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Nigella species have been widely used in traditional medicine. The aim of this study was to evaluate the antiinflammatory and analgesic potentials of Nigella orientalis L. seeds fixed oil (NOO). The acetic acid writhing test and the formaldehyde-induced licking paw were performed to assess the analgesic activity of the oil. The antiinflammatory activity was first evaluated in vitro by the erythrocyte membrane stabilization then in vivo by xylene- and carrageenan-induced ear and paw edema, respectively. To further understand the molecular mechanism of action of the Nigella extract, lipopolysaccharide-activated RAW 264.7 macrophages were used. Nitric oxide (NO) production was measured by Griess reaction and cell viability by MTT assay. The gene and protein expression of inflammatory mediators were assessed by RT-PCR and western blot, respectively. NOO exerted a potent analgesic effect in in vivo models of writhing test and induced edema. The analyzed molecular mechanisms revealed a role for NO and prostaglandins as molecules mediating the pharmacological effects of the extract through a mechanism involving nuclear factor-κB and mitogen-activated protein kinases. This study demonstrates, for the first time, that the fixed oil of N. orientalis has strong antinociceptive and antiinflammatory properties and might be a promising agent for the treatment of certain inflammation-related diseases.

White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key molecule with pleiotropic functions. It is primarily recognized for its role in regulating energy homeostasis and food intake. Currently, further evidence suggests its potent role in reproduction, glucose metabolism, hematopoiesis, and interaction with the immune system. It is implicated in both innate and adaptive immunity, and it is reported to contribute, with other adipokines, in the cross-talking networks involved in the pathogenesis of chronic inflammation and immune-related diseases of the musculoskeletal system such as osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the most recent findings concerning the involvement of leptin in immunity and inflammatory responses in OA and RA. O.G. and F.L. are staff personnel (I3SNS stable researchers) of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff contract (ISCIII/SERGAS). C.R.F. is a predoctoral research scholar funded by ISCIII and FEDER (Exp.18/00188). M.G.R. is a recipient of a pre-doctoral contract funded by Xunta de Galicia (IN606A-2020/010). A.C.B. is a recipient of a pre-doctoral contract funded by Secretaría de Estado de Universidades, Investigación, Desarrollo e Innovación, Ministerio de Universidades (FPU2018-04165). O.G. and MAGG are members of the RICORS Programme, RD21/0002/0025 via ISCIII and FEDER. F.L. is a member of Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). The work of O.G. and J.P. (PI17/00409 and PI20/00902), and F.L. (PI18/00821, PI21/01145) is funded by ISCIII and FEDER. O.G. is a beneficiary of a project funded by the Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (project number 734899). O.G. is beneficiary of a grant funded by Xunta de Galicia, Conselleriá de Educación, Universidade e Formación Profesional, and Conselleriá de Economia, Emprego e Industria (GAIN), GPC IN607B2019/10.

Pinus halepensis Mill. seed (Pinaceae), popularly known as 'Zgougou', is widely consumed in the Mediterranean countries and used traditionally in the treatment of some diseases such as bronchitis, rheumatism, infection, and inflammation. The present study aimed to evaluate the oral safety of cold pressed oil of Pinus halepensis Mill. seeds (COPHS) by acute and 28-day repeated dose toxicities studies in Wistar mice and rats, respectively. In the acute toxicity study, oral administration of COPHS to mice did not provoke mortality or any toxic signs at doses up to 5000 mg/kg bw. After administration of COPHS at doses of 250, 500, and 1000 mg/kg bw/day for 28 days, no abnormal changes were observed in body weight, water intake, food consumption, organ weight, blood haematological, serum biochemistry parameters, and histology profile. Furthermore, there was no animal death or any symptom of toxicity in any group during sub-acute toxicity test period. Our findings demonstrate that COPHS is relatively non-toxic and has a large safety margin (5000 mg/kg). The results of the present research provide basic reference data for food consumption and for future in vivo screening of biological and pharmacological properties of cold pressed oil of Pinus halepensis Mill. seeds.

