Synthesis and comparative analysis of the cytotoxicity and mitochondrial effects of triphenylphosphonium and F16 maslinic and corosolic acid hybrid derivatives.

The cytotoxic profile and antiproliferative and mitochondrial effects of triterpene acid conjugates with mitochondriotropic lipophilic triphenylphosphonium (TPP+) and F16 cations were evaluated. Maslinic and corosolic acids chosen as the investigation objects were synthesized from commercially available oleanolic and ursolic acids. Study of the cytotoxic activity of TPP+ and F16 triterpenoid derivatives against six tumor cell lines demonstrated a comparable synergistic effect in the anticancer activity, which was most pronounced in the case of MCF-7 mammary adenocarcinoma cells and Jurkat and THP-1 leukemia cells. The corosolic and maslinic acid hybrid derivatives caused changes in the progression of tumor cell cycle phases when present in much lower doses than their natural triterpene acid precursors. The treatment of tumor cell lines with the conjugates resulted in the cell cycle arrest in the G1 phase and increase in the cell population in the subG1 phase. The cationic derivatives of the acids were markedly superior to their precursors as inducers of hyperproduction of reactive oxygen species and more effectively decreased the mitochondrial potential in isolated rat liver mitochondria. We concluded that the observed cytotoxic effect of TPP+ and F16 triterpenoid conjugates is attributable to the ability of these compounds to initiate mitochondrial dysfunctions. Their cytotoxicity, antiproliferative action, and mitochondrial effects depend little on the type of cationic groups used.

Development of a Consensus Derived Synoptic Operative Report for Rectal Prolapse: A Report From the Pelvic Floor Disorders Consortium.

BACKGROUND: Narrative operative reports may frequently omit or obscure data from an operation. OBJECTIVE: We aim to develop a synoptic operative report for rectal prolapse that includes core descriptors as developed by an international consensus of expert pelvic floor surgeons. DESIGN: Descriptors for patients undergoing rectal prolapse surgery were generated through review. Members of the Pelvic Floor Disorders Consortium were recruited to participate in a 3 round Delphi process using a 9-point Likert scale. Descriptors that achieved 70% agreement were kept from the first round, descriptors scoring 40-70% agreement were recirculated in subsequent rounds. A final list of operative descriptors was determined at a consensus meeting, with a final consensus meeting more than 70% agreement. SETTINGS: This was a survey administered to members of the Pelvic Floor Disorders Consortium. MAIN OUTCOME MEASURES: Descriptors meeting greater than 70% agreement were selected. RESULTS: One-hundred seventy six surgeons representing colorectal surgeons, urogynecologists, and urologists distributed throughout North America (56%), Latin America (4%), Western Europe (29%), Asia (4%), and Africa (1%) participated in the first round of Delphi voting. After two additional rounds and a final consensus meeting, 16 of 30 descriptors met 70% consensus. Descriptors that met consensus were: surgery type, posterior dissection, ventral dissection, mesh used, type of mesh used, mesh location, sutures used, suture type, pouch of Douglas and peritoneum reclosed, length of rectum imbricated, length of bowel resected, levatoroplasty, simultaneous vaginal procedure, simultaneous gynecologic procedure, simultaneous enterocele repair, and simultaneous urinary incontinence procedure. LIMITATIONS: Survey represents views of members of the Delphi panel, and may not represent viewpoints of all surgeons. CONCLUSIONS/DISCUSSION: This Delphi survey establishes international consensus descriptors for intraoperative variables that have been used to produce a synoptic operative report. This will help establish defined operative reporting to improve clinical communication, quality measures, and clinical research. See Video Abstract.

Colosplenic fistula diagnosis and management: a case series and review of literature.

