Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers.

A new panel of N-sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC50 values of 3.94, 3.76, and 4.43 µM, respectively. Such IC50 values are comparable to vinblastine (IC50 = 3.21, 7.35, 5.83 µM, respectively) and doxorubicin (IC50 = 6.74, 7.52, 8.19 µM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC50 of 0.0554 µM, compared to sorafenib (IC50 = 0.0416 µM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds.

Exploring the dual effect of novel 1,4-diarylpyranopyrazoles as antiviral and anti-inflammatory for the management of SARS-CoV-2 and associated inflammatory symptoms.

COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV Mpro target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC50 values of 2.01, 1.83, and 4.60 µM respectively compared with 12.85 and 82.17 µM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 Mpro. The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 Mpro and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.

Outcomes of Interleukin-2 Receptor Antagonist Induction Therapy in Standard-Risk Renal Transplant Recipients Maintained on Tacrolimus: A Systematic Review and Meta-Analysis.

INTRODUCTION: The additive benefit of interleukin-2 receptor antagonist (IL2-RA) induction in standard-risk kidney transplant recipients, while maintained on tacrolimus-based immunosuppressive therapy, is uncertain. METHODS: We divided the studies included in this meta-analysis into 2 groups: group A (included studies that used same dose of tacrolimus in both arms of each study) and group B (included studies that compared patients who received induction therapy and low-dose tacrolimus vs. those who received no-induction therapy and high dose of tacrolimus). RESULTS: In group A, 11 studies were included (n = 2,886). IL2-RA induction therapy was not associated with significant differences in comparison to no-induction therapy in terms of acute rejection rates at 6 months post-transplant (risk ratio = 1.12 and 95% confidence interval [CI] range: 0.94-1.35) or graft survival at 1 year post-transplant (risk ratio = 0.78 and 95% CI range: 0.45-1.36). In group B, 2 studies were included (n = 669). There was no difference between both arms in terms of acute rejection rates (risk ratio = 0.62, with 95% CI range: 0.33-1.14) or graft survival (risk ratio = 1 and 95% CI range: 0.57-1.74). CONCLUSION: IL2-RA induction therapy does not improve outcomes in patients maintained on tacrolimus-based immunotherapy in standard-risk population.

Effect of Interleukin-2 Receptor Antibody Induction Therapy on Survival in Renal Transplant Patients Receiving Tacrolimus.

BACKGROUND: This study aims to assess outcomes of interleukin-2 (IL-2) receptor blocker induction therapy on allograft and patients' outcomes in standard risk recipients in the tacrolimus era, analysing data form the British Renal Transplant Registry. METHODS: The study population involved all standard-risk renal transplant patients from 2000 till 2015 who were registered in the UK transplant registry and followed up till May 2018. Standard risk transplants were defined as patients with <2DR mismatch, calculated reaction frequency <20%, live donors or donors after brain death and patients with no previous renal transplantation transplant. We used inverse probability weights to adjust different covariates between the groups. Cox regression analysis for adjusted data and treatment effects model were used to assess outcomes. RESULTS: In all, 3,597 renal transplant patients were included in the study. Two groups were identified; induction group (n = 2,858) which included patients who received IL-2 receptor blocker induction therapy and the no-induction group (n = 739). There was no significant difference between both groups in terms of estimated glomerular filtration rate (eGFR) rate at 1-year post-transplant (correlation co-efficient = 1.224, 95% CI ranges from -0.347 to 2.796). Average eGFR was 59.922 mL/min/1.73 m2 in the induction group (SD 29.171) and 64.557 mL/min/1.73 m2 in the no-induction groups (SD 46.763). There was no significant difference between both groups regarding graft survival at 5 years post-transplant (hazard ratio [HR] 0.944, 95% CI ranges from 0.599 to 1.485, p = 0.804), patient survival at 5 years post-transplant (HR 0.809, 95% CI ranges from 0.477 to1.372, p = 0.433). CONCLUSION: In the standard risk renal transplant population, the IL2 receptor blocker induction regimen does not affect eGFR at 1 year or renal and graft outcomes at 5 years.

Synthesis, anticancer evaluation and molecular docking studies of new heterocycles linked to sulfonamide moiety as novel human topoisomerase types I and II poisons.

