Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities-The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice.

Alzheimer's disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., ß-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely V. carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC from Patagonia and V. ferax (Griseb.) Höck and V. effusa Griseb., on different AD-related biological targets. Of these anxiolytic, sedative and sleep-inducing valerians, V. carnosa proved the most promising and was assayed in vivo. All valerians inhibited acetylcholinesterase (IC50 between 1.08-12.69 mg/mL) and butyrylcholinesterase (IC50 between 0.0019-1.46 mg/mL). They also inhibited the aggregation of ß-amyloid peptide, were able to chelate Fe2+ ions, and exhibited a direct relationship between antioxidant capacity and phenolic content. Moreover, V. carnosa was able to inhibit human monoamine oxidase A (IC50: 0.286 mg/mL (0.213-0.384)). A daily intake of aqueous V. carnosa extract by male Swiss mice (50 and 150 mg/kg/day) resulted in anxiolytic and antidepressant-like behavior and improved spatial memory. In addition, decreased AChE activity and oxidative stress markers were observed in treated mouse brains. Our studies contribute to the development of indigenous herbal medicines as therapeutic agents for AD.

Multitarget 2'-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities.

The complex nature of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD) calls for multidirectional treatment. Restoring neurotransmitter levels by combined inhibition of cholinesterases (ChEs) and monoamine oxidases (MAOs, MAO-A and MAO-B), in conjunction with strategies to counteract amyloid ß (Aß) aggregation, may constitute a therapeutically strong multi-target approach for the treatment of NDDs. Chalcones are a subgroup of flavonoids with a broad spectrum of biological activity. We report here the synthesis of 2'-hydroxychalcones as MAO-A and MAO-B inhibitors. Compounds 5c (IC50 = 0.031 ± 0.001 µM), 5a (IC50 = 0.084 ± 0.003 µM), 2c (IC50 = 0.095 ± 0.019 µM) and 2a (IC50 = 0.111 ± 0.006 µM) were the most potent, selective and reversible inhibitors of human (h)MAO-B isoform. hMAO-B inhibitors 1a, 2a and 5a also inhibited murine MAO-B in vivo in mouse brain homogenates. Molecular modelling rationalised the binding mode of 2'-hydroxychalcones in the active site of hMAO-B. Additionally, several derivatives inhibited murine acetylcholinesterase (mAChE) (IC50 values from 4.37 ± 0.83 µM to 15.17 ± 6.03 µM) and reduced the aggregation propensity of Aß. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutyric acid A (GABAA) receptors (1a and 2a with Ki = 4.9 ± 1.1 µM and 5.0 ± 1.1 µM, respectively), and exerted sedative and/or anxiolytic like effects on mice. The biological results reported here on 2'-hydroxychalcones provide an extension to previous studies on chalcone scaffold and show them as a potential treatment strategy for NDDs and their associated comorbidities.

Neurobehavioral evaluation and phytochemical characterization of a series of argentine valerian species.

Folkloric or galenic preparations of valerian roots and rhizomes have been used as sedatives/anxiolytics and sleep inducers since ancient times. "Valerianas" are plants that naturally grow in our region. Although some of them are used in folk medicine, they lack scientific information. We performed a comparative study of the phytochemical composition and the potential in vivo effects of ethanolic extracts of argentine valerian species: Valeriana carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC., from "Patagonia Argentina"; V. ferax (Griseb.) Höck and V. effusa Griseb., from the central part of our country, and V. officinalis (as the reference plant). All these plants were rich in phenolic compounds, evidenced the presence of ligands for the benzodiazepine binding site of the GABAA receptor and were able to induce sedation as assessed by loss-of-righting reflex assays (500 mg/kg, i.p.). Mice treated with V. macrorhiza, V. carnosa and V. ferax extracts showed reduced exploratory behaviors while V. clarionifolia produced anxiolytic-like activities (500 mg/kg, i.p.) in the Hole board test. Oral administrations (300 mg/kg and 600 mg/kg, p.o.) evidenced sedative effects for V. ferax and anxiolytic-like properties for V. macrorhiza, V. carnosa and V. clarionifolia extracts. Our native valerian species are active on the CNS, validating its folkloric use as anxiolytic/sedative and sleep enhancers.

Proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type Ia.

Albino patients are at great risk for developing cutaneous neoplasms, including melanomas. In this paper we describe the dermatoscopic findings of nevi in two patients with oculocutaneous albinism type Ia (OCA-Ia) highlighting that they manifest a vascular pattern similar to that described for amelanotic melanoma. We propose managing these patients with dermoscopy, using the comparative approach, digital follow up (DFU), and reflectance confocal microscopy as a complementary tool for difficult cases.

Dermoscopic findings in a collision tumor composed of a dermatofibroma and a melanocytic nevus mimicking melanoma.