Virola is the largest genus of Myristicaceae in America, comprising about 60 species of medium-sized trees geographically spread from Mexico to southern Brazil. The plant species of this genus have been widely used in folk medicine for the treatment of several ailments, such as rheumatic pain, bronchial asthma, tumors in the joints, intestinal worms, halitosis, ulcers, and multiple infections, due to their pharmacological activity. This review presents an updated and comprehensive summary of Virola species, particularly their ethnomedicinal uses, phytochemistry, and biological activity, to support the safe medicinal use of plant extracts and provide guidance for future research. The Virola spp.’s ethnopharmacology, including in the treatment of stomach pain and gastric ulcers, as well as antimicrobial and tryponosomicidal activities, is attributable to the presence of a myriad of phytoconstituents, such as flavonoids, tannins, phenolic acids, lignans, arylalkanones, and sitosterol. Hence, such species yield potential leads or molecular scaffolds for the development of new pharmaceutical formulations, encouraging the elucidation of not-yet-understood action mechanisms and ascertaining their safety for humans This work was supported by Xunta de Galicia (Servizo Galego de Saude, SERGAS), through a research-staff contract (ISCIII/SERGAS) to O.G. and F.L., who are Staff Personnel (I3SNS stable Researcher); by Instituto de Salud Carlos III (ISCIII) and by FEDER through a “Sara Borrell” Researcher contract to V.F. (CD16/00111); and a predoctoral research scholarship to C.R.-F. (Exp.18/00188). M.G.-R. is a recipient of a predoctoral contract funded by Xunta de Galicia (IN606A-2020/010). A.C.-B. is a recipient of a predoctoral contract funded by Secretaría de Estado de Universidades, Investigación, Desarrollo e Innovación, Ministerio de Universidades (FPU2018-04165). G.R.C. is a doctoral student of the Coordination for the Improvement of Higher Education Personnel (CAPES) with a doctoral scholarship (Finance Code 001). T.M.C.P. is a Research Productivity Fellow of the National Council for Scientific and Technological Development (CNPq), Brazil (TMCP 309277/2019-1). O.G. is a member of the RETICS Programme (RD16/0012/0014) (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via ISCIII and FEDER. F.L. is a member of CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares). ISCIII and FEDER also support O.G. and J.P. (PI17/00409 and PI20/00902). This work was supported by the Research Executive Agency of the European Union in the framework of the MSCA-RISE Action of the H2020 Programme (project number, 734899), and Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional, and Consellería de Economía, Emprego e Industria (GAIN) (GPC IN607B2019/10), supported O.G. SI

Virola is the largest genus of Myristicaceae in America, comprising about 60 species of medium-sized trees geographically spread from Mexico to southern Brazil. The plant species of this genus have been widely used in folk medicine for the treatment of several ailments, such as rheumatic pain, bronchial asthma, tumors in the joints, intestinal worms, halitosis, ulcers, and multiple infections, due to their pharmacological activity. This review presents an updated and comprehensive summary of Virola species, particularly their ethnomedicinal uses, phytochemistry, and biological activity, to support the safe medicinal use of plant extracts and provide guidance for future research. The Virola spp.’s ethnopharmacology, including in the treatment of stomach pain and gastric ulcers, as well as antimicrobial and tryponosomicidal activities, is attributable to the presence of a myriad of phytoconstituents, such as flavonoids, tannins, phenolic acids, lignans, arylalkanones, and sitosterol. Hence, such species yield potential leads or molecular scaffolds for the development of new pharmaceutical formulations, encouraging the elucidation of not-yet-understood action mechanisms and ascertaining their safety for humans.

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration. Acknowledgments: This work was supported by Xunta de Galicia (Servizo Galego de Saude, SERGAS), through a research-staff contract (ISCIII/SERGAS) to OG and FL, which are Staff Personnel (I3SNS stable Researcher), by Instituto de Salud Carlos III (ISCIII) and by FEDER through a predoctoral research scholar to CR-F (Exp.18/00188), and “Miguel Servet” Researcher contract to RG and JC. MG is a recipient of pre-doctoral contract funded by Xunta de Galicia (IN606A-2020/010). AC is a recipient of a pre-doctoral contract funded by Secretaría de Estado de Universidades, Investigación, Desarrollo e Innovación, Ministerio de Universidades (FPU2018-04165). OG is member of RETICS Programme, [RD16/0012/0014] (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via ISCIII and FEDER. FL is a member of CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares). ISCIII and FEDER also support OG and JP [PI17/00409 and PI20/00902]. This work was supported by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme [Project number 734899], and Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN) [GPC IN607B2019/10] to OG. A.M. has received funding from the following sources: The European Commission Framework 7 program (EU FP7; HEALTH.2012.2.4.5-2, project number 305815; Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases). The Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. A.M. also wishes to acknowledge funding from the European Commission through a Marie Curie Intra-European Fellowship for Career Development grant (Project number 625746; acronym: CHONDRION; FP7-PEOPLE-2013-IEF). A.M. also wishes to acknowledge financial support from the European Structural and Social Funds (ES Strukt ¯ urin˙ es Paramos) through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity “Improvement of researchers” qualification by implementing world-class R&D projects’ of Measure No. 09.3.3-LMTK-712 (grant application code: 09.3.3-LMT-K-712-01-0157, agreement No. DOTSUT-215) and the new funding program: Attracting Foreign Researchers for Research Implementation (2018-2022).