Risk of SARS-CoV-2 transmission in the close contacts in a small rural area in the Veneto Region (NE-Italy): past evidence for future scenarios.

Background: During the first pandemic phase of COVID-19, an epidemiological study, named First survey, was conducted on the population of a small rural area in northern Italy. In spring 2020, the results showed how a prolonged lockdown slowed down the spread of the virus. Methods: After contacting positive First Survey subjects and their families, those who decided to join voluntarily underwent a blood test to assess the presence of qualitative lgG about 2 months after the previous one. This was to determine if IgG persisted in individuals who tested positive in the First Survey as well as to assess the antibody status of their close family members, to determine if they were unintentionally infected. Results: Based on serological analysis, 35.1% of the samples contained blood IgG. In subjects who tested positive during the First Survey, 62.5% remained IgG positive more than 2 months later. Among family members who were exposed to a positive relative, 23.7% were infected. Linear regression analysis showed that the presence of an infected person within a household resulted in the infection spreading to the others, but not excessively. Induced isolation extinguished the infection regardless of the extent of the contagion (intra-family or extra-family). Micro-outbreaks of SARS-Cov-2 infection which arose in the same household from extra-familial infections played a decisive role on the statistical significance of IgG-positive subjects (p < 0.001). Discussion: The study reveal 52.6% of the IgG-positive subjects in the Second Survey came from the First Survey and 47.4% were family members previously in contact with positive subjects. Data suggest that there have been undiagnosed patients feeding the spread of the virus since the beginning of the pandemic. In conclusion, for future pandemics, it will be necessary: i) to ensure the rapid isolation of symptomatic patients and the early identification of their close contacts, ii) to carry out the maximum number of tests in the shortest possible time, both on symptomatic and asymptomatic subjects, and iii) to implement information campaigns to make people aware of their risks, and implement clear, non-conflicting communication.

Epidemiological study in a small rural area of Veneto (Italian region) during Sars-Cov-2 Pandemia.

The emergence of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2) and its complications have demonstrated the devastating impact of a new infectious pathogen. The organisational change promulgated by the isolation of affected communities is of extreme importance to achieve effective containment of the contagion and good patient care. The epidemiological study of the population of a small rural community in the North East of Italy revealed how much the virus had circulated during Spring, 2020, and how contagion has evolved after a prolonged lockdown. In the 1st phase, NAAT (Nucleic Acid Amplification Testing) was performed in cases with more or less severe symptoms and a study was performed to trace the infection of family members. Only 0.2% of the population tested positive on NAAT, via nasopharyngeal swab during this 1st phase. In the 2nd phase a random sample of the general population were tested for circulating anti-Sars-Cov-2 immunoglobulins. This showed that approximately 97.9% of the population were negative, while 2.1% (with positive IgG at a distance) of the population had contracted the virus in a mildly symptomatic or asymptomatic form. The main symptom in subjects who developed immunity was fever. Antibodies were found in subjects with forced coexistence with quarantined or infected subjects. The mutual spatial distance by categories has shown higher relative prevalence of IgG positive and IgM negative cases in close proximity but also far from the infected, with respect to an intermediate distance. This suggests that subjects living in thinly populated areas could come in contact with the virus more likely due to intentional/relational proximity, while those living nearby could also be infected through random proximity.

Diverging pathways to topologically complex polycyclic bis-acetals and their ring system interchange.

Carbinol-tethered octalin-diols (1), which differ only by the C11 configuration at the angular position, were transformed selectively to three types of structurally unrelated original scaffolds such as unsymmetrical octahydroanthracenes (5/7), furofuranes (6), or spirans (8/9) via a two-step protocol. The 11S* configuration ensures a C13-C4 Friedel-Crafts type C-C bonding (through an unprecedented oxidative cleavage-triggered domino process) while the 11R* configuration allows for a C13-C2 Marson-type Friedel-Crafts C-C bonding (through a nucleophilic acetal opening).

Toward the discovery of new agents able to inhibit the expression of microsomal prostaglandin E synthase-1 enzyme as promising tools in drug development.

