Neoflavonoids as Inhibitors of HIV-1 Replication by Targeting the Tat and NF-kB Pathways

Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF- B and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 M. The assays of these synthetic 4-phenylchromen-2-ones may aid in the investigation of some aspects of the anti-HIV activity of such compounds and could serve as a scaffold for designing better anti-HIV compounds, which may lead to a potential anti-HIV therapeutic dru

Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB

[EN] Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggabilitySIFinancial support came from Spanish MINECO (CTQ2015-68175-R, AGL2016-79813-C2-1-R, AGL2016-79813-C2-2-R and SAF2017-83575-R), ISCIII-RICET Network (RD12/0018/0002) and Consejería de Educación de la Junta de Castilla y León (LE020P17) co-financed by the Fondo Social Europeo of the European Union (FEDER-EU). P. G. J. acknowledges funding by Fundación Salamanca Ciudad de Cultura y Saberes (’‘Programme for attracting scientific talent to Salamanca’‘

Actividad analgésica y antiinflamatoria de derivados de podofilotoxina

La podofilotoxina es un producto natural inhibidor de la polimerización de la tubulina, que ha servido de prototipo para el desarrollo de distintos agentes antitumorales, actualmente en uso clínico como etopósido, tenipósido y etopophos. Reumacon, otro derivado semisintético similar a los anteriores, llegó a fase clínica para el tratamiento de la artritis reumatoide. Durante un estudio fitoquímico llevado a cabo sobre las hojas de Juniperus thurifera L., se aislaron, entre otros productos, varios ciclolignanos, podofilotoxina, desoxipodofilotoxina, desoxipicropodofilina y ácido thuriférico. Estos compuestos, obtenidos posteriormente mediante semisíntesis, fueron ensayados como analgésicos y antiinflamatorios. Desoxipodofilotoxina, una sustancia conformacionalmente rígida debido a la trans-lactona tensionada, muestra una elevada citotoxicidad; su epímero en C-8’, desoxipicropodofilina, con una cis-lactona más flexible y cien veces menos citotóxica, muestra un potente efecto analgésico, aunque menor actividad antiinflamatoria

Novel compound shows in vivo anthelmintic activity in gerbils and sheep infected by Haemonchus contortus

8 páginas, 2 figuras, 2 tablas.The control of gastrointestinal nematodes in livestock is becoming increasingly difficult due to the limited number of available drugs and the rapid development of anthelmintic resistance. Therefore, it is imperative to develop new anthelmintics that are effective against nematodes. Under this context, we tested the potential toxicity of three compounds in mice and their potential anthelmintic efficacy in Mongolian gerbils infected with Haemonchus contortus. The compounds were selected from previous in vitro experiments: two diamine (AAD-1 and AAD-2) and one benzimidazole (2aBZ) derivatives. 2aBZ was also selected to test its efficacy in sheep. In Mongolian gerbils, the benzimidazole reduced the percentage of pre-adults present in the stomach of gerbils by 95% at a dose of 200 mg/kg. In sheep, there was a 99% reduction in the number of eggs shed in faeces after 7 days at a dose of 120 mg/kg and a 95% reduction in the number of worm adults present in the abomasum. In conclusion, 2aBZ could be considered a promising candidate for the treatment of helminth infections in small ruminants. © 2022, The Author(s).Financial support came from MINECO: RETOS (AGL2016-79813-C2-1R/2R) and MICINN/AEI (PID2020- 119035RB-100). EVG was funded by FPU17/00627, FPU17/05346; VCGA, MAB, MCP and LGP are recipients of Junta de Castilla y León (JCyL) (LE082-18, LE051-18, LE135-19, LE096-20, respectively) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y competitividad; MMV, RYC-2015-18368).Peer reviewe

New oxidized ent-kaurane and ent-norkaurane derivatives from kaurenoic acid

New oxidized ent-kaurane and ent-norkaurane derivatives were synthezised starting from kaurenoic acid. The spectroscopic characterization of all compounds is reported

Country-Specific vs. Common Birthweight-for-Gestational Age References to Identify Small for Gestational Age Infants Born at 24-28 weeks: An International Study

BACKGROUND Controversy exists as to whether birthweight-for-gestational age references used to classify infants as small for gestational age (SGA) should be country specific or based on an international (common) standard. We examined whether different birthweight-for-gestational age references affected the association of SGA with adverse outcomes among very preterm neonates. METHODS Singleton infants (n = 23 788) of 24(0) -28(6) weeks' gestational age in nine high-resource countries were classified as SGA (<10th centile) using common and country-specific references based on birthweight and estimated fetal weight (EFW). For each reference, the adjusted relative risk (aRR) for the association of SGA with composite outcome of mortality or major morbidity was estimated. RESULTS The percentage of infants classified as SGA differed slightly for common compared with country specific for birthweight references [9.9% (95% CI 9.5, 10.2) vs. 11.1% (95% CI 10.7, 11.5)] and for EFW references [28.6% (95% CI 28.0, 29.2) vs. 24.6% (95% CI 24.1, 25.2)]. The association of SGA with the composite outcome was similar when using common or country-specific references for the total sample for birthweight [aRRs 1.47 (95% CI 1.43, 1.51) and 1.48 (95% CI 1.44, 1.53) respectively] and for EFW references [aRRs 1.35 (95% CI 1.31, 1.38) and 1.39 (95% CI 1.35, 1.43) respectively]. CONCLUSION Small for gestational age is associated with higher mortality and morbidity in infants born <29 weeks' gestational age. Although common and country-specific birthweight/EFW references identified slightly different proportions of SGA infants, the risk of the composite outcome was comparable

