Interaction of Some Asymmetrical Porphyrins with U937 Cell Membranes-In Vitro and In Silico Studies.

The aim of the present study was to assess the effects exerted in vitro by three asymmetrical porphyrins (5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin, 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatozinc(II), and 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatocopper(II)) on the transmembrane potential and the membrane anisotropy of U937 cell lines, using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH), respectively, as fluorescent probes for fluorescence spectrophotometry. The results indicate the hyperpolarizing effect of porphyrins in the concentration range of 0.5, 5, and 50 µM on the membrane of human U937 monocytic cells. Moreover, the tested porphyrins were shown to increase membrane anisotropy. Altogether, the results evidence the interaction of asymmetrical porphyrins with the membrane of U937 cells, with potential consequences on cellular homeostasis. Molecular docking simulations, and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy of binding calculations, supported the hypothesis that the investigated porphyrinic compounds could potentially bind to membrane proteins, with a critical role in regulating the transmembrane potential. Thus, both the free base porphyrins and the metalloporphyrins could bind to the SERCA2b (sarco/endoplasmic reticulum ATPase isoform 2b) calcium pump, while the metal complexes may specifically interact and modulate calcium-dependent (large conductance calcium-activated potassium channel, Slo1/KCa1.1), and ATP-sensitive (KATP), potassium channels. Further studies are required to investigate these interactions and their impact on cellular homeostasis and functionality.

Porphyrin Macrocycles: General Properties and Theranostic Potential.

Despite specialists' efforts to find the best solutions for cancer diagnosis and therapy, this pathology remains the biggest health threat in the world. Global statistics concerning deaths associated with cancer are alarming; therefore, it is necessary to intensify interdisciplinary research in order to identify efficient strategies for cancer diagnosis and therapy, by using new molecules with optimal therapeutic potential and minimal adverse effects. This review focuses on studies of porphyrin macrocycles with regard to their structural and spectral profiles relevant to their applicability in efficient cancer diagnosis and therapy. Furthermore, we present a critical overview of the main commercial formulations, followed by short descriptions of some strategies approached in the development of third-generation photosensitizers.

Clinical and Morphological Characteristics of Gastrointestinal Stromal Tumor.

Introduction: Gastrointestinal stromal tumors (GIST) are a rare form of cancer located within the gastrointestinal (GI) tract, defined as tumors with spindle, epithelioid, or occasionally pleomorphic cells. They originate in the interstitial cells of Cajal, with the function of "pacemaker" of gastrointestinal motility. Their behavior is dictated by changes in the c-kit/PDGFRA gene, which is often highlighted by immunolabeling. Methods: We report the clinical, macroscopic, microscopic, and immunohistochemical characteristics of consecutive patients diagnosed with GIST who underwent surgical removal of the tumor in our department between 2008-2022. Results: We included 20 consecutive patients. The presentation was considered a surgical emergency requiring immediate surgical intervention in most subjects. The most common localization is the small intestine (n=9, 45%), followed by the stomach (n=7, 35%), colon (n=3, 15%), and peritoneum (n=1, n=5%). Histologically, the tumors were predominantly mixed (n=10, 50%) followed by spindle type (n=8, 40%) and epithelioid - 2 cases (10%). Conclusion: The clinical presentation of GISTs remains heterogeneous, and the diagnosis is predominantly postsurgical, using complex immunohistochemistry analysis. The tumor size and number of mitoses are strongly associated with the long-term prognosis.

Choledochal Lithiasis. Multidisciplinary Therapeutic Target. Past and Present.

Introduction: Cholelithiasis still remains one of the most frequent pathologies encountered in surgical practice. The authors review the stages which marked the evolution of the treatment of choledochal lithiasis (CL) during the last 50 years, based on their own experience. From the exclusively surgical choledochus, we have reached a multidisciplinary therapy in which both endoscopy and interventional radiology have found their place. Material and Method: The authors studied 2 groups of patients: Group 1 included patients from the period 1959-1997 (38 years - 982 cases of choledocholithiasis) who underwent classical surgery. Group 2 included patients treated between 1997-2017 (20 years â?" 347 cases) in whom both endoscopic surgery and classic surgery were used to obtain choledochal clearance. The types of choledochal lithiasis (CL) according to which the method of obstruction clearance was decided upon and chosen are presented here. Results: All the patients in group 1 underwent classical surgery, representing 9.8% of operations for biliary lithiasis. In group 2, classical surgery was recorded in 23.4% of patients, and endoscopic surgery in 76.6% of them. We mention that there was no laparoscopic approach for the treatment of CL due to the absence of experience. In group 2 we recorded 26.3% endoscopic failure, while in the classical approach group there was 12.3% failure of obstruction clearance, the solution being biliodigestive anastomoses. Conclusions: The authors propose three categories of therapeutic indications in CL. A first category is represented by the "endoscopic choledochus", which includes migrated lithiasis. A second category is the "surgical choledocus". It is the situation of complex and complicated lithiases. Finally, there would be a third category - the "lithogenic choledocus". This last group includes the most aggressive lithiases with repeated relapses, panlithiases, etc. For categories 2 and 3, endoscopic - laparoscopic clearance attempts have no chance of success or are even contraindicated.