In our recent studies, we focused our attention on the synthesis of several gamma-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA(2) enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA(2) inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene gamma-hydroxybutenolide 2, which so far represents the only product, together with resveratrol, able to reduce PGE(2) production through the selective downregulation of mPGES-1 enzyme. In consideration that microsomal prostaglandin E synthase 1 (mPGES-1) is one of the most strategic target involved both in inflammation and in carcinogenesis processes, we decided to explore the biological effects of some structural changes of the gamma-hydroxybutenolide 2, hoping to improve its biological profile. This optimization process led to the identification of three strictly correlated compounds 14g, 16g, and 18 with higher inhibitory potency on PGE(2) production on mouse macrophage cell line RAW264.7 through the selective modulation of mPGES-1 enzyme expression.

Competing domino processes: path-discriminating ability of epoxide stereochemistry at the angular position.

Structurally different products can be reached selectively from unsaturated vicinal bicyclic diols, which differ only by the epoxide configuration at the angular position. It is possible to modify the regiochemical outcome of the domino process in such a way as to create a different pathway, [4 + 2] versus [4 + 3 + 2], and control product distribution by using the configuration bias. No previous example of a domino variant of the [4 + 3 + 2] process appears to have been documented.

Anti-inflammatory and analgesic activity of a novel inhibitor of microsomal prostaglandin E synthase-1 expression.

In a previous study, we reported a new gamma-hydroxybutenolide derivative, 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH), as inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) expression in lypopolysaccharide (LPS) stimulated RAW 264.7 and TPH-1 cells, without affecting cyclooxygenase-2 (COX-2). In this study, we evaluated the in vivo effect of BTH on some acute and chronic inflammatory animal models in relation to its inhibitory profile on mPGES-1 expression. In the zymosan-induced mouse air pouch model, BTH produced a dose-dependent inhibition of prostaglandin E(2) (PGE(2)) production and mPGES-1 protein expression in pouch exudates without any effect on COX-2 protein expression. This behavior was confirmed in the chronic model of collagen-induced arthritis, where administration of BTH (5 mg/kg) clearly reduced PGE(2) and mPGES-1 expression in joint tissues, whereas COX-2 was unaffected. These effects were accompanied by the suppression of clinical and histopathological manifestations of disease such as the loss of proteoglycan, and the destruction of surface cartilage. Other enzymes participating in the metabolism of arachidonic acid, such as prostaglandin I(2) synthase, tromboxane A(2) synthase or 5-lipoxygenase were unaffected by this compound. The acetic acid-induced hyperalgesia model in LPS-sensitized mice showed a dose-dependent analgesic effect of BTH, exerting an ED(50) value of 6.2 mg/kg. Our data suggest that inhibition of mPGES-1 protein expression in acute and chronic inflammatory models by BTH, could provide a potential therapeutic target and a pharmacological tool to discern the role of the inducible enzymes COX-2 and mPGES-1 in inflammatory pathologies.

Development of a second generation of inhibitors of microsomal prostaglandin E synthase 1 expression bearing the gamma-hydroxybutenolide scaffold.

Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, nevertheless we discovered a potent and selective modulator of the expression of microsomal prostaglandin E synthase 1 (mPGES-1), an enzyme highly involved in the inflammatory response, which represents an interesting target for the development of a new class of anti-inflammatory agents. In this paper we report the synthesis of a further collection of nine analogues, having the same scaffold of PM, the gamma-hydroxybutenolide, and bearing, as side chain, more complex aromatic portions, in substitution of the sesterterpene moiety. Their pharmacological behavior against PLA(2) enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and mPGES-1 enzymes is also described.

Total synthesis and structural confirmation of ent-galbanic acid and marneral.

By capitalizing on a highly selective Claisen rearrangement, ent-galbanic acid 1 and (+)-marneral 2 have been synthesized. The relative configurations of (+)- 1 and (+)- 2 were unambiguously established by X-ray crystallographic analysis of the precursors 11a and 20, with the absolute configuration ensuing from their derivation from R-pulegone. In this way, the controversial issue of the configuration of galbanic acid was unequivocally settled.

