMTr2, but the presence of cap1 methylation increases hMTr2 activity. The hMTr2 protein is distributed throughout the nucleus and cytosol, in contrast to the nuclear hMTr1. The details of how and why specific transcripts undergo modification with these ribose methylations remains to be elucidated. The 2'-O-ribose RNA cap methyltransferases are present in varying combinations in most eukaryotic and many viral genomes. With the capping enzymes in hand their biological purpose can be ascertained.

Antiulcer effect of bark extract of Tabebuia avellanedae: activation of cell proliferation in gastric mucosa during the healing process.

Tabebuia avellanedae (syn. Handroanthus impetiginosus) is popularly known as 'ipê-roxo' and has been used in folk medicine as anti-inflammatory and in the treatment of ulcers, bacterial and fungal infections. This study evaluated the gastric ulcer healing property of the ethanolic extract (EET) of barks from Tabebuia avellanedae and investigated the mechanisms that may underlie this effect. Rats were treated with EET (twice a day for 7 days) after induction of chronic gastric ulcers by 80% acetic acid. Following treatment, histological and immunohistochemical analysis were performed in gastric ulcer tissues. Oral administration of EET (100 and 300 mg/kg) significantly reduced the gastric lesion induced by acetic acid in 44 and 36%, respectively. Histopathological evaluation demonstrated a contraction of gastric ulcer size, increase of mucus layer (periodic acid-Schiff stained mucin-like glycoproteins) and cell proliferation (proliferating cell nuclear antigen immunohistochemistry) in animals treated with EET (100 and 300 mg/kg). The results demonstrate that EET significantly accelerates healing of acetic acid induced gastric ulcer in rats through increase of mucus content and cell proliferation, indicating a potential usefulness for treatment of peptic ulcer diseases.

Integrative taxonomic revision of the genus Phaselia Guene, [1858] (Geometridae: Ennominae) in the Middle East and Central Asia.

In the past, the high intraspecific variation of wing pattern within the genus Phaselia Guene, [1858] repeatedly led to misidentifications. In this study, we applied an integrative approach using external and internal morphological characters, along with DNA barcoding and distribution data to review the taxonomy of the genus Phaselia in the Middle East and Central Asia. For this study, 710 specimens, including type specimens and 242 genitalia slides were prepared and examined. As a result, P. phaeoleucaria (Lederer, 1855) stat. rev. is reinstated from synonymy of P. serrularia; P. phaeoleucaria shurensis Wehrli 1941 comb. nov. is regarded as a subspecies of P. phaeoleucaria stat. rev. instead of a subspecies of P. serrularia; P. serrularia catharia Wehrli, 1941 syn. nov. is regarded as a junior synonym of P. phaeoleucaria shurensis comb. nov.; P. narynaria Oberthr, 1913 syn. nov. is regarded as a junior synonym of P. serrularia (Eversmann, 1847); P. pithana Wehrli, 1941 bona sp. is raised to species level from subspecies of P. serrularia. Furthermore, two species and two subspecies are described as new to science: P. smettboi sp. nov., P. sihvoneni sp. nov., P. erika jonubi ssp. nov. and P. erika sindhi ssp. nov. Wing pattern, and both male and female genitalia of all discussed taxa are illustrated, their distribution patterns are shown on a map and CO1 data is evaluated to confirm our taxonomic decisions.

Clostridioides difficile outbreak detection: Evaluation by ribotyping and whole-genome sequencing of a surveillance algorithm based on ward-specific cutoffs.

OBJECTIVE: We evaluated the performance of an early-warning algorithm, based on ward-specific incidence cutoffs for detecting Clostridioides difficile transmission in hospitals. We also sought to determine the frequency of intrahospital Clostridioides difficile transmission in our setting. DESIGN: Diagnostic performance of the algorithm was tested with confirmed transmission events as the comparison criterion. Transmission events were identified by a combination of high-molecular-weight typing, ward history, ribotyping, and whole-genome sequencing (WGS). SETTING: The study was conducted in 2 major and 2 minor secondary-care hospitals with adjacent catchment areas in western Sweden, comprising a total population of ∼480,000 and ∼1,000 hospital beds. PATIENTS: All patients with a positive PCR test for Clostridioides difficile toxin B during 2020 and 2021. METHODS: We conducted culturing and high-molecular-weight typing of all positive clinical samples. Ward history was determined for each patient to find possible epidemiological links between patients with the same type. Transmission events were determined by PCR ribotyping followed by WGS. RESULTS: We identified 4 clusters comprising a total of 10 patients (1.5%) among 673 positive samples that were able to be cultured and then typed by high-molecular-weight typing. The early-warning algorithm performed no better than chance; patient diagnoses were made at wards other than those where the transmission events likely occurred. CONCLUSIONS: In surveillance of potential transmission, it is insufficient to consider only the ward where diagnosis is made, especially in settings with high strain diversity. Transmission within wards occurs sporadically in our setting.