A series of heterocyclic compounds with a sulfonamide moiety were synthesized from reaction of enaminone 4 with active methylene compounds, glycine derivatives, 1,4-benzoquinone, hydroxylamine hydrochloride, hydrazonyl halides and dimethylacetylenedicarboxylate. The newly synthesized sulfonamide derivatives were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and alternative synthetic routes. The reactions products were evaluated for their antiproliferative activity against a panel of three different human cancerous cell lines, MCF-7 (breast), HepG-2 (liver) and HCT-116 (colon) and the results were deployed to derive the structure-activity relationships (SAR). Various test compounds were potent antiproliferative to cancerous cells; reaching very low micromolar levels, as in case of 21 which showed IC50 value of 6.2 µM against HepG-2 cell. In addition, treatment of cancerous cells with the synthesized compounds induced cell apoptosis and G2/M phase arrest evidenced by flow cytometric analysis. Furthermore, the activity of the synthesized compounds against TOP I and II were documented by DNA relaxation assays. Data revealed that compound 24 significantly interfered with TOP I- and II-mediated DNA relaxation, nicking and decatenation, with IC50 values 27.8 and 33.6 µM, respectively. Moreover, the molecular docking studies supported the results from enzymatic assays, where compound 24 was intercalated between nucleotides flanking the DNA cleavage site via pi-pi stacking and hydrophobic interactions. In conclusion, aromatic heterocycles linked to sulfonamides are excellent molecular frameworks amenable for optimization as dual TOP I and II poisons to control various human malignancies.

Targeted potent antimicrobial benzochromene-based analogues: Synthesis, computational studies, and inhibitory effect against 14α-Demethylase and DNA Gyrase.

7H-Benzo[7,8]chromeno[2,3-d]pyrimidin-9(8H)-amine (6a,b) have been synthesized via hydrazinolysis of the imidates (5a,b). Polysubstituted chromenotriazolopyrimidine (7a-j), (12a,b) and Schiff base (8a,b) derivatives have also been prepared. The new heterocyclic derivatives were affirmed by spectral data. The target compounds have been screened for antibacterial and antifungal activity. Compounds 6a,b and 7a-c, g,h displayed the most favorable antimicrobial activities in resemblance to the reference antimicrobial agents by IZ range over 24 mm. In addition, MIC, MBC and MFC were also tested and screen for most active compound 6a by 6.25 µg/mL showing bactericidal effect. SAR study revealed that the antimicrobial vitality of the target compounds was safely influenced by the lipophilicity substituents and the calculated log P value. The potent compounds were subjected into in vitro enzyme screening (14α-Demethylase and DNA Gyrase) against both interesting targets and showed good inhibitory profile. Molecular modeling analyses were introduced and discussed focusing on the docking of active compounds into two essential targets, and their ADMET properties were studied.

Relationship between rabbit anti-thymocyte globulin and development of PTLD and its aggressive form in renal transplant population.

Introduction: The aim of our study is to explore the relationship of rabbit anti-thymocyte globulin (R-ATG) on development of post-transplant lymphoproliferative disease (PTLD) and its aggressive forms (monomorphic PTLD and Hodgkin lymphoma) in renal transplant recipients.Methodology: All patients diagnosed with PTLD post-renal transplant in the United States' Organ Procurement and Transplantation Network from 2003 till 2013 and followed up till 2017 were retrospectively reviewed. Multi-variable logistic regression analysis assessed association of R-ATG to development of PTLD and its aggressive form.Results: Risk of developing PTLD post renal transplant is 1.35%. In comparison to interleukin-2 blocker induction therapy, R-ATG is associated with increased risk of development of PTLD (Odds Ratio = 1.48, confidence interval ranges from 1.04 to 2.11, p = .02) and is associated with higher risk of development of aggressive PTLD (Odds Ratio = 1.83, confidence interval ranges from 1.001 to 3.34, p = .04).Conclusion: We conclude that R-ATG induction is associated with a higher risk of PTLD and its aggressive form (monomorphic PTLD and Hodgkin lymphoma). Careful monitoring for development of PTLD in renal transplant recipients receiving R-ATG induction therapy is advised.

Positive Luminex and negative flow cytometry in kidney transplantation: a systematic review and meta-analysis.