BACKGROUND: A colosplenic fistula (CsF) is an extremely rare complication. Its diagnosis and management remain poorly understood, owing to its infrequent incidence. Our objective was to systematically review the etiology, clinical features, diagnosis, management, and prognosis to help clinicians gain a better understanding of this unusual complication and provide aid if it is to be encountered. METHODS: A systematic review of studies reporting CsF diagnosis in Ovid MEDLINE, Ovid EMBASE, Scopus, Web of Science, and Wiley Cochrane Library from 1946 to June 2022. Additionally, a retrospective review of four cases at our institution were included. Cases were evaluated for patient characteristics (age, sex, and comorbidities), CsF characteristics including causes, symptoms at presentation, diagnosis approach, management approach, pathology findings, intraoperative complications, postoperative complications, 30-day mortality, and prognosis were collected. RESULTS: Thirty patients with CsFs were analyzed, including four cases at our institution and 26 single-case reports. Most of the patients were male (70%), with a median age of 56 years. The most common etiologies were colonic lymphoma (30%) and colorectal carcinoma (17%). Computed tomography (CT) was commonly used for diagnosis (90%). Approximately 87% of patients underwent a surgical intervention, most commonly segmental resection (81%) of the affected colon and splenectomy (77%). Nineteen patients were initially managed surgically, and 12 patients were initially managed nonoperatively. However, 11 of the nonoperative patients ultimately required surgery due to unresolved symptoms. The rate of postoperative complications was (17%). Symptoms resolved with surgical intervention in 25 (83%) patients. Only one patient (3%) had had postoperative mortality. CONCLUSIONS: Our review of 30 cases worldwide is the largest in literature. CsFs are predominantly complications of neoplastic processes. CsF may be successfully and safely treated with splenectomy and resection of the affected colon, with a low rate of postoperative complications.

Ventral mesh rectopexy for recurrent rectal prolapse after Altemeier perineal proctosigmoidectomy: feasibility and outcomes.

PURPOSE: Recurrence of rectal prolapse following the Altemeier procedure is reported with rates up to 40%. The optimal surgical management of recurrences has limited data available. Ventral mesh rectopexy (VMR) is a favored procedure for primary rectal prolapse, but its role in managing recurrences after Altemeier is unclear. VMR for recurrent prolapse involves implanting the mesh on the colon, which has a thinner wall, more active peristalsis, no mesorectum, less peritoneum available for covering the mesh, and potential diverticula. These factors can affect mesh-related complications such as erosion, migration, or infection. This study assessed the feasibility and perioperative outcomes of VMR for recurrent rectal prolapse after the Altemeier procedure. METHODS: We queried our prospectively maintained database between 01/01/2008 and 06/30/2022 for patients who had experienced a recurrence of full-thickness rectal prolapse following Altemeier's perineal proctosigmoidectomy and subsequently underwent ventral mesh rectopexy. RESULTS: Ten women with a median age of 67 years (range 61) and a median BMI of 27.8 kg/m2 (range 9) were included. Five (50%) had only one Altemeier, and five (50%) had multiple rectal prolapse surgeries, including Altemeier before VMR. No mesh-related complications occurred during a 65-month (range 165) median follow-up period. Three patients (30%) experienced minor postoperative complications unrelated to the mesh. Long-term complications were chronic abdominal pain and incisional hernia in one patient, respectively. One out of five (20%) patients with only one previous prolapse repair had a recurrence, while all patients (100%) with multiple prior repairs recurred. CONCLUSION: Mesh implantation on the colon is possible without adverse reactions. However, high recurrence rates in patients with multiple previous surgeries raise doubts about using VMR for secondary or tertiary recurrences.

Conjugation of Triterpenic Acids of Ursane and Oleanane Types with Mitochondria-Targeting Cation F16 Synergistically Enhanced Their Cytotoxicity against Tumor Cells.

The present work shows the cytotoxic effects of novel conjugates of ursolic, oleanolic, maslinic, and corosolic acids with the penetrating cation F16 on cancer cells (lung adenocarcinoma A549 and H1299, breast cancer cell lines MCF-7 and BT474) and non-tumor human fibroblasts. It has been established that the conjugates have a significantly enhanced toxicity against tumor-derived cells compared to native acids and also demonstrate selectivity to some cancer cells. The toxic effect of the conjugates is shown to be due to ROS hyperproduction in cells, induced by the effect on mitochondria. The conjugates caused dysfunction of isolated rat liver mitochondria and, in particular, a decrease in the efficiency of oxidative phosphorylation, a decrease in the membrane potential, and also an overproduction of ROS by organelles. The paper discusses how the membranotropic- and mitochondria-targeted effects of the conjugates may be related to their toxic effects.