Water-soluble polysaccharides from Piper regnellii (Pariparoba) leaves: Structural characterization and antinociceptive and anti-inflammatory activities.

Piper regnellii is a plant popularly known as "Pariparoba" and it is widely used in folk medicine to treat pain, inflammation, among others. This work presents the extraction, purification and characterization of polysaccharides present in the plant leaves and evaluation of their anti-inflammatory and antinociceptive activities. From the crude aqueous extract of P. regnellii leaves, a polysaccharide fraction named PR30R, predominantly constituted of arabinose, galactose and galacturonic acid monosaccharide units, was obtained. Methylation and NMR analysis showed that the main polysaccharides of PR30R are a type II arabinogalactan, formed by a ß-D-Galp-(1 â†’ 3) main chain, substituted at O-6 by side chains of ß-D-Galp-(1 â†’ 6), which are substituted at O-3 by non-reducing α-L-Araf ends, and a homogalacturonan, formed by →4)-α-D-GalpA-(1→ units. Intraperitoneal administration of the crude polysaccharide fraction PRSF reduced significantly nociception induced by acetic acid in mice at the doses tested, and the PR30R fraction, derived from PRSF, presented antinociceptive and anti-inflammatory effects at a dose of 0.1096 mg/kg (PRSF ED50). These data support the use of the plant leaves in folk medicine as an herbal tea to treat pain and inflammation.

Investigation of the chemical structure and analgesic and anti-inflammatory properties of polysaccharides that constitute the dietary fibers of soursop (Annona muricata) fruit.

Soursop fruits are widely used in the folk medicine to treat a variety of health conditions. Once the chemical structure of dietary fibers from fruits is closely related to its biological functions in the human body, we aimed to explore structural features and biological activity of dietary fibers from soursop. Polysaccharides that constitute the soluble and insoluble fibers were extracted and further analyzed using monosaccharide composition, methylation, molecular weight determination and 13C NMR data. Soursop soluble fibers (SWa fraction) were characterized as having type II arabinogalactan and a highly methyl esterified homogalacturonan, while non-cellulosic insoluble fibers (SSKa fraction) were mainly composed by a pectic arabinan, a xylan-xyloglucan complex and a glucuronoxylan. The oral pre-treatment with SWa and SSKa promoted antinociception in mice writhing test, reducing the number of pain-like behaviors (in 84.2 % and 46.9 %, respectively, at 10 mg/kg) and peritoneal leucocyte migration (55.4 % and 59.1 %, at 10 mg/kg), effects possibly associated with the pectins present in fruit pulp extractions. SWa also significantly inhibited the plasmatic extravasation of Evans blue dye in 39.6 % at 10 mg/kg. This paper describes for the first time the structural features of soursop dietary fibers that may be of biological significance in future.

CPW partially attenuates DSS-induced ulcerative colitis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the gastrointestinal tract. The etiology is not fully understood, but environmental, microbial, and immunologic factors, as well as a genetic predisposition, play a role. UC is characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss, severe colonic inflammation, and ulceration. Despite the increase in the frequency of UC and the deterioration of the quality of life, there are still patients who do not respond well to available treatment options. Against this background, natural products such as polysaccharides are becoming increasingly important as they protect the intestinal mucosa, promote wound healing, relieve inflammation and pain, and restore intestinal motility. In this study, we investigated the effect of a polysaccharide isolated from the biomass of Campomanesia adamantium and Campomanesia pubescens (here referred to as CPW) in an experimental model of acute and chronic ulcerative colitis induced by dextran sulfate sodium (DSS). CPW reversed weight loss, increased disease activity index (DAI), bloody diarrhea, and colon shortening. In addition, CPW reduced visceral mechanical hypersensitivity, controlled oxidative stress and inflammation, and protected the mucosal barrier. CPW is not absorbed in the intestine, does not inhibit cytochrome P450 proteins, and does not exhibit AMES toxicity. These results suggest that CPW attenuates DSS-induced acute and chronic colitis in mice and may be a potential alternative treatment for UC.

Identification of miR-34-3p as a candidate follicular phase serum marker for endometriosis: a pilot study.

