Engineered extracellular vesicles encapsulated Bryostatin-1 as therapy for neuroinflammation

Targeted and effective drug delivery to central nervous system (CNS) lesions is a major challenge in the treatment of multiple sclerosis (MS). Extracellular vesicles (EVs) have great promise as a...

Effective drug release from safe ultrasound-triggered nanocarriers

Selective delivery of medication into specified tissue targets would realize the promise ofpersonalized medicine with minimal side effects. Such an approach could be particularlytransformative for patients with brain disorders, in whom drugs could be released in the impairedbrain circuits at high concentration while sparing other brain regions and organs. Focusedultrasound provides noninvasive and practical means to release drugs from nanocarriers selectivelyat its target. However, which nanoparticle formulations provide safe and effective release andunder which ultrasound parameters has been unclear. To expedite regulatory approval, wetested release effectiveness from nanocarriers filled with perfluorocarbon cores of relatively highboiling points (up to 142◦C). We confirmed the safety of these nanocarriers in non-humanprimates. Crucially, we found that these safe, high-boiling-point nanocarriers can be used foreffective release so long as they are activated by ultrasound of frequencies lower than thoseused previously (300 kHz). This study informs the formulation and release parameters for safeand effective drug delivery in specific parts of the body or brain regions.

Naringenin: a potential bioactive compound and pathways of biosynthesis – a review

Naringenin is a member of the flavonoid family. This natural compound represents a large proportion of secondary metabolites produced by higher plants and is a rich part of the human diet. Naringenin also has been used in the pharmaceutical and medical fields as an effective drug for anti-oxidative, anti-cancer, anti-obesity, and anti-inflammatory activities. Naringenin is also a typical plant metabolite, that has never been reported to be produced in prokaryotes. Recently, many papers reported that various members of the Streptomyces family, a genus of actinobacteria, had a novel pathway to produce naringenin. As a result, this review focuses on some clinical pharmacological effects and promising applications in the medical of naringenin, also its pathways of biosynthesis.

Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements

A challenge in designing treatment regimens for tuberculosis is the necessity to use three or more antibiotics in combination. The combination space is too large to be comprehensively assayed; therefore, only a small number of possible combinations are tested. We narrowed the prohibitively large search space of combination drug responses by breaking down high-order combinations into units of drug pairs. Using pairwise drug potency and drug interaction metrics from in vitro experiments across multiple growth environments, we trained machine learning models to predict outcomes associated with higher-order combinations in the BALB/c relapsing mouse model, an important preclinical model for drug development. We systematically predicted treatment outcomes of >500 combinations among twelve antibiotics. Our classifiers performed well on test data and predicted many novel combinations to be improved over bedaquiline + pretomanid + linezolid, an effective regimen for multidrug-resistant tuberculosis that also shortens treatment in BALB/c mice compared to the standard of care. To understand the design features of effective drug combinations, we reformulated classifiers as simple rulesets to reveal guiding principles of constructing combination therapies for both preclinical and clinical outcomes. One example ruleset is to include a drug pair that is synergistic in dormancy and another pair that is potent in a cholesterol-rich growth environment. These rulesets are predictive, intuitive, and practical, thus enabling rational construction of effective drug combinations based on in vitro pairwise drug synergies and potencies. As more preclinical and clinical drug combination data become available, we expect to improve predictions and combination design rules.

The Antimalaria Drug Artesunate Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication via Activating AMPK and Nrf2/HO-1 Signaling Pathways

Porcine Reproductive and Respiratory Syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide. Currently, vaccine strategies provide limited protection against PRRSV transmission, and no effective drug is commercially available. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV pandemics. This study showed that artesunate (AS), one of the antimalarial drugs, potently suppressed PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs) at micromolar concentrations. Furthermore, we demonstrated that this suppression was closely associated with AS-activated AMPK (energy homeostasis) and Nrf2/HO-1 (inflammation) signaling pathways. AS treatment promoted p-AMPK, Nrf2 and HO-1 expression, and thus inhibited PRRSV replication in Marc-145 and PAM cells in a time- and dose-dependent manner. These effects of AS were reversed when AMPK or HO-1 gene was silenced by siRNA. In addition, we demonstrated that AMPK works upstream of Nrf2/HO-1 as its activation by AS is AMPK-dependent. Adenosine phosphate analysis showed that AS activates AMPK via improving AMP/ADP:ATP ratio rather than direct interaction with AMPK. Altogether, our findings indicate that AS could be a promising novel therapeutics for controlling PRRSV and that its anti-PRRSV mechanism, which involves the functional link between energy homeostasis and inflammation suppression pathways, may provide opportunities for developing novel antiviral agents. Importance Porcine reproductive and respiratory syndrome virus (PRRSV) infections have been continuously threatened the pork industry worldwide. Vaccination strategies provide very limited protection against PRRSV infection, and no effective drug is commercially available. We show that artesunate (AS), one of the antimalarial drugs, is a potent inhibitor against PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs). Furthermore, we demonstrate that AS inhibits PRRSV replication via activation of AMPK-dependent Nrf2/HO-1 signaling pathways, revealing a novel link between energy homeostasis (AMPK) and inflammation suppression (Nrf2/HO-1) during viral infection. Therefore, we believe that AS may be a promising novel therapeutics for controlling PRRSV, and its anti-PRRSV mechanism may provide a potential strategy to develop novel antiviral agents.