Effect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage.

Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood-brain barrier's (BBB´s) and blood-cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells.

LC-MS metabolomic evidence metabolites from Oenothera rosea L´ Hér. ex Ait with antiproliferative properties on DU145 human prostate cancer cell line.

Prostate cancer remains one of the leading health issues without a fully effective treatment. Medicinal plants are one of the primary sources of compounds for treating numerous ailments. In this sense, the Oenothera genus contains metabolites with antiproliferative activity on cancer cells. For this, the study aimed to explore the antiproliferative activity of its extracts against prostate cancer and identify its metabolites (under metabolomics analyses) associated with anticancer and/or antiproliferative properties. For this reason, a LC-MS/MS-based metabolomic analysis was performed to demonstrate the possible metabolites present in O. rosea. In addition, the antiproliferative activity of different extracts in the human prostate cancer cell line DU145 was evaluated. All extracts have antiproliferative effects on DU145 cells at 72 h, with moderate activity being the best ethanolic either 48 or 72 h. Finally, by LC-MS/MS-based metabolomics, 307 compounds from aqueous, methanolic, ethanolic, and ethyl acetate extracts from which 40 putative metabolites identified were organized as anti-inflammatory, anticancer, and/or antiproliferative activities according to previously reported. These results provide evidence that O. rosea could be used as an antiproliferative agent due to its chemical contents used as polypharmacy with low concentration levels.

Exploratory toxicology studies of 2,3-substituted imidazo[1,2-a]pyridines with antiparasitic and anti-inflammatory properties.

Background: Trichomoniasis and amoebiasis are neglected diseases and still remain as a global health burden not only for developing countries, from where are endemic, but also for the developed world. Previously, we tested the antiparasitic activity of a number of imidazo[1,2-a]pyridine derivatives (IMPYs) on metronidazole-resistant strains of Entamoeba Hystolitica (HM1:IMSS), and Trichomonas Vaginalis (GT3). Their anti-inflammatory activity was also evaluated. Objective: The present work is a part of a project whose aim is to find new alternatives to standard treatments for these maladies, and to address the current concern of emerging resistant parasite strains. Here we report a non-clinical study focused on exploratory toxicology assays of seven IMPYs that showed the best antiparasitic and/or anti-inflammatory properties. Methods: Acute, and subacute toxicity tests were carried out. After 14-day oral treatment, liver and kidney functionality assays in combination with chemometric methods were implemented to detect hepatic and/or kidney damage. Results: Some compounds produced off-target effects. Vehicle effects were also detected. However, no signs of hepatic or renal toxicity were observed for any IMPY. Conclusion: These compounds can continue non-clinical evaluations, and if possible, clinical trials as new candidates to treat trichomoniasis and amoebiasis, and inflammatory diseases. Further studies are also needed to fully elucidate a proposed dual effect that may exert these molecules against trichomoniasis and amoebiasis, which may also signify a novel mechanism of action to treat these infections.

Antinociceptive activity of the ethanolic extract of Trixis angustifolia DC.

The antinociceptive activity of the ethanolic extract of Trixis angustifolia DC. (EETx) was investigated using the acetic acid-induced writhing and the hot-plate tests in mice. In the acetic acid-induced writhing test, mice treated with EETx (50, 100 and 200 mg/kg, p.o.) exhibited reduced writhing (38%, 67%, and 74%, respectively). In the hot-plate test, the three doses administrated increased the nociceptive response time. The phytochemical analysis of EETx led to the isolation of three known compounds, hygric acid (1), 5,6-Dihydroxy-7,8,4'-trimethoxyflavone (2) and xanthomicrol (3). Compound 1 was identified for the first time in this species. These results demonstrate that T. angustifolia has potential central and peripheral antinociceptive effects and support the ethnomedicinal use of this plant.

Arthrospira maxima (Spirulina) prevents endoplasmic reticulum stress in the kidney through its C-phycocyanin.

