Multi-target design strategies for the improved treatment of Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial syndrome resulting in profound misery and poses a substantial burden on human health, economy, and society throughout the world. Based on the numerous AD-related targets in the disease network, multi-target design strategy is a crucial direction to seek for enhanced therapy, and multi-target drugs have the ability to regulate more targets than single-target drugs, affecting the disease network with more potency. Herein, we highlight nine major targets associated with AD, which are acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), and phosphodiesterases (PDEs), and their respective relationship to the disease network. Furthermore, eleven multi-target design strategies classified by the involvement of AChE and related promising compounds for improved therapy of AD in recent years are described based on the nine major targets

Small molecules as inhibitors of PCSK9: current status and future challenges

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed

Increased Expression of Histone Proteins during Estrogen-Mediated Cell Proliferation

There is concern about the potential risk posed by compounds with estrogen-like activity present in the environment. As previous studies have shown that combined exposure to such compounds results in dose additivity, it should be possible to assess estrogen exposure with suitable biomarkers of effect

Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling

Human skin has the capacity to metabolise foreign chemicals (xenobiotics), but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin

Effects of Vaccinium

The beneficial effects of anthocyanins consumption on cardiovascular risk are supported by mechanistic and epidemiologic evidence. In order to explore the effects of Vaccinium berries rich in anthocyanins on serum lipids, we conducted a meta-analysis of relevant randomized controlled trials (RCTs). Sixteen studies with 1109 subjects were included in this meta-analysis. Significant heterogeneity confirmed differential effects between Vaccinium subclasses. The whortleberry group is significantly superior to placebo in lipids improvement. Besides, bilberry groups show significant differences in reducing LDL-C and increasing HDL-C in comparison with other treatments. For many of the other subgroups and comparison arms, there was insufficient evidence to draw conclusions about efficacy

Gastroretentive technologies in tandem with controlled-release strategies: A potent answer to oral drug bioavailability and patient compliance implications

There have been many efforts to improve oral drug bioavailability and therapeutic efficacy and patient compliance. A variety of controlled-release oral delivery systems have been developed to meet these needs. Gastroretentive drug delivery technologies have the potential to achieve retention of the dosage form in the upper gastrointestinal tract (GIT) that can be sufficient to ensure complete solubilisation of the drugs in the stomach fluids, followed by subsequent absorption in the stomach or proximal small intestine. This can be beneficial for drugs that have an “absorption window” or are absorbed to a different extent in various segments of the GIT. Therefore, gastroretentive technologies in tandem with controlled-release strategies could enhance both the therapeutic efficacy of many drugs and improve patient compliance through a reduction in dosing frequency. The paper reviews different gastroretentive drug delivery technologies and controlled-release strategies that can be combined and summarises examples of formulations currently in clinical development and commercially available gastroretentive controlled-release products. The different parameters that need to be considered and monitored during formulation development for these pharmaceutical applications are highlighted

Plant-Derived Products with Therapeutic Potential against Gastrointestinal Bacteria

The rising burden of antimicrobial resistance and increasing infectious disease outbreaks, including the recent COVID-19 pandemic, has led to a growing demand for the development of natural products as a valuable source of leading medicinal compounds. There is a wide variety of active constituents found in plants, making them an excellent source of antimicrobial agents with therapeutic potential as alternatives or potentiators of antibiotics. The structural diversity of phytochemicals enables them to act through a variety of mechanisms, targeting multiple biochemical pathways, in contrast to traditional antimicrobials. Moreover, the bioactivity of the herbal extracts can be explained by various metabolites working in synergism, where hundreds to thousands of metabolites make up the extract. Although a vast amount of literature is available regarding the use of these herbal extracts against bacterial and viral infections, critical assessments of their quality are lacking. This review aims to explore the efficacy and antimicrobial effects of herbal extracts against clinically relevant gastrointestinal infections including pathogenic Escherichia coli, toxigenic Clostridioides difficile, Campylobacter and Salmonella species. The review will discuss research gaps and propose future approaches to the translational development of plant-derived products for drug discovery purposes for the treatment and prevention of gastrointestinal infectious diseases

Effects of Vaccinium Berries on Serum Lipids: A Meta-Analysis of Randomized Controlled Trials

The beneficial effects of anthocyanins consumption on cardiovascular risk are supported by mechanistic and epidemiologic evidence. In order to explore the effects of Vaccinium berries rich in anthocyanins on serum lipids, we conducted a meta-analysis of relevant randomized controlled trials (RCTs). Sixteen studies with 1109 subjects were included in this meta-analysis. Significant heterogeneity confirmed differential effects between Vaccinium subclasses. The whortleberry group is significantly superior to placebo in lipids improvement. Besides, bilberry groups show significant differences in reducing LDL-C and increasing HDL-C in comparison with other treatments. For many of the other subgroups and comparison arms, there was insufficient evidence to draw conclusions about efficacy

Controllable thioester-based hydrogen sulfide slow-releasing donors as cardioprotective agents

Hydrogen sulfide (H2S) is an important signaling molecule with promising protective effects in many physiological and pathological processes. However, the study of H2S has been impeded by the lack of appropriate H2S donors that could mimic its slow-releasing process in vivo. Herein, we report the rational design, synthesis, and biological evaluation of a series of thioester-based H2S donors. These cysteine-activated H2S donors release H2S in a slow and controllable manner. Most of the donors comprising an allyl moiety showed significant cytoprotective effects in H9c2 cellular models of oxidative damage. The most potent donor 5e decreased the mitochondrial membrane potential (MMP) loss and lactate dehydrogenase (LDH) release in H2O2-stimulated H9c2 cells. More importantly, donor 5e exhibited a potent cardioprotective effect in an in vivo myocardial infarction (MI) mouse model by reducing myocardial infarct size and cardiomyocyte apoptosis. Taken together, our studies demonstrated that these new allyl thioesters are potential cardioprotective agents by releasing H2S

Novel hybrids of natural β-elemene bearing isopropanolamine moieties: synthesis, enhanced anticancer profile, and improved aqueous solubility

A series of novel β-elemene isopropanolamine derivatives were synthesized and evaluated for their antitumor activity. The results indicated that all of the compounds showed stronger antiproliferative activities than β-elemene as well as improved aqueous solubility. In particular dimer 6q showed the strongest cytotoxicity against four tumor cell lines (SGC-7901, HeLa, U87 and A549) with IC50 values ranging from 4.37 to 10.20 μM. Moreover, combination of 6q with cisplatin exhibited a synergistic effect on these cell lines with IC50 values ranging from 1.21 to 2.94 μM, and reversed the resistance of A549/DPP cells with an IC50 value of 2.52 μM. The mechanism study revealed that 6q caused cell cycle arrest at the G2 phase and induced apoptosis of SGC-7901 cells through a mitochondrial-dependent apoptotic pathway. Further in vivo study in H22 liver cancer xenograft mouse model validated the antitumor activity of 6q with a tumor inhibitory ratio (TIR) of 60.3%, which was higher than that of β-elemene (TIR, 49.1%) at a dose of 60 mg/kg. Altogether, the potent antitumor activity of 6qin vitro and in vivo warranted further preclinical investigation for potential anticancer chemotherapy