The presence of pre-formed donor-specific antibodies (DSAs) in kidney transplantation is associated with worse overall outcomes compared with DSA-negative transplantation. A positive complement-dependant cytotoxic crossmatch presents a high immunological risk, while a negative flow cytometry crossmatch is at the lower end of the risk spectrum. Yet, the presence of low-level DSA detected by Luminex alone, that is, positive Luminex and negative flow (PLNF) cytometry crossmatch lacks robust scientific exploration. In this systematic review and pooled analysis, we investigate the glomerular filtration rate, acute rejection (AR), graft survival and patient survival of PLNF transplants compared with DSA-negative transplants. Our analysis identified seven retrospective studies consisting of 429 PLNF transplants and 10 677 DSA-negative transplants. Pooled analysis identified no significant difference in the incidence of AR at 1 year [relative risk (RR) = 1.35, 95% confidence interval (CI) 0.90-2.02, Z = 1.46, P = 0.14, I2 = 0%], graft failure at 1 year (RR = 1.66, 95% CI 0.94-2.94, Z = 1.75, P = 0.08, I2 = 23%), graft failure at 5 years (RR = 1.29, 95% CI 0.90-1.87, Z = 1.38, P = 0.17, I2 = 0%), patient mortality at 1 year (RR = 0.89, 95% CI 0.31-2.56, Z = 0.22, P = 0.82, I2 = 0%) and patient mortality at 5 years (RR = 1.76, 95% CI 0.48-6.48, Z = 0.85, P = 0.39, I2 = 61%). Pooled analysis of graft function was not possible due to insufficient data. Current evidence suggests that low-level DSA detected by Luminex alone does not pose significant risk at least in the short-medium term. Considering the shortage of kidney transplants and the ever-increasing waiting time, the avoidance of PLNF transplants may be unwarranted especially in patients who have been enlisted for a long time.

Antiproliferative effect, cell cycle arrest and apoptosis generation of novel synthesized anticancer heterocyclic derivatives based 4H-benzo[h]chromene.

Novel ß-enaminonitrile/ester compounds (4, 6) and an imidate of 4 (9) were utilized as key scaffolds for the synthesis of newly 2-substituted 4H-benzo[h]chromene (7, 8, 10, 11, 13, 14) and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives (15-19). The spectral data confirmed the successful isolation of the desired compounds. The targeted compounds were assessed for their in vitro anticancer activity against mammary gland breast cancer cell line (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2), while doxorubicin, vinblastine, and colchicine were utilized as standard references drugs. Some of the examined compounds displayed high growth inhibitory activity against the three different cell lines. For example, the aminoimino derivative (18) exhibited excellent antitumor activity versus all cancer cell lines with IC50 values = 0.45 µg/mL, 0.7 µg/mL, and 1.7 µg/mL. Among the tested molecules, compounds 9, 15, and 18 were selected for further study regarding their effects on cell cycle analysis, apoptosis assay, caspase 3/7 activity, and DNA fragmentation. We found that these three potent cytotoxic compounds induce cell cycle arrest at the S and G2/M phases, which causes apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. Finally, the SAR survey highlighted the antitumor activity of the new molecules that was remarkably influenced by the hydrophilicity of substituent as well the fused rings at certain positions.

Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors.

Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4-33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 µM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.

Design and Synthesis of Novel Heterocyclic-Based 4H-benzo[h]chromene Moieties: Targeting Antitumor Caspase 3/7 Activities and Cell Cycle Analysis.

Novel fused chromenes (4,7⁻11) and pyrimidines (12⁻16) were designed, synthesized, and evaluated for their mammary gland breast cancer (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2) activities. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR, and mass spectroscopy. The preliminary results of the bioassay disclosed that some of the target compounds were proven to have a significant antiproliferative effect against the three cell lines, as compared to Doxorubicin, Vinblastine, and Colchicine, used as reference drugs. Particularly, compounds 7 and 14 exerted promising anticancer activity towards all cell lines and were chosen for further studies, such as cell cycle analysis, cell apoptosis, caspase 3/7 activity, DNA fragmentation, cell invasion, and migration. We found that these potent cytotoxic compounds induced cell cycle arrest at the S and G2/M phases, prompting apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. The structure-activity relationship (SAR) survey highlights that the antitumor activity of the desired compounds was affected by the hydrophobic or hydrophilic nature of the substituent at different positions.

Synthesis, biological activity and molecular modeling study of new Schiff bases incorporated with indole moiety.

A new series of heterocyclic Schiff bases 2-9 containing indole moiety were synthesized by facile and efficient condensation of indole-3/2/5-carboxaldehyde (1a/1b/1c) with different aromatic and heterocyclic primary amines using conventional and/or microwave irradiation methods. The structures of the obtained compounds were assigned by sophisticated spectroscopic and spectrometric techniques (1D-NMR, 2D-NMR and MS). The synthesized compounds were screened for their cytotoxicity and antibacterial activities. In vitro cytotoxicity screening revealed that compound 5 exhibited moderate activity against KB-3-1 cell line (IC50=57.7 µM) while 5-indolylimino derivative 7 indicated close to the activity (IC50=19.6 µM) in comparison with the positive control (+)-Griseofulvin (IC50=19.2 µM), while the tested compounds 5, 6b, 7 and 9 revealed good or moderate antibacterial activity. In addition, molecular docking study of Schiff bases 2-9 was performed by Molecular Operating Environment (MOE 2014.09) program on the matrix metalloproteinase-8 (MMP-8) (Protein Data Bank (PDB) ID: 1MNC) in an attempt to explore their mode of action as anticancer drugs.