Collision tumors consist of two different neoplasms occurring concurrently in the same lesion. This association has been described for both benign and malignant neoplasms that may be difficult to identify. Therefore, dermoscopy is a valuable tool to make a correct diagnosis. We report a very unusual collision tumor composed of both a dermatofibroma and a melanocytic nevus mimicking melanoma.

Dermoscopic findings in different clinical variants of lichen planus. Is dermoscopy useful?

Lichen planus (LP) is a papulosquamous dermatosis that involves the skin, scalp, nails and mucous membranes. Although its pathogenesis is still unknown, there is evidence that an imbalance of immunologic cellular reactivity plays an important role. Histopathologic examination reveals characteristic interface dermatitis. Dermoscopy is a non-invasive tool, useful in the assessment of inflammatory dermatoses, such as lichen planus. In this paper we describe the dermoscopic findings of different variants of LP (ungual, cutaneous, planopilaris, pigmentosus).

Síndrome de pelo impeinable / Uncombable hair syndrome

El síndrome de pelo impeinable o pili trianguli et canaliculi es un trastorno estructural del pelo, poco frecuente y de etiología desconocida. Se caracteriza por presentar un pelo rebelde, difícil de peinar. Presentamos el caso de un paciente de 9 años de edad con manifestaciones clínicas y hallazgos en la microscopia electrónica de barrido compatibles con esta entidad...

Dermoscopic findings in bowenoid papulosis: report of two cases.

Bowenoid papulosis (BP) corresponds to an in situ squamous cell carcinoma (SCC) located in the anogenital region. It is related to HPV, and presents with gray-brown elevated papules or plaques. A biopsy is needed to confirm the diagnosis; however, dermoscopy may be useful to differentiate this disease from other conditions, such as genital warts, seborrheic keratosis and lichen planus. In this paper we describe the dermoscopic findings in two patients with this disease.

Xantogranuloma juvenil: evolución en el tiempo de un caso con compromiso cutáneo extenso / Juvenile Xanthogranuloma: evolution over time of a case with cutaneous involvement

El xantogranuloma juvenil (XGJ) es una de las formas más frecuentes de la histocitosis no células de Langerhans. Su curso es generalmente benigno y autorresolutivo. Presentamos el caso clínico de un varón con lesiones cutáneas generalizadas que evolucionaron hacia la anetodermia...

Juvenile xanthogranuloma is one of the most frequent forms of non Langerhans cell histiocytosis, generally benign and autoresolutive. We present a case of a boy with generalized cutaneous involvement that evolved to anethodermia...

Panarteritis nodosa cutánea / Panarteritis nodosa skin

La panarteritis nodosa (PAN) es un tipo de vasculitis necrotizante que se clasificahabitualmente en una forma cutánea (c-PAN) y otra sistémica (s-PAN).La primera se caracteriza por presentar un cuadro limitado a la piel, de cursocrónico y pronóstico benigno. Por el contrario, la forma sistémica cursa consíntomas generales, compromiso visceral y es de muy mal pronóstico. Ladistinción entre estas dos variantes es aún controvertida: algunos autoressostienen que la forma cutánea sería una variedad abortiva o de comienzo dela forma sistémica, mientras que otros afirman que se trataría de dos entidadesseparadas, sin posibilidad de pasaje de una forma a la otra.Presentamos una paciente de sexo femenino, de 42 años de edad, queconsulta a nuestro Servicio por presentar nódulos en las piernas, artralgias ymialgias. La biopsia de piel informa panarteritis de arteriolas de dermis profunday tejido celular subcutáneo, compatible con panarteritis nodosa. Sedescarta el compromiso sistémico arribando al diagnóstico de PAN cutánea.Se indica tratamiento con prednisona y metotrexato con respuesta variable alo largo de su evolución...

Panarteritis nodosa (PAN) is a necrotizing vasculitis that is classified as a cutaneousform (c-PAN) and a systemic form (s-PAN). The former represents askin-limited disorder that has a benign and chronic course. The latter is a multisystemicdisease with visceral involvement and a severe clinical course. Thedistinction of c-PAN from s-PAN is still controversial: some authors considerthe cutaneous form as an abortive or an initial manifestation of the systemicdisease, while others state that c-PAN is an individual disorder, with no possibilitiesof progressing to s-PAN.We present a 42 year-old female with nodules on the legs, arthralgias andmyalgias. A skin biopsy showed panarteritis affecting arterioles in the deepdermis and superficial sub cutis, as found in polyarteritis nodosa. Systemicinvolvement was ruled out and a c-PAN diagnosis was confirmed. She wasstarted on oral steroids and methotrexate with variable response.We discuss different aspects of this infrequent disease that represents atherapeutic challenge for dermatologists...