Arthrospira maxima (Spirulina) is a cyanobacterium which is considered a nutraceutical because it has antioxidant, anti-inflammatory, and cytoprotective properties in different renal disease models (Rodriguez-Sánchez et al., 2012; Aziz et al., 2018; Memije-Lazaro et al., 2018). The therapeutic effects are due to the presence of metabolites with biological effects similar to those of essential fatty acids ω-3 and ω-6, vitamins A, C and E, and accessory pigments such as phycobiliproteins. One of the most abundant phycobiliproteins in A. maxima is C-phycocyanin (Mysliwa-Kurdziel and Solymosi, 2017). This molecule is responsible for nephroprotective action in a model of acute kidney injury (AKI) because it reduces oxidative stress and caspase activation (Rodriguez-Sánchez et al., 2012; Rojas-Franco et al., 2018). However, both A. maxima and its C-phycocyanin are related to the reduction of the redox environment. Thus, they probably help to maintain the adequate function of the intracellular organelles like the endoplasmic reticulum. However, this therapeutic action has not been evaluated previously.

NMR-based metabonomic approach reveals changes in the urinary and fecal metabolome caused by resveratrol.

An untargeted NMR-based metabonomics approach was used to evaluate the effects of pure resveratrol (RSV, 50 and 250 mg/kg per os) on the urinary and faecal metabolome of normal female Wistar rats. Multivariate data analysis on both the endogenous and xenobiotic metabotype of RSV provided an insight into its metabolic fate and influence on endogenous metabolites. The xenobiotic trajectory shows that RSV is highly metabolized within the first 12 h, the period of the most significant variation of endogenous metabolites. The results reveal alterations in gut microbiota co-metabolites, mainly at the high dose of RSV, such as hippurate, phenylacetyl glycine (PAG), p-cresyl glucuronide (p-CG), p-cresyl sulfate (p-CS) and 3-indoxylsulfate (3IS), as well as in osmolytes (creatine, creatinine, taurine and proline betaine). This metabolic variation could mean that RSV modulates the composition and/or function of the gut microbiota as well as its interaction with the host through the gut-microbiome-liver-kidney axis. For instance, RSV may interact with conjugating enzymes present in the intestine and liver. There were also modifications in metabolites of the tricarboxylic acid (TCA) cycle and energy metabolism (2-oxoglutarate, lactate and alanine), and diet-derived metabolites (pantothenate and trans-aconitate). These effects of RSV are perhaps related to its capacity to control energy homeostasis, provide renal protection, and downregulate some biomarkers of oxidative stress (e.g., glycoproteins). Such changes contribute to reduced oxidative stress and inflammation, which are associated with RSV-induced biological activity to improve various conditions, including metabolic disorders, obesity, and chronic and cardiovascular diseases.

Oenothera rosea L´Hér. ex Ait attenuates acute colonic inflammation in TNBS-induced colitis model in rats: in vivo and in silico myeloperoxidase role.

Oenothera rosea L´Hér. ex Ait is a species traditionally used in the treatment of inflammation, headache, stomach pain, infections, among others. The aim of this study was evaluating the acute anti-inflammatory activity of the aqueous extract of O. rosea by 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Rats were randomized into six groups: (I) Sham; (II) EtOH; (III) TNBS; and (IV-VI) 250, 500 and 750 mg/Kg, respectively. The colonic injury was induced (groups III-VI) by intrarectal instillation of 0.25 mL of TNBS (10 mg) in 50% ethanol. Groups I and II received an enema (0.25 mL) of physiological saline solution or 50% ethanol, respectively. Treatments were administered by oral gavage 48, 24 and 1 h prior, and 24 h after the induction. The inflammatory response was assessed considering the macroscopic and microscopic damage, the serum nitric oxide (NO), the colonic IL-1ß levels, and the myeloperoxidase (MPO) activity. Moreover, we performed an LC-MS-based metabolite profiling, and a docking on the MPO. Doses of 500 and 750 mg/Kg showed a protective effect in the TNBS-induced colonic damage. This activity was related to the downregulation of evaluated parameters. Also, considering previous reports, 29 metabolites of 91 detected were selected for the docking, of which Isolimonic acid (29) and Kaempferol 3-(2'',4''-diacetylrhamnoside) (10) showed the highest affinity to MPO. The aqueous extract of O. rosea protected the TNBS-induced colonic damage in rats, an effect that could be associated with the presence of polyphenolic compounds, alkaloids, and terpenes; as well as their ability to down-regulate MPO activity.