Renal Transplant in Elderly End-Stage Renal Disease Patients: Impact of Comorbidities and Posttransplant Adverse Events on Outcomes.

OBJECTIVES: Elderly renal transplant continues to be debated because of age-related factors affecting transplant success and long-term prognosis. We investigated the effects ofrecipient age and predictors of renal transplant outcomes in elderly renal transplant recipients. MATERIALS AND METHODS: We retrospectively analyzed 506 patients who had a first renal transplant between January 2010 and December 2020; there were 165 recipients aged ≥60 years (elderly) and 341 recipients aged <60 years (young).We collected recipient, donor, and transplant characteristics and assessed 1-, 3-, and 5-year overall patient and death-censored graft survival and risk factors influencing outcomes ofrenal transplant in elderly recipients. RESULTS: Elderly recipients showed significantly lower 1-, 3-, and 5-year patient survival rates (96.3%, 89.8%, 80.9%) than young recipients (98.8%, 98.5%, 97.8%; P < .001). However, death-censored graft survival rates were not significantly different (P = .459) between elderly (96.3%, 94.3%, 93.2%) and young recipients (97.7%, 97.0%, 93.9%). Advanced recipient age was identified as an independent risk factor for patient survival, irrespective of donor age. In elderly recipients, male gender (hazard ratio 2.013; 95% CI, 1.110-3.649), pretransplant cardiovascular disease (hazard ratio 1.774; 95% CI, 1.030-3.553), and posttransplant chestinfection (hazard ratio 2.421; 95% CI, 1.439-4.076) were significant predictors of inferior patient survival. Proteinuria at 1 month (hazard ratio 1.006; 95% CI, 1.000-1.011) and low estimated glomerular filtration rate at 3 months (hazard ratio 0.943; 95% CI, 0.899-0.988) posttransplant were early predictors of worse death-censored graft survival. CONCLUSIONS: Elderly renaltransplantrecipients showed promising 5-year patient and death-censored graft survival, exceeding 80%, despite higher mortality risk compared with young recipients. Optimizing outcomes of elderly renal transplant necessitates a multifaceted approach encompassing meticulous pretransplant cardiovascular disease assessment, rigorous posttransplant chest infection prevention and management, and proactive monitoring for early posttransplant kidney dysfunction, to permit timely intervention.

Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking.

Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10 µM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC50 of 1.569 ± 0.06 µM. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 µM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.

Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC₅₀ of 1.569 ± 0.06 µM. Moreover, compound 6a exhibited an IC₅₀ of 31.89 ± 1.19 µM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC₅₀ = 0.225 ± 0.01 µM compared with alpelisib (IC₅₀ = 0.061 ± 0.003 µM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 µg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.

Hematopoietic cell-based and non-hematopoietic cell-based strategies for immune tolerance induction in living-donor renal transplantation: A systematic review.

INTRODUCTION: Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed. MATERIALS AND METHODS: Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed. RESULTS: From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias. CONCLUSIONS: This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.

Inflammatory Bowel Diseases and Kidney Transplantation: A Narrative Review of Clinical Management Approaches.

Inflammatory bowel disease is not uncommon among kidney transplant recipients. In transplant patients with chronic diarrhea and abdominal pain, de novo inflammatory bowel disease can be considered among differential diagnoses, after exclusion of infectious causes and drug-induced diarrhea. Inflammatory bowel disease, in the cnnnontext of organ transplant, is associated with a higherrisk of morbidity, increased rate of hospitalization, and higher mortality.Therefore, a multidisciplinary approach, before and after transplant, among a gastroenterologist specialized in inflammatory bowel disease, a gastrointestinal surgeon, and a transplant clinician is essential, given the higher clinical complexity for this subgroup of patients. Limited data are available on management of inflammatory bowel disease in kidney transplant recipients, although the concurrent use of immunosuppressive therapy can mitigate flare-ups but with increased infection risks. Colorectal cancer can be a serious complication of inflammatory bowel disease; hence, patient compliance with regular colonoscopy surveillance programs is crucial. Patients with inflammatory bowel disease who are undergoing kidney transplant have a shorter overall survival rate compared with matched control groups. However, inferences based on studies involving inflammatory bowel disease in kidney transplant recipients are blighted by small sample sizes,thus making it difficult to draw accurate conclusions. Our review was undertaken to comprehensively report the clinical approaches to kidney transplant recipients with inflammatory bowel disease, describing their clinical course, outcomes, and management plan.

