Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named “non-neuronal cells.” In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells—and therefore the control of neuroinflammation—depends on the local “on demand” synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide—either by decreasing its degradation or exogenous administration—is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.

Moringa oleifera Lam. is a tropical plant widely used in traditional medicines and as a food supplement. It is characterized by the presence of glucosinolates and isothiocyanates; the stable isothiocyanate 4-[(α-l-rhamnosyloxy)benzyl]isothiocyanate (moringin) has been widely studied for its bioactivity as hypoglycemic, antimicrobial, anticancer and in particular for its involvement in nociception and neurogenic pain. Moringa extracts and pure moringin were submitted to in vitro assays with the somatosensory TRPA1 ion channel, proving that moringin is a potent and effective agonist of this receptor involved in nociceptive function and pain states. Moringin do not activate or activates very weakly the vanilloids somatosensory channels TRPV1,2,3 and 4, and the melastatin cooling receptor TRPM8. The comparison of moringin’s activity with other known agonists of natural origin is also discussed.

There is growing evidence that perturbation of the gut microbiome, known as “dysbiosis”, is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond.

Thermokarst lakes are one of the most abundant types of microbial ecosystems in the circumpolar North. These shallow basins are formed by the thawing and collapse of ice-rich permafrost, with subsequent filling by snow and ice melt. Until now, permafrost thaw lakes have received little attention for isolation of microorganisms by culture-based analysis. The discovery of novel psychrophiles and their biomolecules makes these extreme environments suitable sources for the isolation of new strains, including for potential biotechnological applications. In this study, samples of bottom sediments were collected from three permafrost thaw lakes in subarctic Québec, Canada. Their diverse microbial communities were characterized by 16S rRNA gene amplicon analysis, and subsamples were cultured for the isolation of bacterial strains. Phenotypic and genetic characterization of the isolates revealed affinities to the genera Pseudomonas, Paenibacillus, Acinetobacter,Staphylococcus and Sphingomonas. The isolates were then evaluated for their production of extracellular enzymes and exopolymers. Enzymes of potential biotechnological interest included α and β-glucosidase, α and β-maltosidase, β-xylosidase and cellobiohydrolase. One isolate, Pseudomonas extremaustralis strain 2ASCA, also showed the capability to produce, in the loosely bound cell fraction, a levan-type polysaccharide with a yield of 613 mg/L of culture, suggesting its suitability as a candidate for eco-sustainable alternatives to commercial polymers.

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC₅₀ of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.

Sisymbrium officinale (L.) Scop. is a wild common plant of the Brassicaceae family. It is known as “the singers’ plant” for its traditional use in treating aphonia and vocal disability. Despite its wide use in herbal preparations, the molecular mechanism of action of S. officinale extracts is not known. The plant is rich in glucosinolates and isothiocyanates, which are supposed to be its active compounds. Some members of this family, in particular allylisothiocyanate, are strong agonists of the transient receptor potential ankyrin 1 (TRPA1) channel, which is involved in the somatosensory perception of pungency as well as in the nociception pathway of inflammatory pain. This study aims to isolate the glucosinolates and isothiocianates from fresh S. officinale to identify the major components and test their activity in in vitro assays with a cloned TRPA1 channel. Samples of cultivated S. officinale have been extracted and the active compounds isolated by column chromatography, HPLC and PTLC. The main components glucoputranjivin, isopropylisothiocyanate and 2-buthylisothiocianate have been tested on TRPA1. The glucosinolates glucoputranjivin and sinigrin turned out to be inactive, while isopropylisothiocyanate and 2-buthylisothiocyanate are potent agonists of TRPA1, with an EC₅₀ in the range of the high potency natural agonists identified so far for this somatosensory channel.