Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer’s disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

Dandruff (also called Pityriasis capitis) is a seborrhoeic dermatitis of the scalp. It has been correlated with the pathological colonization of the scalp with yeast from the genus Malassezia; this illness has a worldwide distribution and represents 25% of all scalp dermatosis cases. It has been demonstrated that the extract obtained from leaves of the plant Solanum chrysotrichum possesses biological activity against dermatophytes and yeast. Different steroidal saponins with antimycotic activity have been isolated from the active extract. Clinical trials with standardized extracts prepared with this vegetal species report high rates of clinical and mycological effectiveness in the treatment of Tinea pedis,without producing secondary effects. The aim of this randomized, double blind and controlled clinical study, was to compare the therapeutic effectiveness and tolerability of a shampoo containing a standardized extract of S. chrysotrichum (applied every third day, for 4 weeks), against 2% ketoconazole in the topical treatment of Pityriasis capitis. From a total of 120 patients with the clinical diagnosis of Pityriasis capitis, 14 subjects were eliminated because the presence of Malassezia was not proved, an-other two patients withdrew from the study due to non-medical causes and one more withdrew because Tinea capitis was diagnosed. Therefore, the final analysis included 51 subjects in the experimental group and 52 in the control; in 45.6% of the cases M. furfur was identified as the pathogenic agent, in 44.66% M. globosa was isolated, and 9.71 % of the patients had a mixed infestation. At the end of the treatment period, the prepared phytopharmaceutical with the standardized extract from S. chrysotrichum achieved a clinical effectiveness (total absence of signs and symptoms produced by Pityriasis capitis) of 92.16%;the mycological effectiveness (absence of Malassezia spp. in the direct examination and culture) was 68.63 %; whilst the tolerability (absence of side effects that prompt subjects to abandon the treatment) was 100%. The therapeutic success (clinical and mycological effectiveness plus tolerability) was 64.71%. The comparison of these results with that obtained from the group treated with 2% ketoconazole, showed no significant differences (Z2, p >0.23). These results show the therapeutic effectiveness and tolerability of the standardized extract from S. chrysotrichum on the local treatment of Pityriasis capitis associated with the yeast of the genus Malassezia.

Solanum chrysotrichum is utilized in traditional Mexican medicine for the treatment of mycotic skin infections. Several microbiological studies have provided evidence of its antifungal activity against dermatophytes and yeasts. S. chrysotrichum saponins have been identified as a group of compounds with antifungal activity and saponin SC-2 has demonstrated to be the most active. Previous clinical studies have shown the therapeutic effectiveness of S. chrysotrichum-derived saponin-standardized herbal products in the treatment of Tinea pedis and Pityriasis capitis. There is no previous evidence of the activity of these saponins against Candida non-albicans species, or fluconazole- and ketoconazole-resistant Candida strains. The present study reports the biological activity of the SC-2 saponin (inhibitory concentration [IC (50)] and minimum fungicide concentration [MFC]), against 12 Candida strains of clinical significance ( C. albicans, five strains; C. glabrata and C. parapsilosis, two; C. krusei, C. lusitaniae and C. tropicalis, one), including some fluconazole (Fluco)- and ketoconazole (Keto)-resistant clinical isolates. In addition, SC-2-associated microstructural alterations were reported in four of the above-mentioned Candida species. Seven strains had IC (50) of 200 microg/mL for SC-2, 400 microg/mL was found in four strains, and 800 microg/mL for a sole C. glabrata strain. Susceptibility to SC-2 saponin was as follows: C. albicans = C. lusitaniae > C. krusei > C. glabrata. The MFC was 800 microg/mL for the majority of strains (nine), 400 microg/mL for C. albicans (two strains) and C. lusitaniae. The ultrastructural Candida changes originated by SC-2 included the following: 1) damage on cytoplasmic membrane and organelles; 2) changes in cell wall morphology and density, with separation of cytoplasmatic membrane from cell wall and disintegration of the latter; and 3) total degradation of cellular components and death. Changes were manifested from 6 h of incubation, reaching their maximum effect at 48 h. In conclusion, the saponin SC-2 possesses fungicide and fungistatic activity on different Candida albicans and non- albicans species (including some azole-resistant strains) with IC (50) values of 200 microg/mL (in Fluco-susceptible strains) and of 400 - 800 mug/mL (in Fluco-resistant strains). Additionally, we observed by transmission electron microscopy (TEM) that saponin SC-2 causes severe changes in all fungal cell membranes, and to a lesser degree on the cell wall.

Pulmonary coccidioidomycosis shares characteristics with other pulmonary pathologies. In tissue, spherules containing endospores are markers of Coccidioides immitis and C. posadasii infection. Mycelial forms presenting without classical parasitic structures are often misdiagnosed. The study was performed at the National Institute of Respiratory Diseases (INER) of Mexico between September 1991 and June 2005 and analyzed the association between cases, controls, and risk factors, including co-morbidity. A case was defined as any patient who presented mycelial forms and a control as any patient who presented only spherules or no parasitic forms. All patients (n = 44) with pulmonary coccidioidomycosis were diagnosed by culture, histopathology, cytology, and immunology. Type 2 diabetic patients with pulmonary coccidioidomycosis were four times more likely than non-diabetics to develop parasitic mycelial forms (95% confidence interval [CI], 0.85-20.10; P < 0.01). We formulated a comprehensive definition based on the results as follows: patients with pulmonary coccidioidomycosis with an evolution longer than 8 months, cough, hemoptysis, radiological evidence of a cavitary lesion, and type 2 diabetes mellitus, develop parasitic mycelial forms of Coccidioides spp. Based on microscopic images of patient specimens, we propose incorporating mycelial forms into the parasitic phase of Coccidioides spp. in patients with type 2 diabetes mellitus and chronic and cavitary pulmonary coccidioidomycosis.

Mexican traditional medicine uses Solanum chrysotrichum to treat fungi-associated dermal and mucosal illness; its methanolic extract is active against dermatophytes and yeasts. Different spirostanic saponins (SC-2-SC-6) were identified as the active molecules; SC-2 was the most active in demonstrating a fungicidal effect against Candida albicans and non-albicans strains. The aim of the present study was to compare the clinical (elimination of signs and symptoms) and mycological effectiveness (negative mycological studies) of an S. chrysotrichum herbal medicinal product (Sc-hmp), standardized in 1.89 mg of SC-2, against ketoconazole (400 mg) in the topical treatment of cervical and/or vaginal infection by Candida. Both treatments (vaginal suppositories) were administered daily during 7 continuous nights. The study included 101 women (49 in the experimental group) with a confirmed clinical condition and positive mycological studies (direct examination and/or culture) of Candida infection. Basal conditions did not show differences between the groups; a moderate clinical picture was present in 62% of the cases, direct examination was positive in 69%, and the culture was positive with C. albicans predominating (65%). At the end of the administration period, both treatments demonstrated 100% tolerability, and clinical cure in 57.14% of S. chrysotrichum-treated cases and in 72.5% of ketoconazole-treated cases (p = 0.16), as well as 62.8% and 97.5% of mycological effectiveness, respectively (p = 0.0 001). We conclude that, at the doses used, Sc-hmp exhibits the same clinical effectiveness as ketoconazole, but with lower percentages of mycological eradication. Additional clinical studies with Sc-hmp are necessary, with increasing doses of SC-2, for improving the clinical and mycological effectiveness.