The Ethanolic Extract of Eysenhardtia polystachya (Ort.) Sarg. Bark and Its Fractions Delay the Progression of Rheumatoid Arthritis and Show Antinociceptive Activity in Murine Models.

Eysenhardtia polystachya is widely used in folk medicine as an anti-rheumatic and analgesic agent, but no systematic study of its effects on several markers associated with rheumatoid arthritis and its ethnomedical use as analgesic agent has been performed. We evaluated the anti-arthritic and antinociceptive properties of an ethanolic extract of E. polystachya (EE) bark and its rich-flavonoids fractions in murine models. The EE was administered orally at doses of 25, 50, 100, and 200 mg/kg/day, and its fractions at 25 mg/kg/day in all animal models. Anti-arthritic activity was evaluated using a complete Freund´s adjuvant (CFA)-induced rheumatoid arthritis model in rats. The severity of arthritis was evaluated by changes in paw oedema, body weight, arthritic index, radiological scores, histological assessment of synovial joints, erythrocyte sedimentation rate, haematocrit, haemoglobin, serum rheumatoid factor, serum C-reactive protein and serum levels of the pro-inflammatory cytokines IL-1ß, IL-6, TNF-α, IL-18, IFN-γ, GM-CSF, and anti-inflammatory cytokines IL-4, IL-10, IL-13. Antinociceptive activity was evaluated using an acetic acid-induced abdominal contraction test and a hot-plate test in mice. EE and its rich-flavonoids fractions inhibited secondary inflammatory reactions, diminished the specific histopathological alterations in the joint capsule and reduced the serum concentrations of the pro-inflammatory cytokines IL-6, TNF-α, and GM-CSF in arthritic rats. EE also reduced the number of writhes produced by acetic acid and increased the response time on the hot plate for mice. Our findings support the use of Eysenhardtia polystachya bark for the treatment of rheumatoid arthritis and pain management.

Diuretic effect of alkaloids fraction extracted from Selaginella lepidophylla (Hook. et Grev.) Spring / Efecto diurético de la fracción con contenido de alcaloides extraída deSelaginella lepidophylla (Hook. et Grev.) Spring

The aerial parts of Selaginella lepidophylla (Hook. et Grev.) Spring, are used in Mexican folk medicine to treat renal diseases. The aim of this study was to measure the diuretic response of an aqueous extract (200 mg/kg) and alkaloids fraction at different doses (10, 40 y 100 mg/kg) of this plant and compare it with that induced by furosemide (4 mg/kg). Extract, alkaloids fraction, furosemide and vehicle were administered orally to adult rats and the effects in sodium, potassium and water balance were measured. The extract, the alkaloids fraction and the furosemide produced important and significant increments in urinary excretion of sodium, potassium and water with respect to control group. This increment was dose dependent of the alkaloids fraction, the highest dose produced a major effect. Potassium excretion increased but it was less than the one induced by furosemide. These results suggest that the aqueous extract and rich fraction in alkaloids from S. lepidophylla induce diuretic response.

Las partes aéreas de Selaginella lepidophylla (Hook. et Grev.) Spring, son usadas en la medicina tradicional mexicana para tratar enfermedades renales. El objetivo del estudio fue medir la respuesta diurética de un extracto acuoso (200 mg/kg) y de diferentes dosis de la fracción de alcaloides (10, 40 y 100 mg/kg) de esta planta y compararla con la inducida por furosemida (4 mg/kg). El extracto, la fracción de alcaloides, la furosemida y el vehículo fueron administrados por vía oral a ratas adultas y se midieron los efectos en el balance de sodio, potasio e hídrico. El extracto, la fracción de alcaloides y la furosemida produjeron importantes y significativos incrementos en la excreción urinaria de sodio, potasio y agua con respecto al grupo testigo. Este incremento fue dependiente de la dosis de la fracción de alcaloides, la dosis más alta produjo el mayor efecto. El incremento en la excreción de potasio fue menor al de furosemida. Los resultados sugieren que el extracto acuoso y la fracción rica en alcaloides de S. lepidophylla inducen una respuesta diurética.