We designed a class of small dimeric cyclic guanidine derivatives, which display potent antibacterial activity against both multidrug-resistant Gram-negative and Gram-positive bacteria. They could compromise bacterial membranes without developing resistance, inhibit biofilms formed by E. Coli, and exhibit excellent in vivo activity in the MRSA-infected thigh burden mouse model.

Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.

Background: Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response. Methods: Double transgenic APPswe/PS1ΔE9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained. Results: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC’s natural immunomodulatory properties. Conclusion: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody’s specificity for these “oligomeric” Aβ species could provide the opportunity to produce some clinical benefits in AD subjects.

A few polymyxin derivatives with broad-spectrum antimicrobial activity were developed. Lead compound P1 disrupted bacterial membranes rapidly without developing resistance.

Alpha-synuclein is considered the major pathological protein associated with Parkinson’s disease, but there is still no effective immunotherapy which targets alpha-synuclein. In order to create a safer and more effective therapy against PD, we are targeting an epitope of alpha-synuclein rather than full-length alpha-synuclein. We have selected several antigenic domains (B-cell epitope) through antigenicity prediction, and also made several recombinant protein fragments from alpha-synuclein upon antigenicity prediction in an E. coli system. We then tested the function of each of the peptides and recombinant fragments in aggregation, their toxicity and antigenicity. We have discovered that the full-length recombinant (aa1–140) can aggregate into oligomers or even fibrils, and fragment aa15–65 can promote the aggregation of aa1–140. It is worth noting that it not only promotes whole protein aggregation, but also self-aggregates as seen by western blotting and silver staining assays. We have tested all candidates on primary neurons for their toxicity and discovered that aa15–65 is the most toxic domain compared to all other fragments. The antibody targeting this domain also showed both anti-aggregation activity and some therapeutic effect. Therefore, we believe that we have identified the most potent therapeutic domain of alpha synuclein as a therapeutic target.