Dopamine-Derived Guanidine Alkaloids from a Didemnidae Tunicate: Isolation, Synthesis, and Biological Activities.

Mellpaladines A-C (1-3) and dopargimine (4) are dopamine-derived guanidine alkaloids isolated from a specimen of Palauan Didemnidae tunicate as possible modulators of neuronal receptors. In this study, we isolated the dopargimine derivative 1-carboxydopargimine (5), three additional mellpaladines D-F (6-8), and serotodopalgimine (9), along with a dimer of serotonin, 5,5'-dihydroxy-4,4'-bistryptamine (10). The structures of these compounds were determined based on spectrometric and spectroscopic analyses. Compound 4 and its congeners dopargine (11), nordopargimine (15), and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)ethan-1-amine (16) were synthetically prepared for biological evaluations. The biological activities of all isolated compounds were evaluated in comparison with those of 1-4 using a mouse behavioral assay upon intracerebroventricular injection, revealing key functional groups in the dopargimines and mellpaladines for in vivo behavioral toxicity. Interestingly, these alkaloids also emerged during a screen of our marine natural product library aimed at identifying antiviral activities against dengue virus, SARS-CoV-2, and vesicular stomatitis Indiana virus (VSV) pseudotyped with Ebola virus glycoprotein (VSV-ZGP).

Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni.

Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni, is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni. In addition to known waixenicins A (1) and B (2), we purified six xenicane diterpenes, 7S,8S-epoxywaixenicins A (3) and B (4), 12-deacetylwaixenicin A (5), waixenicin E (6), waixenicin F (7), and 20-acetoxyxeniafaraunol B (8). We elucidated the structures of 3-8 by NMR and MS analyses. Compounds 1, 2, 3, 4, and 6 inhibited TRPM7 activity in a cell-based assay, while 5, 7, and 8 were inactive. A preliminary SAR emerged showing that alterations to the nine-membered ring of 1 did not reduce activity, while the 12-acetoxy group, in combination with the dihydropyran, appears to be necessary for TRPM7 inhibition. The bioactive compounds are proposed to be latent electrophiles by formation of a conjugated oxocarbenium ion intermediate. Whole-cell patch-clamp experiments demonstrated that waixenicin A inhibition is irreversible, consistent with a covalent inhibitor, and showed nanomolar potency for waixenicin B (2). Conformational analysis (DFT) of 1, 3, 7, and 8 revealed insights into the conformation of waixenicin A and congeners and provided information regarding the stabilization of the proposed pharmacophore.

TRPM7 in neurodevelopment and therapeutic prospects for neurodegenerative disease.

Neurodevelopment, a complex and highly regulated process, plays a foundational role in shaping the structure and function of the nervous system. The transient receptor potential melastatin 7 (TRPM7), a divalent cation channel with an α-kinase domain, mediates a wide range of cellular functions, including proliferation, migration, cell adhesion, and survival, all of which are essential processes in neurodevelopment. The global knockout of either TRPM7 or TRPM7-kinase is embryonically lethal, highlighting the crucial role of TRPM7 in development in vivo. Subsequent research further revealed that TRPM7 is indeed involved in various key processes throughout neurodevelopment, from maintaining pluripotency during embryogenesis to regulating gastrulation, neural tube closure, axonal outgrowth, synaptic density, and learning and memory. Moreover, a discrepancy in TRPM7 expression and/or function has been associated with neuropathological conditions, including ischemic stroke, Alzheimer's disease, and Parkinson's disease. Understanding the mechanisms of proper neurodevelopment may provide us with the knowledge required to develop therapeutic interventions that can overcome the challenges of regeneration in CNS injuries and neurodegenerative diseases. Considering that ion channels are the third-largest class targeted for drug development, TRPM7's dual roles in development and degeneration emphasize its therapeutic potential. This review provides a comprehensive overview of the current literature on TRPM7 in various aspects of neurodevelopment. It also discusses the links between neurodevelopment and neurodegeneration, and highlights TRPM7 as a potential therapeutic target for neurodegenerative disorders, with a focus on repair and regeneration.

Antioxidant, anti-tyrosinase, hepatoprotective, and anti-inflammatory potential in flowers and seeds of Ochna integerrima (Lour.) Merr.

This study explored, for the first time, the antioxidant (total antioxidant content, reducing power, ferric ion reducing antioxidant power, hydroxyl radical scavenging, ferrous ion-chelating assays), anti-tyrosinase, anti-inflammatory properties, and hepatoprotective effect in HepG2 cell lines of Ochna integerrima (Loureiro) Merrill flowers and seeds. All extracts except n-hexane exhibited significant antioxidant activity, with high levels of tannin and proanthocyanidins. Luteolin (1), 6-γ,γ-dimethylallylkaempferol7-O-ß-d-glucopyranoside (2), 6-γ,γ-dimethylallylquercetin7-O-ß-d-glucopyranoside (3), and 6-γ,γ-dimethylallyldihydrokaempferol 7-O-ß-d-glucopyranoside (4) were isolated using semi-preparative HPLC. Compounds 1-3 demonstrated good anti-tyrosinase activity. The most active hepatoprotective extracts were found to be aqueous extracts. The flower extracts exhibited greater anti-inflammatory properties by the decrease of NO in RAW 264.7 cells and bovine serum albumin protein. Among them, the n-hexane and EtOAc extracts from flowers displayed promising anti-inflammatory activity. This was predicted by in silico analysis of 1-4. In summary, O. integerrima appears to be a promising natural source for antioxidant, anti-tyrosinase, and anti-inflammatory applications.

Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma-(PDAC) needs innovative approaches due to its 12% 5-year survival despite current therapies. We show marked sensitivity of pancreatic cancer cells to the combination of a novel eIF4A inhibitor, des-methyl pateamine A (DMPatA), and a histone deacetylase inhibitor, romidepsin, inducing epigenetic reprogramming as an innovative therapeutic strategy. Exploring the mechanistic activity of this combination showed that with a short duration of romidepsin at low doses, robust acetylation persisted up to 48h with the combination, while histone acetylation rapidly faded with monotherapy. This represents an unexpected mechanism of action against PDAC cells that triggers transcriptional overload, metabolic stress, and augmented DNA damage. Structurally different class I HDAC inhibitors exhibit the same hyperacetylation patterns when co-administered with DMPatA, suggesting a class effect. We show efficacy of this combination regimen against tumor growth in a MIA PaCa-2 xenograft model of PDAC with persistent hyperacetylation confirmed in tumor samples. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma, a significant clinical challenge, could benefit from the latent potential of epigenetic therapies like HDAC inhibitors-(HDIs), typically limited to hematological malignancies. Our study shows that a synergistic low dose combination of HDIs with an eIF4A-inhibitor in pancreatic cancer models results in marked pre-clinical efficacy, offering a promising new treatment strategy.

Guía clínica para el manejo interdisciplinario del paciente con secuelas de pérdida masiva de peso durante la cirugía plástica reconstructive / Interdisciplinary clinical guidelines for massive weight loss patients during plastic reconstructive surgery

Antecedentes y Objetivos. La obesidad está considerada como una pandemia y México ocupa uno de los primeros lugares mundiales en número de casos en población adulta y el primero en el grupo infantil. Desde 2008 se pusieron en marcha Unidades de Cirugía Bariátrica para el manejo del paciente obeso, con lo cual se inició también la Reconstrucción postpérdida masiva de peso por los Servicios de Cirugía Plástica. Sin embargo, no existen protocolos descritos de manejo perioperatorio de este tipo de pacientes en nuestro país. El objetivo del presente trabajo es crear una guía clínica para el manejo interdisciplinario del paciente con secuelas de pérdida masiva de peso basada en los resultados obtenidos en un centro de reconstrucción postbariátrica. Material y Método. Creamos para ello un equipo de expertos de cada área involucrada y se estandarizó el manejo pre, trans y postoperatorio de todos los pacientes con secuelas de pérdida masiva de peso a fin de evaluar los resultados obtenidos. Resultados. Se realizaron 314 procedimientos reconstructivos en 144 pacientes postbariátricos. El 93% fueron de sexo femenino. La edad promedio fue de 37.2 años. Los procedimientos realizados fueron: abdominoplastia en un 39.17%; mastopexia en un 10.5%; torsoplastia en un 7.69%; braquioplastia en un 7.01%; cruroplastia en un 5.09%; y ritidoplastia en un 2.54%. El tiempo quirúrgico promedio fue de 221.2 minutos, con un sangrado transoperatorio medio de 275 ml. Las complicaciones presentadas alcanzaron el 4.77% y la mortalidad fue de 0%. Las recomendaciones emitidas por cada experto involucrado en el proceso de reconstrucción permitieron obtener resultados favorables en relación a la morbi-mortalidad, que fue equiparable e incluso inferior a la reportada en otras series. Conclusiones. Creemos que el seguimiento de una guía clínica basada en la estandarización del manejo de 314 procedimientos en una población con características similares, nos permite realizar la reconstrucción postpérdida masiva de peso de forma eficaz y segura (AU)

Background and Objectives. Obesity is now considered a pandemic problem. México occupies one of the highest places in the world with adults and children with obesity or overweight. In 2008 multiple Bariatric Surgery Centers were created in the country. Therefore, the massive weight loss reconstruction started to be performed by Plastic Surgery Services. They lack of clinical practice guidelines. Our objective is to create an interdisciplinary clinical practice guidelines for the massive weight loss patient reconstruction, based on the results and experience of a Postbariatric Reconstruction Center. Methods. A highly specialized interdisciplinary team was created in order to perform a complete clinical evaluation before the patients was operated by Plastic Surgery. All the perioperative management was standarized by every clinical area and we described the guidelines based on the final results. Results. AA total of 314 reconstruction procedures were performed in 144 postbariatric patients. The 93% of the population were female. Average age was 37.2 years old. The procedures performed were: abdominoplasty in 39.17%; mastope; and rhytidectomy in 2.54%. Average surgical time were 221.2 minutes. Intraoperative haemorrage was 275 ml as an average. Complications were developed in the 4.77% of the procedures with a mortality rate of 0%. The recomendations emitted by every clinical expert, awolled to obtain a good outcome concerning about the low rate of morbility and mortality, even better than other international series described. Conclusions. The application of clinical guidelines in the management of massive weight patient sustained in a 314 postbariatric Plastic Surgery procedure in a standarized population allows to perform an effective and safe surgery (AU)