The enduring metabolic improvement of combining dual amylin and calcitonin receptor agonist and semaglutide treatments in a rat model of obesity and diabetes.

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 months, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide and the combination lowered body weight significantly compared to the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels, and improved glucose tolerance compared to vehicle-treated rats. Further, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared to vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss and improved glucose control. Further, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs.

A case of Muir-Torre syndrome on [18F]FDG PET/CT.

Muir-Torre syndrome (MTS) is a rare genetic disorder, considered a subtype of Lynch syndrome, that causes sebaceous cutaneous tumors and increases the risk of internal visceral tumors. We present a case of a 63-year-old male with a history of MTS with sebaceous tumors, colorectal, and urothelial cancers who underwent fluorine-18-deoxyglucose positron emission tomography/ computed tomography [18F]FDG PET/CT to follow-up on multiple [18F]FDG avid skin lesions and right pelvic lymph nodes. Although few reports are available detailing the utility of [18F]FDG PET/CT in this rare disease, this modality appears useful, and superior, to computed tomography in the diagnosis and follow-up of MTS.

Actinomycetes are a natural resource for sustainable pest control and safeguarding agriculture.

Actinomycetes, a diverse group of bacteria with filamentous growth characteristics, have long captivated researchers and biochemists for their prolific production of secondary metabolites. Among the myriad roles played by actinomycete secondary metabolites, their historical significance in the field of biocontrol stands out prominently. The fascinating journey begins with the discovery of antibiotics, where renowned compounds like streptomycin, tetracycline, and erythromycin revolutionized medicine and agriculture. The history of biocontrol traces its roots back to the early twentieth century, when scientists recognized the potential of naturally occurring agents to combat pests and diseases. The emergence of synthetic pesticides in the mid-twentieth century temporarily overshadowed interest in biocontrol. However, with growing environmental concerns and the realization of the negative ecological impacts of chemical pesticides, the pendulum swung back towards exploring sustainable alternatives. Beyond their historical role as antibiotics, actinomycete-produced secondary metabolites encompass a rich repertoire with biopesticide potential. The classification of these compounds based on chemical structure and mode of action is highlighted, demonstrating their versatility against both plant pathogens and insect pests. Additionally, this review provides in-depth insights into how endophytic actinomycete strains play a pivotal role in biocontrol strategies. Case studies elucidate their effectiveness in inhibiting Spodoptera spp. and nematodes through the production of bioactive compounds. By unraveling the multifunctional roles of endophytic actinomycetes, this review contributes compelling narrative knowledge to the field of sustainable agriculture, emphasizing the potential of these microbial allies in crafting effective, environmentally friendly biocontrol strategies for combating agricultural pests.

Discovery of novel octahydroquinazoline scaffolds endowed with dual inhibition of tubulin polymerization/Eg5 against HCC: Apoptotic and radio-chemotherapeutic studies.

Mitotic kinesin Eg5 isozyme as a motor protein plays a critical role in cell division of tumor cells. Kinesin Eg5 selective inhibitors and Colchicine binding site suppressors are essential targets for many anticancer drugs and radio chemotherapies. On this work, a new series of octahydroquinazoline as anti-mitotic candidates 2-13 has been synthesized with dual inhibition of tubulin polymerization/Eg5 against HCC cell line. All octahydroquinazolines have been in vitro assayed against HepG-2 cytotoxicity, Eg5 inhibitory and anti-tubulin polymerization activities. The most active analogues 7, 8, 9, 10, and 12 against HepG-2 were further subjected to in vitro cytotoxic assay against HCT-116 and MCF-7 cell lines. Chalcones 9, 10, and 12 displayed the most cytotoxic potency and anti-tubulin aggregation in comparable with reference standard colchicine and potential anti-mitotic Eg5 inhibitory activity in comparison with Monastrol as well. Besides, they exhibited cell cycle arrest at the G2/M phase. Moreover, good convinced apoptotic activities have been concluded as overexpression of caspase-3 levels and tumor suppressive gene p53 in parallel with higher induction of Bax and inhibition of Bcl-2 biomarkers. Octahydroquinazoline 10 displayed an increase in caspase-3 by 1.12 folds compared to standard colchicine and induce apoptosis and demonstrated cell cycle arrest in G2/M phase arrest by targeting p53 pathway. Analogue 10 has considerably promoted cytotoxic radiation activity and boosted apoptotic induction in HepG-2 cells by 1.5 fold higher than standard colchicine.

Pathological Extramural Venous Invasion in High-stage Urothelial Carcinoma of the Bladder has Shorter Locoregional Recurrence-free Survival.