Novel compound shows in vivo anthelmintic activity in gerbils and sheep infected by Haemonchus contortus

[EN] The control of gastrointestinal nematodes in livestock is becoming increasingly difficult due to the limited number of available drugs and the rapid development of anthelmintic resistance. Therefore, it is imperative to develop new anthelmintics that are effective against nematodes. Under this context, we tested the potential toxicity of three compounds in mice and their potential anthelmintic efficacy in Mongolian gerbils infected with Haemonchus contortus. The compounds were selected from previous in vitro experiments: two diamine (AAD-1 and AAD-2) and one benzimidazole (2aBZ) derivatives. 2aBZ was also selected to test its efficacy in sheep. In Mongolian gerbils, the benzimidazole reduced the percentage of pre-adults present in the stomach of gerbils by 95% at a dose of 200 mg/kg. In sheep, there was a 99% reduction in the number of eggs shed in faeces after 7 days at a dose of 120 mg/kg and a 95% reduction in the number of worm adults present in the abomasum. In conclusion, 2aBZ could be considered a promising candidate for the treatment of helminth infections in small ruminantsSIFinancial support came from MINECO: RETOS (AGL2016-79813-C2-1R/2R) and MICINN/AEI (PID2020- 119035RB-100). EVG was funded by FPU17/00627, FPU17/05346; VCGA, MAB, MCP and LGP are recipients of Junta de Castilla y León (JCyL) (LE082-18, LE051-18, LE135-19, LE096-20, respectively) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y competitividad; MMV, RYC-2015-18368

Trends, Characteristic, and Outcomes of Preterm Infants Who Received Postnatal Corticosteroid: A Cohort Study from 7 High-Income Countries

INTRODUCTION Our objective was to evaluate the temporal trend of systemic postnatal steroid (PNS) receipt in infants of 24-28 weeks' gestational age, identify characteristics associated with PNS receipt, and correlate PNS receipt with the incidence of bronchopulmonary dysplasia (BPD) and BPD/death from an international cohort included in the iNeo network. METHODS We conducted a retrospective study using data from 2010 to 2018 from seven international networks participating in iNeo (Canada, Finland, Israel, Japan, Spain, Sweden, and Switzerland). Neonates of 24 and 28 weeks' gestational age who survived 7 days and who received PNS were included. We assessed temporal trend of rates of systemic PNS receipt and BPD/death. RESULTS A total of 47,401 neonates were included. The mean (SD) gestational age was 26.4 (1.3) weeks and birth weight was 915 (238) g. The PNS receipt rate was 21% (12-28% across networks) and increased over the years (18% in 2010 to 26% in 2018; p &lt; 0.01). The BPD rate was 39% (28-44% across networks) and remained unchanged over the years (35.2% in 2010 to 35.0% in 2018). Lower gestation, male sex, small for gestational age status, and presence of persistent ductus arteriosus (PDA) were associated with higher rates of PNS receipt, BPD, and BPD/death. CONCLUSION The use of PNS in extremely preterm neonates increased, but there was no correlation between increased use and the BPD rate. Research is needed to determine the optimal timing, dose, and indication for PNS use in preterm neonates

The Triterpenoid Betulin Protects against the Neuromuscular Effects ofBothrops jararacussuSnake VenomIn Vivo

[EN] We confirmed the ability of the triterpenoid betulin to protect against neurotoxicity caused by Bothrops jararacussu snake venom in vitro in mouse isolated phrenic nerve-diaphragm (PND) preparations and examined its capability of in vivo protection using the rat external popliteal/sciatic nerve-tibialis anterior (EPSTA) preparation. Venom caused complete, irreversible blockade in PND (40 g/mL), but only partial blockade (∼30%) in EPSTA (3.6 mg/kg, i.m.) after 120 min. In PND, preincubation of venom with commercial bothropic antivenom (CBA) attenuated the venom-induced blockade, and, in EPSTA, CBA given i.v. 15 min after venom also attenuated the blockade (by ∼70% in both preparations). Preincubation of venom with betulin (200 g/mL) markedly attenuated the venom-induced blockade in PND; similarly, a single dose of betulin (20 mg, i.p., 15 min after venom) virtually abolished the venom-induced decrease in contractility. Plasma creatine kinase activity was significantly elevated 120 min after venom injection in the EPSTA but was attenuated by CBA and betulin. These results indicate that betulin given i.p. has a similar efficacy as CBA given i.v. in attenuating the neuromuscular effects of B. jararacussu venom in vivo and could be a useful complementary measure to antivenom therapy for treating snakebite