Studies on the Synthesis, Photophysical and Biological Evaluation of Some Unsymmetrical Meso-Tetrasubstituted Phenyl Porphyrins.

Abstract: We designed three unsymmetrical meso-tetrasubstituted phenyl porphyrins for further development as theranostic agents for cancer photodynamic therapy (PDT): 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (P2.2), Zn(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Zn(II)2.2) and Cu(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Cu(II)2.2). The porphyrinic compounds were synthesized and their structures were confirmed by elemental analysis, FT-IR, UV-Vis, EPR and NMR. The compounds had a good solubility in polar/nonpolar media. P2.2 and, to a lesser extent, Zn(II)2.2 were fluorescent, albeit with low fluoresence quantum yields. P2.2 and Zn(II)2.2 exhibited PDT-acceptable values of singlet oxygen generation. A "dark" cytotoxicity study was performed using cells that are relevant for the tumor niche (HT-29 colon carcinoma cells and L929 fibroblasts) and for blood (peripheral mononuclear cells). Cellular uptake of fluorescent compounds, cell viability/proliferation and death were evaluated. P2.2 was highlighted as a promising theranostic agent for PDT in solid tumors considering that P2.2 generated PDT-acceptable singlet oxygen yields, accumulated into tumor cells and less in blood cells, exhibited good fluorescence within cells for imagistic detection, and had no significant cytotoxicity in vitro against tumor and normal cells. Complexing of P2.2 with Zn(II) or Cu(II) altered several of its PDT-relevant properties. These are consistent arguments for further developing P2.2 in animal models of solid tumors for in vivo PDT.

In Silico and In Vitro Studies on an Asymmetrical Porphyrin Derivative with Therapeutic Potential in Skin Disorders.

For developing novel photosensitizers with therapeutic potential in non-malignant and malignant cutaneous disorders, the unsymmetrical porphyrin, 5-(2-hydroxy-3-methoxyphenyl)-10, 15, 20-tris-(4-carboxymethylphenyl) porphyrin, was evaluated in silico and in vitro. The cellular uptake of the investigated porphyrin and its ability to perform photodynamic therapy were investigated in terms of the viability, proliferation, and necrosis of human HaCaT keratinocytes and human Hs27 skin fibroblasts, in correlation with the predictions regarding diffusion through cell membranes, ADMET profile (absorption, distribution, metabolism, elimination, toxicity), and potential pharmacological mechanism. Molecular docking and 250 ns molecular dynamics simulations revealed that P5.2 has the potential to form a relatively stable complex with the carbonic anhydrase IX catalytic site, the lowest predicted free energy of binding (MM/PBSA) being -39.097 kcal/mol. The results of the in vitro study showed that P5.2 is incorporated within 24 h in the investigated cells, especially in HaCaT keratinocytes, indicating its photosensitizing ability. Nevertheless, P5.2 does not exert significant cytotoxicity in "dark" conditions. In turn, PDT induced a decrease in the number of metabolically active HaCaT keratinocytes within 24 h, accompanied by a 4-fold increase in lactate dehydrogenase release, indicating its ability to perform PDT in human skin cells. The experimental results suggest that the asymmetrical porphyrin is a promising candidate theranostics agent for skin disorders.

Specific Septic Complications after Rectal Cancer Surgery: A Critical Multicentre Study.

