Current Topics in Medicinal Chemistry - Volume 16, Issue 8, 2016

Vanadium compounds are promising anti-diabetic agents. Although BEOV was not able to succeed in phase II clinical trial, great progresses have been made in the past three decades on the discovery and development of anti-diabetic vanadium compounds. A vast of knowledge has been obtained on the molecular mechanisms of both the pharmacological and toxicological effects of vanadium complexes. It has been revealed that vanadium compounds exert insulin enhancement effects and cell protection via a multiple mechanism involving inhibition of PTP1B, activation of PPARs- AMPK signaling, regulation of unfolded protein responses (UPRs), and stimulation of antioxidant enzymes, while vanadium-induced oxidative stress and inflammatory response could primarily be attributed to vanadium toxicity. Based on the present results concerning the relationship between structures, biological activities and biochemical properties, the rationale for future design of anti-diabetic vanadium compounds has been discussed.

There is growing evidence to suggest that chronic, low-grade inflammation occurs in abdominal obesity, insulin resistance, type 2 diabetes mellitus and related complications, and that proinflammatory cytokines play an important role in the onset and progression of type 2 diabetes. These findings consequently provide new opportunities for the use of anti-inflammatory strategies to correct the metabolic disorders. Discovery of new synthetic bioactive small molecules to interfere with chronic, low-grade inflammation and type 2 diabetes has attracted considerable attention in medicinal chemistry. To date, a number of organoselenium small molecules and chromium(III) complexes have been shown to have the potential to alleviate chronic low-grade inflammation and type 2 diabetes, including ebselen, selenomethionine, chromium picolinate, chromium dinicocysteinate, chromium phenylalaninate, trinuclear chromium propionate, chromium histidinate, chromium nicotinate, etc. Here, we review recent advances in development of organoselenium small molecules and chromium(III) complexes to intervene in chronic low-grade inflammation and type 2 diabetes, and discuss their mode of action, potential molecular mechanisms and toxicity.

Alzheimer’s disease is a devastating and invariably fatal neurodegenerative brain disorder with no cure. AD is characterized by two pathological protein deposits, the senile plaques composed mainly of amyloid-β (Aβ) peptide and the neurofibrillary tangles which are bundles of paired helical filaments (PHF) of protein tau. In addition, oxidative stress, disorders in signal transduction and metal ions dyshomeostasis also play significant roles in the development of AD. A large body of studies suggests that selenium (Se), either as Se-containing compounds or as selenoproteins, may be beneficial in reducing Alzheimer’s pathology. Se is involved in most of the molecular pathways that are important in the progression of AD. We reviewed the literature regarding Se and AD and discussed the roles and mechanisms of Se in AD, as well as the potential of Se in AD prevention.

Mitochondrial dysfunction and neuroinflammation occur in Alzheimer’s disease (AD). The causes of these pathologic lesions remain uncertain, but links between these phenomena are increasingly recognized. In this review, we discuss data that indicate mitochondria or mitochondrial components may contribute to neuroinflammation. While mitochondrial dysfunction could cause neuroinflammation, neuroinflammation could also cause mitochondrial dysfunction. However, based on the systemic nature of AD mitochondrial dysfunction as well as data from experiments we discuss, the former possibility is perhaps more likely. If correct, then manipulation of mitochondria, either directly or through manipulations of bioenergetic pathways, could prove effective in reducing metabolic dysfunction and neuroinflammation in AD patients. We also review some potential approaches through which such manipulations may be achieved.

Coenzyme Q10 (CoQ10) is a component of electron transport chain and acts as an antioxidant. It is also used for preventing neurodegeneration against mitochondrial deficiency and oxidative stress. Therefore, CoQ10 has received increasing attention as therapeutic and preventive intervention for neurodegenerative diseases. This review article focuses mainly on the structure of CoQ10, the function of CoQ10 and the relationship between mitochondrial impairment, oxidative stress and neurodegenerative diseases. In addition, the effects of CoQ10 on Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are also discussed. Finally, future perspectives regarding development of successful treatment for neurodegenerative diseases are proposed.

Dementia is an acquired progressive cognitive dysfunction, affecting the content of consciousness rather than the level of consciousness. Most dementia is senile dementia, accounting for the majority of dementia. The most important and common form of senile dementia is refractory dementia, which includes Alzheimer's disease (AD) and vascular dementia (VD). Due to the diversity and uncertainty of the pathogenic mechanism of VD and AD, no significantly effective drug currently exists. Berberine is a natural isoquinoline alkaloid extracted from Coptis chinensis that has a wide range of pharmacological effects. studies in recent years have also found that berberine can additionally treat senile dementia by affecting neurotransmitter, anti-oxidative stress, metabolism and other multi-target pathways. Multi-target treatment of senile dementia by berberine is a potential avenue of study for senile dementia treatment.

Alginate is a naturally occurring acidic linear polysaccharide obtained from marine brown seaweed. Low molecular weight structurally diverse derivatives and oligosaccharides derived from alginate have shown various tremendous biological and pharmacological activities. It has been demonstrated that immuno-inflammation is involved in many prevalent human diseases, such as cancer, severe infection and neurodegeneration. Given the activities of marine natural products in the regulation of immune responses, increasing efforts are being made toward the development of lowmolecular- weight natural compounds that aid in the prevention and treatment of immune- and inflammatory-related diseases. In this review, we describe the development of chemical modification and molecular depolymerization methods that modify the physicochemical and biological characteristics of alginate. Additionally, current progress in research on immuno-inflammatory, anti-neurodegenerative and anti-tumor activities of alginate derivatives is highlighted.

As an important hallmark in cancer progress, inflammation attracts more and more interests in recent years. Lots of evidences support the positive effect of n-3 PUFA in inflammation-associated diseases, the supplement of these fatty acids is thought to be promising in the prevention and treatment of cancers. In this review, we summarize some current knowledge of the mechanisms by which n-3 PUFA are thought to attenuate cancer associated inflammation, and we also introduce the current situation of n-3 PUFA in clinic.