Recessive dystrophic epidermolysis bullosa (RDEB) manifests with blistering and erosions of the skin and mucous membranes due to mutations in COL7A1. The repetitive wound healing processes lead to extensive cutaneous scarring. The scarring is driven by inflammatory processes, particularly the TGF-β signaling pathways, resulting in excess synthesis and deposition of the extracellular matrix, especially collagen. There is currently no effective or specific treatment for RDEB. Losartan, an angiotensin II type 1 receptor antagonist, is an inhibitor of TGF-β activity. Previous preclinical studies with hypomorphic Col7a1 mice recapitulating features of RDEB have suggested that losartan may improve the clinical features of RDEB. In this case series, we assessed the effects of losartan on the clinical and histopathologic features in seven patients with RDEB; three females and four males; aged 18.1 ± 9.1 years. The diagnosis was based on characteristic clinical features and the presence of biallelic loss-of-function mutations in COL7A1. Daily oral administration of losartan (0.7 mg/kg) for six weeks resulted in subjective improvement of the clinical features, as judged by the treating physicians and the patients, and the severity of the disease objectively improved based on Birmingham Epidermolysis Bullosa Severity (BEBS) score (30.1 ± 12.8 versus 23.3 ± 10.4, before and after treatment, p = 0.018), accompanied by improvement of quality of life, as determined by the EB-QoL questionnaire (24.0 ± 8.1 versus 17.7 ± 5.5, p = 0.018). Histopathology of the selected lesions revealed after treatment increased number of mast cells, and enhanced microvasculature in the mid and lower dermis. The width of collagen bundles in dermis was suggested to be decreased in four samples and changed from dense to loose in appearance. In summary, this case series reports beneficial effects of losartan on RDEB as a potentially novel treatment.An efficient and stereoselective CoIII -catalyzed sequential C-H bond addition to 1,3-enynes and aldehydes is disclosed. This transformation represents the first example of sequential C-H bond additions to 1,3-enynes and a second coupling partner and provides the first example of preparing allenes by C-H bond addition to 1,3-enynes. A wide range of aldehydes, C-H bond substrates and 1,3-enynes with large substituents on the alkynes are effective substrates. The allenyl alcohol products can be further converted to dihydrofurans with high stereoselectivity either in situ or under Ag-mediated cyclization conditions. The allenyl silyl group can also be transferred to the adjacent alcohol by a Brook rearrangement. Moreover, a mechanism for the transformation is proposed supported by X-ray structural characterization of a cobaltacycle intermediate.A two-step synthesis of less accessible spiro[cyclobutene-1,9′-fluorene] compounds from biaryl-alkynes and 2-(2-fluoropyridin-1-ium-1-yl)-1,1-bis((trifluoromethyl)sulfonyl)ethan-1-ide, which serves as a potent precursor for outstandingly electrophilic Tf2 C=CH2 , has been developed. This synthetic methodology includes selective formation of gem-bis(triflyl)cyclobutenes from biaryl-alkynes and Tf2 C=CH2 followed by desulfinative spirocyclisation mediated by 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP). Besides, on the basis of the chameleonic reactivity of sulfone functionality, several derivatisations of triflylated spiro[cyclobutene-1,9′-fluorene] products have been successfully achieved.In contrast to p-quinodimethane tetraesters, which undergo facile polymerization due to their diradical character, newly synthesized 1 and 2 consisting of a chalcogenadiazole fused to a p-naphthoquinodimethane tetraester are thermodynamically stable due to butterfly-shaped deformation. Such a folded molecular structure is also favorable for chalcogen bond (ChB) formation through intermolecular close contacts between a chalcogen atom (E Se or S) and the oxygen atoms of ester groups in a crystal. The less-explored chelating-ChB through a C=O⋅⋅⋅E⋅⋅⋅O=C contact [Se⋅⋅⋅O 2.94-3.37 Å] is the key supramolecular synthon for the formation of a one-dimensional rod-like assembly in a crystal, which is commonly observed in selenadiazole-tetraesters (1) with OMe, OEt, and OiPr groups. The formation of inclusion cavities between the rods shows that 1 could serve as solid-state host molecules for clathrate formation, as found in a hexane-solvated crystal. In contrast, thiadiazole-tetraesters (2) are less suitable for the formation of a rod-like assembly since the ChB involving S is less effective, and thus is overwhelmed by weak hydrogen bonds through C-H⋅⋅⋅O contacts.

Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair.

To investigate the effect and potential mechanism of ALCAR in the treatment of NED.

Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50mg/kg/day) group, BCNI + higher-dose (100mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro.

We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen contentibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED.

ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED.One of the main pathological features of Parkinson’s disease (PD) is the loss of dopaminergic neurons in the substantia nigra compacta (SNc). Cistanoside A (CA) has a strong neuroprotective effect in PD, but the exact mechanism is unclear. In the present study, the MPTP-stimulated mouse model of PD and MPP+ -treated PD model in the MES23.5 neuronal cell model of PD were used to investigate the neuroprotective effects of CA on PD and its potential mechanism. The in vivo experiment results indicated that CA improved the motor function in mice and increased the number of tyrosine hydroxylase positive cells in SNc. In vitro experiments showed that CA reduced the MPP+ -induced decrease in neurons and mitochondrial membrane potential and promoted the activation of autophagosomes. Furthermore, we found that CA promoted the recruitment of PINK1 and Parkin aggregation to impair mitochondrial membranes and inhibited mitochondrial damage via LC3- and p62-mediated autophagy. In conclusion, CA protects against MPTP-induced neurotoxicity in vivo and MPP+ -induced neurotoxicity in vitro, possibly by promoting the PINK1/Parkin/p62 pathway to accelerate the degradation of damaged mitochondria thereby reducing oxidative stress.Limonene-1,2-diol is a limonene oxygenated metabolite that possesses eight different stereoisomers, which could result in different biological properties. Nonetheless, the relation between its spatial configuration and biological function is still little explored. The present study aimed to perform the stereoisomers identification using nuclear magnetic resonance (NMR) investigation of the limonene-1,2-diol produced via R-(+)- and S-(-)-limonene biotransformation by Colletotrichum nymphaeae and S-(-)-limonene biotransformation by Fusarium oxysporum 152B. Besides, in vitro antiproliferative activity was evaluated against human tumor and nontumor cell lines. The NMR analysis showed that R-(+)-limonene biotransformation afforded exclusively (+)-(1S,2S,4R-limonene-1,2-diol), whereas S-(-)-limonene biotransformation afforded exclusively (-)-(1R,2R,4S-limonene-1,2-diol) independent on the fungi used. Despite no significant cytostatic effects, a possible influence of stereogenic center on the antiproliferative activity of these limonene biotransformation products was evidenced. Moreover, the lack of in vitro antiproliferative effect of limonene-1,2-diol against nontumor cells suggested a safe dose range for further in vivo evaluations, including food applications.S-F-bond activation of sulfur tetrafluoride at [Rh(Cl)(tBu xanPOP)] (1; tBu xanPOP=9,9-dimethyl-4,5-bis-(di-tert-butylphosphino)-xanthene) led to the formation of the cationic complex [Rh(F)(Cl)(SF2 )(tBu xanPOP)][SF5 ] (2 a) together with trans-[Rh(Cl)(F)2 (tBu xanPOP)] (3) and cis-[Rh(Cl)2 (F)(tBu xanPOP)] (4) which both could also be obtained by the reaction of SF5 Cl with 1. In contrast to that, the conversion of SF4 at the methyl complex [Rh(Me)(tBu xanPOP)] (5) gave the isolable and room-temperature stable cationic λ4 -trifluorosulfanyl complex [Rh(Me)(SF3 )(tBu xanPOP)][SF5 ] (6). Treatment of 6 with the Lewis acids BF3 or AsF5 produced the dicationic difluorosulfanyl complex [Rh(Me)(SF2 )(tBu xanPOP)][BF4 ]2 (8 a) or [Rh(Me)(SF2 )(tBu xanPOP)][AsF6 ]2 (8 b), respectively. Refluorination of 8 a was possible with the use of dimethylamine giving [Rh(Me)(SF3 )(tBu xanPOP)][BF4 ] (9). A reaction of 6 with trichloroisocyanuric acid (TClCA) gave the fluorido complex [Rh(F)(Cl)(SF2 )(tBu xanPOP)][Cl] (2 b) together with chloromethane and SF5 Cl.Monoclonal immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%-50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti-MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin scale (mRS). From 2011 to 2018, 64 patients were studied 34 were treated with R and 30 with ICT. JAK Inhibitor I datasheet According to our treatment decision-making process, the median mRS was higher in the ICT group (mRS 2) than in the R group (mRS 1). At one year, improvements of the mRS rates were 46% and 18% in the ICT and R groups of patients respectively, with median times to response of eight and 13 months (p = 0.023). Adverse effects were higher in the ICT group 62% vs 15% (p ˂ 0.01), all grades included. One secondary acute leukaemia occurred five years after treatment with ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti-MAG neuropathy symptoms.In the development of photolabile protecting groups, it is of high interest to selectively modify photochemical properties with structural changes as simple as possible. In this work, knowledge of fluorophore optimization was adopted and used to design new coumarin- based photocages. Photolysis efficiency was selectively modulated by inactivating competitive decay channels, such as twisted intramolecular charge transfer (TICT) or hydrogen-bonding, and the photolytic release of the neurotransmitter serotonin was demonstrated. Structural modifications inspired by the fluorophore ATTO 390 led to a significant increase in the uncaging cross section that can be further improved by the simple addition of a double bond. Ultrafast transient absorption spectroscopy gave insights into the underlying solvent-dependent photophysical dynamics. The chromophores presented here are excellently suited as new photocages in the visible wavelength range due to their simple synthesis and their superior photochemical properties.