Comparative Study of Cytotoxic and Membranotropic Properties of Betulinic Acid-F16 Conjugate on Breast Adenocarcinoma Cells (MCF-7) and Primary Human Fibroblasts.

The present study evaluates the cytotoxicity of a previously synthesized conjugate of betulinic acid (BA) with the penetrating cation F16 on breast adenocarcinoma (MCF-7) and human fibroblast (HF) cell lines, and also shows the mechanism underlying its membranotropic action. It was confirmed that the conjugate exhibits higher cytotoxicity compared to native BA at low doses also blocking the proliferation of both cell lines and causing cell cycle arrest in the G0/G1 phase. We show that the conjugate indeed has a high potential for accumulation in mitochondria, being visualized in these organelles, which is most pronounced in cancer cells. The effect of the conjugate was observed to be accompanied by ROS hyperproduction in both cancerous and healthy cells, despite the lower base level of ROS in the latter. Along with this, using artificial liposomes, we determined that the conjugate is able to influence the phase state of lipid membranes, make them more fluid, and induce nonspecific permeabilization contributing to the overall cytotoxicity of the tested agent. We conclude that the studied BA-F16 conjugate does not have significant selective cytotoxicity, at least against the studied breast cancer cell line MCF-7.

Conjugation of Natural Triterpenic Acids with Delocalized Lipophilic Cations: Selective Targeting Cancer Cell Mitochondria.

Currently, a new line of research on mitochondria-targeted anticancer drugs is actively developing in the field of biomedicine and medicinal chemistry. The distinguishing features of this universal target for anticancer agents include presence of mitochondria in the overwhelming majority, if not all types of transformed cells, crucial importance of these cytoplasmic organelles in energy production, regulation of cell death pathways, as well as generation of reactive oxygen species and maintenance of calcium homeostasis. Hence, mitochondriotropic anticancer mitocan agents, acting through mitochondrial destabilization, have good prospects in cancer therapy. Available natural pentacyclic triterpenoids are considered promising scaffolds for development of new mitochondria-targeted anticancer agents. These secondary metabolites affect the mitochondria of tumor cells and initiate formation of reactive oxygen species. The present paper focuses on the latest research outcomes of synthesis and study of cytotoxic activity of conjugates of pentacyclic triterpenoids with some mitochondria-targeted cationic lipophilic molecules and highlights the advantages of applying them as novel mitocan agents compared to their prototype natural triterpenic acids.

Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation.

This work demonstrates the effects of a newly synthesized conjugate of the plant triterpenoid betulin and the penetrating cation F16 used for mitochondrial targeting. The resulting F16-betulin conjugate revealed a mitochondria-targeted effect, decreasing the mitochondrial potential and inducing superoxide overproduction in rat thymocytes in vitro. It has been suggested that this may cause the cytotoxic effect of the conjugate, which significantly exceeds the effectiveness of its precursors, betulin and F16. Using isolated rat liver mitochondria, we found that the F16-betulin conjugate has a surface-active effect on mitochondrial membranes, causing organelle aggregation. This effect of the derivative resulted in a dose-dependent decrease in mitochondrial transmembrane potential, as well as suppression of respiration and oxidative phosphorylation, especially in the case of nicotinamide adenine dinucleotide (NAD)-fueled organelles. In addition, the F16-betulin conjugate caused an increase in H2O2 generation by mitochondria fueled with glutamate and malate. These effects of the derivative can presumably be due to the powerful suppression of the redox activity of complex I of the mitochondrial electron transport chain. The paper discusses how the mitochondria-targeted effects of the F16-betulin conjugate may be related to its cytotoxic effects.

Mitochondria-targeted prooxidant effects of betulinic acid conjugated with delocalized lipophilic cation F16.

