The multiple beneficial effects on human health of the short-chain fatty acid butyrate, synthesized from non-absorbed carbohydrate by colonic microbiota, are well documented. At the intestinal level, butyrate plays a regulatory role on the transepithelial fluid transport, ameliorates mucosal inflammation and oxidative status, reinforces the epithelial defense barrier, and modulates visceral sensitivity and intestinal motility. In addition, a growing number of studies have stressed the role of butyrate in the prevention and inhibition of colorectal cancer. At the extraintestinal level, butyrate exerts potentially useful effects on many conditions, including hemoglobinopathies, genetic metabolic diseases, hypercholesterolemia, insulin resistance, and ischemic stroke. The mechanisms of action of butyrate are different; many of these are related to its potent regulatory effects on gene expression. These data suggest a wide spectrum of positive effects exerted by butyrate, with a high potential for a therapeutic use in human medicine.

Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK–acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance.

Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-α (peroxisome proliferator-activated receptor-α) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-α agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and palmitoylethanolamide (PEA) reduced nocifensive behaviors elicited in mice by intraplantar (i.pl.) injection of formalin or i.p. injection of magnesium sulfate. These effects were absent in PPAR-α-null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcription-independent mechanism. Consistent with this hypothesis, blockade of calcium-operated IK_ca (K_Ca3.1) and BK_ca (K_Ca1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR-α agonists may inhibit nocifensive responses by acting on peripheral PPAR-α. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-α was expressed in dorsal root ganglia neurons of wild-type but not PPAR-α-null mice; and (ii) GW7647 and PEA prevented formalin-induced firing of spinal cord nociceptive neurons in rats. In addition to modulating nociception, GW7647 and PEA reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain; these effects were also contingent on PPAR-α expression and were observed following either acute or subchronic PPAR-α agonist administration. Finally, acute administration of GW7647 and PEA reduced hyperalgesic responses in the complete Freund9s adjuvant and carrageenan models of inflammatory pain. Our results suggest that PPAR-α agonists may represent a novel class of analgesics.

Bisphenol A (BPA) is a non-persistent anthropic and environmentally ubiquitous compound widely employed and detected in many consumer products and food items; thus, human exposure is prolonged. Over the last ten years, many studies have examined the underlying molecular mechanisms of BPA toxicity and revealed links among BPA-induced oxidative stress, male and female reproductive defects, and human disease. Because of its hormone-like feature, BPA shows tissue effects on specific hormone receptors in target cells, triggering noxious cellular responses associated with oxidative stress and inflammation. As a metabolic and endocrine disruptor, BPA impairs redox homeostasis via the increase of oxidative mediators and the reduction of antioxidant enzymes, causing mitochondrial dysfunction, alteration in cell signaling pathways, and induction of apoptosis. This review aims to examine the scenery of the current BPA literature on understanding how the induction of oxidative stress can be considered the “fil rouge” of BPA’s toxic mechanisms of action with pleiotropic outcomes on reproduction. Here, we focus on the protective effects of five classes of antioxidants—vitamins and co-factors, natural products (herbals and phytochemicals), melatonin, selenium, and methyl donors (used alone or in combination)—that have been found useful to counteract BPA toxicity in male and female reproductive functions.