OBJECTIVE: To identify early follicular phase microribonucleic acids (miRNAs) that are altered in serum of women with endometriosis. DESIGN: Case-control study. SETTING: Large university-affiliated in vitro fertilization center. PATIENT(S): Women with (n = 21) and without (n = 24) endometriosis. INTERVENTION(S): Serum samples were obtained from laparoscopy-confirmed patients with endometriosis. MAIN OUTCOME MEASURE(S): The differential expression of serum miRNAs relative to controls was measured using the NanoString nCounter technology and validated by quantitative real-time polymerase chain reaction in an independent cohort of 27 patients with endometriosis and controls (n = 24). Microribonucleic acid target signaling pathways and genes were analyzed bioinformatically. A chemically modified stable miR-34-3p oligonucleotide was used to examine the effect on proliferation of VK2E6/E7 endometrial cells in vitro. RESULT(S): Eighteen miRNAs were significantly up-regulated, and 1 miRNA (hsa-miR-34c-3p) was significantly down-regulated in the follicular phase of patients with endometriosis. The analysis of target signaling pathways using TargetScan predicted regulation of the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, Hippo, adenosine monophosphate-activated protein kinase, transforming growth factor beta, and endometrial cancer pathways, which have been implicated in the pathogenesis of endometriosis, by these miRNAs. The analysis of sequence complementarity identified prostaglandin E2 receptor 4, interleukin 6 signal transducer, and polo-like kinase 4 genes as possible direct targets of hsa-miR-34-3p. DSDI-1, a chemically modified stable miR-34-3p oligonucleotide, reduced cell proliferation in VK2E6/E7 endometrial cells in vitro. CONCLUSION(S): The follicular phase miRNA levels are altered in serum of women with endometriosis and may be useful as reproducible detection biomarkers for early diagnosis of endometriosis. hsa-miR-34-3p is significantly down-regulated in endometriosis, targets endometriosis genes, and reduces endometrial cell proliferation in vitro. These results support hsa-miR-34-3p as a potential therapeutic target in endometriosis.

Local effects of natural alkylamides from Acmella oleracea and synthetic isobutylalkyl amide on neuropathic and postoperative pain models in mice.

Neuropathic and postoperative pain are clinical conditions that impair the patient's quality of life. The current pharmacotherapy of both painful states is ineffective and accompanied by several side effects. In order to develop new therapeutics targets, the secondary metabolites of plants have been extensively studied. Acmella oleracea ("jambu") is a native plant from the Amazon region and rich in alkylamides, bioactive compounds responsible for inducing anesthetic and chemesthetic sensations. We previously demonstrated that the intraplantar administration of an hexanic fraction (HF) rich in alkylamides from jambu and the synthetic isobutylalkyl amide (IBA) at 0.1 µg/20 µL can promote antinociceptive and anti-inflammatory effects. Thus, this study aimed to evaluate the local effect of HF and IBA (0.1 µg/20 µL) on neuropathic (partial sciatic nerve ligation, PSNL) and postoperative pain (plantar incision surgery, PIS) models in mice. Seven days after the PSNL, the mechanical (von Frey test) and cold (acetone-evoked evaporative cooling) allodynia, and digital gait parameters were analyzed. The intraplantar HF and IBA treatments attenuated the mechanical and cold allodynia as well as the static (max. Contact and print area) and dynamic (stand duration) parameters of digital gait analyses. On the day after PIS, the mechanical allodynia, heat hyperalgesia (hot plate, 52 ± 0.1°C), and spontaneous nociception scores were evaluated. Topical treatment with HF reduced the mechanical allodynia, heat hyperalgesia, and spontaneous nociception scores. In contrast, IBA treatment only partially reduced the mechanical allodynia. In summary, the local treatment with HF was effective on both neuropathic and postoperative pain, as opposed to IBA, which only had an effect on neuropathic pain.

Dietary polysaccharides from guavira pomace, a co-product from the fruit pulp industry, display therapeutic application in gut disorders.

Inflammatory bowel disease (IBD) includes two distinct diseases: Crohn's disease (CD) and ulcerative colitis (UC). IBD is a chronic systemic disease of the gastrointestinal tract, characterized by an inflammatory process. The mechanisms by which diseases develop are still unknown, but it is known that it results from a complex interaction between genetic variability, the host's immune system, and environmental factors. One of the main complaints of patients is abdominal pain, which may be associated with the release of inflammatory mediators, changes in the normal motility of the digestive tract, and increased intestinal permeability. Currently available drugs for abdominal pain are not satisfactory, therefore, it is extremely necessary to seek new therapeutic options for the treatment of abdominal pain. Polysaccharides extracted from fruits have attracted interest, as these molecules protect the intestinal mucosa and promote wound healing, attenuating inflammation, pain, and altered intestinal motility. In this study, we investigated the ability of pectic polysaccharides obtained from guavira pomace, named CPW to reduce visceral hypersensitivity, regulate intestinal motility, and control diarrhea in mice. Acetic acid, capsaicin, or mustard oil were used to assess visceral pain in normal mice. CPW reduced abdominal writhing, cell migration, and capsaicin-induced visceral nociception. Furthermore, it regulated intestinal motility and all measured parameters of castor oil-induced diarrhea. CPW treatment reversed the increase in mucosal permeability, TEER, and tissue weight caused by acetic acid. In addition, molecular docking analysis showed that specific the CPW units binds to the 3N8V, 5COX, 2J67 and 6RBF proteins. Thus, the results suggest that CPW has attractive therapeutic characteristics for the treatment of abdominal pain and ulcerative colitis.