Enantioselective synthesis of iridal, the parent molecule of the iridal triterpenoid class.

The monocyclic triterpene iridal 1 (parent molecule) is synthesized by an approach that allows access for several representatives of the iridal family as well as diversely substituted analogues. The success of the proposed synthetic plan depends upon the effortless stereoselective establishment of the trans C10/C11 dimethyl relationship in B-ring moiety 7 using a domino-based methodology and the higly efficient Miyaura-Suzuki type sp3-sp2 segment coupling 7 and 8, respectively.

Synthesis and pharmacological evaluation of a selected library of new potential anti-inflammatory agents bearing the gamma-hydroxybutenolide scaffold: a new class of inhibitors of prostanoid production through the selective modulation of microsomal prostaglandin E synthase-1 expression.

As a part of our drug discovery effort, recently we clarified the molecular basis of phospholipase A2 (PLA2) inactivation by petrosaspongiolide M (PM), an interesting metabolite belonging to a marine sesterterpene family, containing in its structural architecture a gamma-hydroxybutenolide moiety and showing potent anti-inflammatory activity. In the attempt to expand structural diversity as well as to simplify crucial synthetic features of the parent compound, we decided to develop a selected library based on the densely functionalized gamma-hydroxybutenolide scaffold. The synthesized products were tested for their ability to inhibit PLA2 enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), two key enzymes highly involved in the inflammatory event, in order to discover new promising anti-inflammatory agents with better pharmacological profiles. This led us to the discovery of a promising inhibitor (4e) of prostanoid production acting by in vitro and in vivo selective modulation of microsomal prostaglandin E synthase 1 expression.

Chemistry and biology of anti-inflammatory marine natural products: molecules interfering with cyclooxygenase, NF-kappaB and other unidentified targets.

The majority of the anti-inflammatory drugs routinely used nowadays are COX (cyclo-oxygenase) inhibitors. The important role of this enzyme, once known as prostaglandin synthase, in inflammation came a consequence of the discovery by the Nobel prize winner John Vane with his path-breaking discovery that aspirin and similar drugs exert their action by blocking the biosynthesis of the prostaglandin group of lipid mediators. (John R. Vane, Nobel Lecture, December 8, 1982 and references cited therein) In the last five years it has become clear that there are two such enzymes involved. One of the "cyclo-oxygenases", called COX1 is responsible for making prostaglandins, which among other things, protect the stomach and kidney from damage. It is now clear that inhibition of COX1 accounts for the unwanted side effects of aspirin-like drugs such as gastric irritation and renal damage. The other enzyme, COX2, is induced by inflammatory stimuli and it is prostaglandins made by this enzyme that contribute to the inflammation in diseases such as rheumatoid arthritis. However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes. In recent years, it has steadily become more clear, that modulation in the expression of genes underlies most cellular responses, and inflammation is certainly not an exception in this sense. It does not come as surprise that molecules showing ability to interfere with factors involved in the modulation of genes expression, such as NF-kB, have also to be considered potential anti-inflammatory agents. Also in this respect, marine natural products (MNP) have brought a collection of novel molecular entities displaying ability to target COX1/COX2, NF-kappaB or acting through molecular mechanisms yet-to-be-discovered. Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-molecular targets. Chemical synthesis of particular relevant molecules will be also discussed, especially in those cases where the natural products can be considered as lead compounds for the development of simplified derivatives or analogues of potential pharmaceutical interest.

Chemistry and biology of chromatin remodeling agents: state of art and future perspectives of HDAC inhibitors.

Chromatin remodeling is a fundamental phenomenon in the life of eukaryotic cells, bearing implications to numerous physiological and pathological phenomena. This review outlines the chemistry of natural and synthetic agents endowed with the ability to interfere with such biological function, with a particular emphasis on histone deacetylase (HDAC) inhibitors. Other aspects covered in this article comprise structure activity relationships (SAR) and modes of action at molecular level, including the description of crystal structures of enzyme-inhibitor complexes.