The paper examines the molecular mechanisms of the cytotoxicity of conjugates of betulinic acid with the penetrating cation F16. The in vitro experiments on rat thymocytes revealed that all the obtained F16-betulinic acid derivatives showed more than 10-fold higher cytotoxicity as compared to betulinic acid and F16. In this case, 0.5-1 µM of all conjugates showed mitochondria-targeted action, inducing superoxide overproduction and reducing the mitochondrial potential of cells. Experiments on isolated rat liver mitochondria revealed the ability of conjugates to dose-dependently reduce the membrane potential of organelles, as well as the intensity of respiration and oxidative phosphorylation, which is also accompanied by an increase in the production of hydrogen peroxide by mitochondria. It was shown that these actions of derivatives may be due to several effects: the reversion of ATP synthase, changes in the activity of complexes of the respiratory chain and permeabilization of the inner mitochondrial membrane. All compounds also demonstrated the ability to induce aggregation of isolated rat liver mitochondria. Using the model of lecithin liposomes, we found that the F6 conjugate (2 µM) induces the permeability of vesicle membranes for the fluorescent probe sulforhodamine B. High concentrations (25 µM) of the F6 derivative have been found to induce dynamic processes in the liposome membrane leading to aggregation and/or fusion of vesicle membranes. The paper discusses the relationship between the mitochondria-targeted effects of F16-betulinic acid conjugates and their cytotoxicity.

Does the Length of the Prolapsed Rectum Impact Outcome of Surgical Repair?

BACKGROUND: There are many surgical options for the treatment of rectal prolapse with varying recurrence rates reported. The association between rectal prolapse length and recurrence risk has not been explored previously. OBJECTIVE: The purpose of this study was to determine whether length of prolapse predicts a risk of recurrence. DESIGN: Consecutive patients from a prospectively collected institutional review board-approved data registry were evaluated. SETTINGS: The study was conducted at the Cleveland Clinic Department of Colorectal Surgery. PATIENTS: All patients from 2010 to 2018 who underwent surgical intervention for rectal prolapse were included. INTERVENTION: Perineal repair with Delorme procedure and Altemeier, as well as abdominal repair with ventral rectopexy, resection rectopexy, and posterior rectopexy, was included. MAIN OUTCOME MEASURES: Prolapse length, recurrence, type of surgery, and primary or secondary procedure were measured. RESULTS: In total, 280 patients had prolapse surgery over 8 years, mean age was 59 years (SD = 18 y), and 92.4% were female. Seventy percent had a prolapse length documented as <5 cm, and 30% had prolapse length documented as >5 cm. The mean prolapse length was 4.8 cm (SD = 2.9 cm). The overall rate of recurrent prolapse was 18%. There were 51 patients who had a recurrent prolapse after their first prolapse surgery. Factors significant for recurrence on univariate analysis were a perineal approach (p = 0.03), previous Delorme procedure (p < 0.001), and prolapse length >5 cm (p = 0.04). On multivariate analysis there was significantly increased recurrence with length of prolapse >5 cm (OR = 2.2 (95% CI, 1.1-4.4); p = 0.02) and having a previous Delorme procedure (OR = 4.0 (95% CI, 1.6-10.1); p = 0.004). For each 1-cm increase in prolapse, the odds of recurrence increased by a factor of 2.2. LIMITATIONS: This was a retrospective study of a heterogenous patient cohort. CONCLUSIONS: The greater the length of prolapsed rectum, the greater the risk of recurrence. The length of prolapse should be considered when planning the most appropriate surgical repair to modify the recurrence risk. See Video Abstract at http://links.lww.com/DCR/B463. EL TAMAÑO DEL RECTO PROLAPSADO AFECTA EL RESULTADO DE LA REPARACIÓN QUIRÚRGICA?: Existen muchas opciones quirúrgicas para el tratamiento del prolapso de recto con diferentes tasas de recurrencia publicadas. La asociación entre el tamaño del prolapso rectal y el riesgo de recurrencia no se han explorado previamente.Determinar si el largo en el tamaño del prolapso predice un riesgo de recidiva.Se evaluaron pacientes consecutivos de un registro de datos aprobado por el IRB recopilado prospectivamente.Departamento de cirugía colorrectal de la Clínica Cleveland, en Ohio.Todos aquellos pacientes que entre 2010 y 2018 se sometieron a una intervención quirúrgica por prolapso completo de recto.La reparación perineal incluyó los procedimientos de Altemeier y Delorme. Las reparaciones abdominales incluidas fueron la rectopexia ventral, la rectopexia con resección y la rectopexia posterior.Tamaño del prolapso, recurrencia, tipo de intervención quirúrgica y tipo de procedimiento (primario o secundario).En total, 280 pacientes se sometieron a cirugía de prolapso rectal durante 8 años, la edad media fue de 59 años (DE 18) donde el 92,4% eran mujeres. El 70% tenían un tamaño de prolapso documentado como < 5 cm y 30% tenían un tamaño de prolapso documentada como > 5 cm. La longitud media del prolapso fue de 4,8 cm (DE 2,9).La tasa general de recidiva del prolapso fue de 18%. Hubo 51 pacientes que presentaron recidiva del prolapso después de una primera cirugía. Los factores significativos para la recidiva en el análisis univariado fueron el abordaje perineal (p = 0.03), un procedimiento de Delorme previo (p <0.001) y el tamaño del prolapso > 5 cm (p = 0.04). En el análisis multivariado, hubo un aumento significativo de la recidiva en aquellos prolapsos de > 5 cm (OR 2,2; IC del 95%: 1,09-4,4; p = 0,02) con un procedimiento de Delorme previo (OR 4; IC del 95%: 1,6 a 10,1; p = 0,004). Por cada centímetro de tamaño del prolapso, las probabilidades de recidiva aumentaron en un factor de 2,2.Estudio retrospectivo de una cohorte de pacientes heterogénea.Cuanto mayor es el tamaño del recto prolapsado, mayor es el riesgo de recidiva. Se debe evaluar muy cuidadosamente el tamaño de los prolapsos para escoger la corrección quirúrgica más apropiada y así disminuir el riesgo de recidivas.Consulte Video Resumen en http://links.lww.com/DCR/B463. (Traducción-Dr Xavier Delgadillo).

Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation.

A series of 34 new amine- and guanidine-functionalized derivatives of betulinic, ursolic, and oleanolic acids were synthesized and tested for their antimicrobial activity against the growth of four bacterial strains (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)) and two fungal strains (Candida albicans and Cryptococcus neoformans). The obtained compounds were also tested for the cytotoxic effect against HEK293 human embryonic kidney cell line and hemolytic activity against human red blood cells. Most of the prepared amino and guanidinium derivatives of betulinic, ursolic, and oleanolic acids showed a considerably higher bacteriostatic activity against methicillin-resistant S. aureus than the parent compounds. The most active compounds (MICs ≤ 0.25 µg/ml or 0.4-0.5 µM) were superior over the clinically used antibiotic vancomycin in the antibacterial effect (MIC of 1 µg/ml or 0.7 µM). Apart from antibacterial activity, new triterpene acid derivatives exhibited excellent antifungal activity against Cryptococcus neoformans, with MICs values being as low as 0.25 µg/ml (0.4 µM), and were approximately 65 times as active as fluconazole, a known antifungal agent. Four most promising compounds we identified (7, 13, 24, and 33) showed not only high bacteriostatic effect, but also low cytotoxicity against mammalian HEK293 cells and high hemolytic selectivity.

Synthesis and Evaluation of Anticancer Activities of Novel C-28 Guanidine-Functionalized Triterpene Acid Derivatives.

Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4⁻7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9b⁻12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis.

Mitochondria-targeted betulinic and ursolic acid derivatives: synthesis and anticancer activity.

A series of new betulinic and ursolic acid conjugates with a lipophilic triphenylphosphonium cation, meant to enhance the bioavailability and mitochondriotropic action of natural triterpenes, have been synthesized. The in vitro experiments on three human cancer cell lines (MCF-7, HCT-116 and TET21N) revealed that all the obtained triphenylphosphonium triterpene acid derivatives not only showed higher cytotoxicity as compared to betulinic acid but were also markedly superior in triggering mitochondria-dependent apoptosis, as assessed using a range of apoptosis markers such as cytochrome c release, stimulation of caspase-3 activity, and cleavage of poly(ADP-ribose) polymerase, which is one of the targets of caspase 3. The IC50 was much lower for all triphenylphosphonium derivatives when compared to betulinic acid. Out of the tested group of conjugates, the most potent toxicity was exhibited by the betulinic acid conjugate 9 (for 9, the IC50 values against MCF-7 and TET21N cells were 0.70 µM and 0.74 µM; for betulinic acid (BA), IC50 > 25 µM against MCF-7 cells).

Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo.

We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76 µg/mL) and 11 (IC50 of 0.64 µg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo.