**1. Introduction**

Endophytic fungi are defined as fungi inhabiting tissues and organs of healthy plants during certain stages of their life cycle without causing apparent symptoms. The concept of endophytism, introduced by De Bary in 1866 and almost completely neglected for over a century, has recently become of common usage concomitantly to advances in knowledge on occurrence and functions of this component of biodiversity. Increasing attention by the scientific community is boosted by the opportunity to exploit the unique aptitudes and properties of these microbial associates of plants [1].

As a consequence of the long-term association of endophytes with medicinal plants, based on mutually beneficial relationships, the former may also participate in metabolic paths and boost their own natural biosynthetic activity, or may gain some genetic information to synthesize biologically active compounds closely related to those directly produced by the host plant [2,3]. Endophytic fungi derived from medicinal plants are becoming more and more popular, due to specific modes of action and the ability to provide multiple benefits, which make them relevant for both agricultural and pharmaceutical applications [3]. This review is devoted to an analysis of the biochemical potential of endophytic fungi reported from species of sage (*Salvia* spp.), examining the advances in this particular field made by the scientific community in recent years.

## **2.** *Salvia***: The Largest Genus of Lamiaceae**

Lamiaceae is one of the most important herbal families, including a wide variety of plants with multiple medical, culinary and industrial applications. Within the subfamily Nepetoideae, sage species are ascribed to the genus *Salvia*, a name deriving from the Latin word "*salvere*", which refers to the curative properties of these plants. It represents the largest genus of the family counting between 700 and 1000 species [4]. Uncertainty of this number is basically due to the broad geographical range of distribution, covering all continents and climatic areas, which makes taxonomic verification problematic.

As for many plants and other organisms, the application of biomolecular techniques in taxonomy has determined several basic reassessments in classification. Until a few years ago, the genus name *Salvia* was only used for species displaying the typical morphological features of sage. Nevertheless, recent systematic work has emphasized close relationships with the genera *Dorystaechas*, *Meriandra*, *Perovskia*, *Rosmarinus* and *Zhumeria*, which resulted to be clearly embedded in *Salvia* in dedicated phylogenetic analyses, so that their separation is no more justified [4,5]. Although not consolidated in the common use yet, this new taxonomic sorting is basically followed in this paper. However, by reason of several peculiar aspects concerning geographical distribution and biotechnological applications, the species *Salvia rosmarinus* (=*Rosmarinus o*ffi*cinalis*) will be the subject of a dedicated analysis in a forthcoming paper.

Medicinal properties of sages derive from their ability to produce a multitude of bioactive secondary metabolites, many of which have been reported for antibiotic, antitumor, antiviral, antiprotozoal, insecticidal and antioxidant effects, or even to be responsible for allelopathic interactions with other plants [6]. These varied bioactivities are reflected by quite diverse chemical structures. In fact, besides flavonoids and simple phenolic compounds like caffeic, rosmarinic and salvianolic acids, which are mainly known for their radical scavenging effects, these products include monoterpenoids, sesquiterpenoids, triterpenoids and diterpenoids. Structural diversity is particularly evident within this latter grouping, including labdanes, ent-kauranes, abietanes, icetexanes, clerodanes, and pimaranes, as well as phenolic diterpenoids, such as carnosol and carnosic acid [6]. Moreover, some abietanes are rearranged, to form the important scaffold of tanshinones [7]. These latter products are particularly considered for pharmaceutical application based on their antioxidant [8], antibacterial [9], antidiabetic [10], anti-inflammatory [11], and antiproliferative [12] properties, and are currently the subject of a specific project at our laboratories, in which the species *Salvia abrotanoides* (formerly *Perovskia abrotanoides*) and *Salvia yangii* (formerly *Perovskia atriplicifolia*), regarded as an alternative source of tanshinones, are analyzed through combined metabolomics and transcriptomics approaches, also with reference to the associated endophytic fungi.