Management of pre-renal transplant secondary hyperparathyroidism: parathyroidectomy versus cinacalcet.

Background: Secondary hyperparathyroidism is a common consequence of end-stage renal disease. Despite the efficacy of kidney transplantation in treating renal failure, many transplant recipients still suffer from persistent or tertiary hyperparathyroidism. Furthermore, the impact of secondary hyperparathyroidism therapy choices on other renal transplant outcomes is poorly understood. Methods: We retrieved the clinical data of 334 patients who received a kidney allograft between January 2007 and December 2014 at the Sheffield Teaching Hospitals, NHS Foundation Trust, United Kingdom. We identified three groups: parathyroidectomy group (34 patients), including patients who had parathyroidectomy before transplantation; cinacalcet group (31 patients), including patients who received cinacalcet before transplantation; and control group (269 patients), including patients who receive a transplant in the same period but did not have any evidence of hyperparathyroidism. We reviewed the demographic data, biochemical parameters and graft survival of all groups. Results: Patients who underwent parathyroidectomy before transplantation had significantly better post-transplant calcium and parathyroid hormone levels than patients in the cinacalcet group (p=0.003). In addition, a significantly lower number of patients had tertiary hyperparathyroidism in the parathyroidectomy group than in the cinacalcet group at 1 year of follow-up (p=0.001). However, short-term and long-term graft survival was comparable in all groups. Conclusions: Renal allograft survival was comparable in all groups. However, tertiary hyperparathyroidism was less likely to occur in patients who underwent parathyroidectomy than in those who were administered cinacalcet.

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation.

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones.Communicated by Ramaswamy H. Sarma.

A novel class of phenylpyrazolone-sulphonamides rigid synthetic anticancer molecules selectively inhibit the isoform IX of carbonic anhydrases guided by molecular docking and orbital analyses.

All the previously reported phenylpyrazoles as carbonic anhydrase inhibitors (CAIs) were found to have small sizes and high levels of flexibility, and hence showed low selectivity profiles toward a particular isoform of CA. Herein, we report the development of a more rigid ring system bearing a sulfonamide hydrophilic head and a lipophilic tail to develop novel molecules that are suggested to have a better selectivity toward a special CA isoform. Accordingly, three novel sets of pyrano[2,3-c]pyrazoles attached with sulfonamide head and aryl hydrophobic tail were synthesized to enhance the selectivity toward a specific isoform of human carbonic anhydrases (hCAs). The impact of both attachments on the potency and selectivity has been extensively discussed in terms of in vitro cytotoxicity evaluation under hypoxic conditions, structure-activity relationship and carbonic anhydrase enzyme assay. All of the new candidates displayed good cytotoxic activities against breast and colorectal carcinomas. Results of the carbonic anhydrase enzyme assay demonstrated the preferential of compounds 22, 24 and 27 to inhibit the isoform IX of hCAs selectively. Wound-healing assay has also been performed and revealed the potential of 27 to decrease the wound closure percentage in MCF-7 cells. Molecular docking and molecular orbital analysis have finally been conducted. Results indicate the potential binding interactions of 24 and 27 with several crucial amino acids of the hCA IX.Communicated by Ramaswamy H. Sarma.

Posterior Reversible Encephalopathy Syndrome in Organ Transplantation.

Posterior reversible encephalopathy syndrome encompasses a spectrum of disorders with a constellation of clinical symptoms and neuroradiological features. It is commonly encountered in organ transplant where it poses a challenge in the diagnosis and treatment in the absence of strong evidence. The underlying pathophysiology of posterior reversible encephalopathy syndrome is the loss of cerebral autoregulation following elevated blood pressure and/or endothelial dysfunction. It is more likely to happen in patients treated with cyclosporine versus with tacrolimus. Posterior reversible encephalopathy syndrome manifests as headache, visual disturbances, seizure, and abnormal mentation. The characteristic radiological features are the result of posterior- circulation vasogenic edema secondary to blood-brain barrier disruption. Treatment varies based on the etiology of the condition. In addition to the symptomatic management of hypertension and seizure disorders, switching or replacing the calcineurin inhibitor with another immunosuppressant or decreasing the dose of the calcineurin inhibitor is the key in calcineurin inhibitor-associated posterior reversible encephalopathy syndrome. Here, we have reviewed the terminology, pathogenesis, clinical features, diagnosis, and treatment of posterior reversible encephalopathy syndrome with special reference to its presence in the posttransplant period.