The postoperative septic complications in gastrointestinal surgery impact immediate as well as long-term outcomes, which lead to reinterventions and additional costs. The authors presented the experience of three surgery clinics in Romania regarding the specific septic complications occurring in patients operated on for rectal cancer. The study group comprised 2674 patients who underwent surgery over a 5-year period (2017-2021). Neoplasms of the middle and lower rectum (76%) were the majority. There were 85% rectal resections and 15% abdominoperineal excisions of the rectum. In total, 68.54% of patients were operated on laparoscopically, and 31.46% received open surgery. Without taking wound infections into account, 97 (3.67%) patients had abdominal-pelvic septic complications. The aim was to evaluate the causes of the complications. The percentage of suppurations after surgery of the rectum treated by radiochemotherapy was considerably higher than after surgery of the non-radiated upper rectum. The fatality rate was 5.15%. The risk of fistulas was significantly associated with the preoperative treatment, tumour position and type of intervention. Sex, age, TNM stage or grade were not significant at 0.05 the threshold. The risk of fistulas is reduced with low anterior resection, but the gravity of these complications is higher in the lower rectum compared with the superior rectum. Preoperative radiochemotherapy is a contributing factor to septic complications.

Assessment of Some Unsymmetrical Porphyrins as Promising Molecules for Photodynamic Therapy of Cutaneous Disorders.

In order to select for further development novel photosensitizers for photodynamic therapy in cutaneous disorders, three unsymmetrical porphyrins, namely 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2), 5-(2-hydroxy-5-methoxyphenyl)-10,15,20-tris-(4-carboxymethylphenyl) porphyrin (P3.2), and 5-(2,4-dihydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P4.2), along with their fully symmetrical counterparts 5,10,15,20-tetrakis-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.1) and 5,10,15,20-tetrakis-(4-carboxymethylphenyl) porphyrin (P3.1) were comparatively evaluated. The absorption and fluorescence properties, as well as atomic force microscopy measurements were performed to evaluate the photophysical characteristics as well as morphological and textural properties of the mentioned porphyrins. The cellular uptake of compounds and the effect of photodynamic therapy on the viability, proliferation, and necrosis of human HaCaT keratinocytes, human Hs27 skin fibroblasts, human skin SCL II squamous cell carcinoma, and B16F10 melanoma cells were assessed in vitro, in correlation with the structural and photophysical properties of the investigated porphyrins, and with the predictions regarding diffusion through cell membranes and ADMET properties. All samples were found to be isotropic and self-similar, with slightly different degrees of aggregability, had a relatively low predicted toxicity (class V), and a predicted long half-life after systemic administration. The in vitro study performed on non-malignant and malignant skin-relevant cells highlighted that the asymmetric P2.2 porphyrin qualified among the five investigated porphyrins to be a promising photosensitizer candidate for PDT in skin disorders. P2.2 was shown to accumulate well within cells, and induced by PDT a massive decrease in the number of metabolically active skin cells, partly due to cell death by necrosis. P2.2 had in this respect a better behavior than the symmetric P.2.1 compound and the related asymmetric compound P4.2. The strong action of P2.2-mediated PDT on normal skin cells might be an important drawback for further development of this compound. Meanwhile, the P3.1 and P3.2 compounds were not able to accumulate well in skin cells, and did not elicit significant PDT in vitro. Taken together, our experiments suggest that P2.2 can be a promising candidate for the development of novel photosensitizers for PDT in skin disorders.

The Portosystemic Shunt for the Control of Variceal Bleeding in Cirrhotic Patients: Past and Present.

Based on an experience of more than 50 years in the treatment of portal hypertension (PHT), the authors review and analyze the evolution of the surgical portocaval shunt (PCS). We would like to provide an insight into the past of PCS, in order to compare it with the current state of the treatment of PHT complications. As a landmark of the past, we shall present statistics of more than 500 cases of PHT operated between 1968 and 1983. From this group, 238 patients underwent surgical portocaval shunting during a fifteen-year period. The behavior of the portal hemodynamics following PCS was studied and the postoperative decrease in portal pressure (PP), as well as the residual PP, were recorded. The portal manometric determinations were made by electronic recordings using the Hellige device and direct intraoperative recordings through the catheterization of a ramus in the portal area. The results of PCS are superposable, in terms of hemodynamic efficiency, with those of the intrahepatic shunt (TIPS-transjugular intrahepatic portosystemic shunt). The authors discuss the current place of PCS, in obvious decline in comparison with the situation 50 years ago. The current methods of controlling variceal bleeding represent obvious progress. PCS remains with very limited indications, in specific situations when the other therapeutic methods have failed or are not recommended.