Extramural venous invasion is an independent prognostic factor in colorectal cancers; the pathological identification of extramural venous invasion in bladder cancer remains unclear. By focusing on high-stage urothelial carcinoma of the bladder, we provide insights into the pathological identification of extramural venous invasion in this particular clinical context. Clinical and demographic details and pathological reports were extracted from electronic medical records. Histological sections were reviewed for the pathological identification of extramural venous invasion. Statistical analysis was done using SPSS version 23 software. Survival analysis was done using Kaplan-Meier method. In patients with available follow-up data, 62% (n = 21) exhibited pathologically evidenced extramural venous invasion, whereas 38% (n = 13) did not. The extramural venous invasion positive group showed trends toward more advanced and pathological staging and a higher occurrence of extra-nodal extension. Positive margins were more frequent in the extramural venous invasion positive group (33%) compared to the extramural venous invasion negative group (8%). However, these differences were not statistically significant. Notably, all instances of recurrence were in the extramural venous invasion positive group of patients. The extramural venous invasion positive group of patients showed a significantly shorter locoregional recurrence-free survival (P-value of 0.045). However, extramural venous invasion did not emerge as a significant factor in univariate analyses for recurrence-free survival. These findings highlight the potential role of extramural venous invasion as a prognostic factor in bladder cancer but underscore the need for further research with larger cohorts to confirm its significance.

Embryonal rhabdomyosarcoma of the testis in a 17-year-old male.

Primary rhabdomyosarcoma of the testis is an exceptionally rare and highly malignant sarcoma. To date, there are only 23 reported cases in the literature. We report a 17-year-old male patient presented with massive scrotal swelling that had been progressively enlarging over seven-months. Scrotal ultrasound and contrast-enhanced CT revealed a 10 × 10cm left testicular heterogeneously enhancing mass that extends into the spermatic cord. A left inguinal orchiectomy was performed, and histopathological examinations showed findings consistent with Rhabdomyosarcoma, Embryonic-type. Primary embryonal testicular rhabdomyosarcoma has poor prognosis, particularly for adolescents, and tumour size greater than 10cm. Early diagnosis and radical orchiectomy improve the prognosis.

σ-Hole Site-Based Interactions within Hypervalent Pnicogen, Halogen, and Aerogen-Bearing Molecules with Lewis Bases: A Comparative Study.

σ-Hole site-based interactions in the trigonal bipyramidal geometrical structure of hypervalent pnicogen, halogen, and aerogen-bearing molecules with pyridine and NCH Lewis bases (LBs) were comparatively examined. In this respect, the ZF5···, XF3O2···, and AeF2O3···LB complexes (where Z = As, Sb; X = Br, I; Ae = Kr, Xe; and LB = pyridine and NCH) were investigated. The electrostatic potential (EP) analysis affirmations outlined the occurrence of σ-holes on the systems under consideration with disparate magnitudes that increased according to the following order: AeF2O3 < XF3O2 < ZF5. In line with EP outcomes, the proficiency of σ-hole site-based interactions increased as the atomic size of the central atom increased with a higher favorability for the pyridine-based complexes over NCH-based ones. The interaction energy showed the most favorable negative values of -35.97, -44.53, and -56.06 kcal/mol for the XeF2O3···, IF3O2···, and SbF5···pyridine complexes, respectively. The preferentiality pattern of the studied interactions could be explained as a consequence of (i) the dramatic rearrangement of ZF5 molecules from the trigonal bipyramid geometry to the square pyramidal one, (ii) the significant and tiny deformation energy in the case of the interaction of XF3O2 molecules with pyridine and NCH, respectively, and (iii) the absence of geometrical deformation within the AeF2O3···pyridine and ···NCH complexes other than the XeF2O3···pyridine one. Quantum theory of atoms in molecules and noncovalent interaction index findings reveal the partially covalent nature of most of the investigated interactions. Symmetry-adapted perturbation theory affirmations declared that the electrostatic component was the driving force beyond the occurrence of the considered interactions. The obtained findings will help in improving our understanding of the effect of geometrical deformation on intermolecular interactions.

Metabolite profiling and in-silico studies show multiple effects of insecticidal actinobacterium on Spodoptera littoralis.

The polyphagous pest, Spodoptera littoralis (Boisduval), poses a significant global economic threat by gregariously feeding on over a hundred plant species, causing substantial agricultural losses. Addressing this challenge requires ongoing research to identify environmentally safe control agents. This study aimed to elucidate the insecticidal activity of the metabolite (ES2) from a promising endophytic actinobacterium strain, Streptomyces sp. ES2 EMCC2291. We assessed the activity of ES2 against the eggs and fourth-instar larvae of S. littoralis through spectrophotometric measurements of total soluble protein, α- and ß-esterases, polyphenol oxidase (PPO), and catalase enzyme (CAT). The assessments were compared to commercial Biosad® 22.8% SC. Untargeted metabolomics using LC-QTOF-MS/MS identified 83 metabolic compounds as chemical constituents of ES2. The median lethal concentration (LC50) of ES2 (165 mg/mL) for treated Spodoptera littoralis eggs showed significant differences in polyphenol oxidase and catalase enzymatic activities, while the LC50 of ES2 (695 mg/mL) for treated S. littoralis fourth instar larvae showed lower significance in α- and ß-esterase activities. Molecular docking of ES2 identified seven potent biocidal compounds, showing strong affinity to PPO and catalase CAT proteins in S. littoralis eggs while displaying limited binding to alpha and beta esterase proteins in the larvae. The results contribute to the understanding of ES2 as a promising alternative biopesticide, providing insights for future research and innovative applications in sustainable pest management strategies.

Novel Pyrimidine-5-Carbonitriles as potential apoptotic and antiproliferative agents by dual inhibition of EGFRWT/T790M and PI3k enzymes; Design, Synthesis, biological Evaluation, and docking studies.

A new series of 6-(4-fluorophenyl)-2-(methylthio) pyrimidine-5-carbonitrile derivatives were designed and synthesized as EGFR/PI3K dual inhibitors, and potential antiproliferative agents. The new 22 compounds were screened by DTP-NCI against all NCI60 cell lines. Almost all compounds showed cytotoxic activity. Compound 7c showed a promising antitumour activity on CNS cancer (SNB-75), and ovarian cancer (OVAR-4) with IC50 < 0.01, and 0.64 µM, respectively. Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold. Compound 7c displayed selective inhibitory activity on EGFRt790m over EGFRWT with IC50 = 0.08, and 0.13 µM, respectively, wherefore it might overcome EGFR-TKIs resistance. In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC50 = 0.64 µM Compared with LY294002 IC50 = 7.6 µM. Compound 7c arrested the cell cycle of SNB-75 & OVAR-4 at the G0-G1 phase coupled with apoptosis induction. The western blotting analysis approved decreasing the expression level of p-AKT coupled with an increase in Casp3, Casp9, and BAX proteins in the SNB-75 & OVAR-4 after being treated with 7c which may support the suggested mechanism of action of 7c as EGFR/PI3K dual inhibitor. Physicochemical parameters were forecasted using SwissADME online tool. MD showed the interaction of 7c with the crucial amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group.

Chemotherapy-related adverse effects with anthracycline and taxane-containing regimens in patients with localized Breast cancer: a descriptive study : Mohammed VI University Hospital, Medical Oncology Department, Marrakech, Morocco.

BACKGROUND: Although the side effects of chemotherapy are frequently described in research studies, there is little evidence on how common they are in everyday clinical care. This study's goal was to assess the most prevalent short-term side effects experienced by patients with localized breast cancer, undergoing chemotherapy based on anthracyclines and taxane-containing treatments, at the medical oncology department of the Mohammed VI University Hospital of Marrakech, Morocco. METHODS: This was a descriptive study. We conducted a listening session at the outpatient department of the hospital with the help of a structured questionnaire. The session engaged 122 women who had undergone cycles of chemotherapy. A chi-square test was used to compare the incidence and relative risk of short side effects with both anthracycline and taxane-containing regimens. RESULTS: The average age of participants was 49.1 years. In both regimens, the findings highlighted the frequency and relative risk of the following adverse effects: systemic symptoms (fever, asthenia and sleep disorder), gastrointestinal toxicity (Vomiting, nausea, diarrhoea, constipation, mucositis and loss of appetite), dermatological toxicity (Skin reactions on hands/feet, nail toxicity, allergies, alopecia and peripheral edema), neurological toxicity (neuropathy), arthromyalgia and ocular toxicity. CONCLUSIONS: In conclusion, it is crucial for healthcare professionals to be conscious of the significance of these adverse effects. They must also know how to manage them. Likewise, the listening approach highlights its importance in the daily follow-up and monitoring of patients.

Novel indolyl 1,2,4-triazole derivatives as potential anti-proliferative agents: in silico studies, synthesis, and biological evaluation.

A new series of indolyl 1,2,4-triazole scaffolds was designed, synthesised, and biologically evaluated for their inhibitory activity against both CDK4 and CDK6. The results ranged from 0.049 µM to 3.031 µM on CDK4 and from 0.075 µM to 1.11 µM on CDK6 when compared to staurosporine, with IC50 values of 1.027 and 0.402 µM, respectively. Moreover, all compounds were tested for their cytotoxicity against two breast cancer cell lines, MCF-7 and MDA-MB-231. All of the synthesised compounds showed promising anti-proliferative activity, with two compounds Vf (IC50 = 2.91 and 1.914 µM, respectively) and Vg (IC50 = 0.891 and 3.479 µM, respectively) having potent cytotoxic activity in comparison to the reference staurosporine (IC50 = 3.144 and 4.385 µM, respectively). Vf and Vg were also found to significantly induce apoptosis to 45.33% and 37.26% (control = 1.91%) where Vf arrested the cell cycle at the S phase while Vg arrested the cycle at the G0/G1 phase. The binding mode and interactions of all compounds were studied and found to mimic those of the FDA approved CDK4/6 inhibitor palbociclib that was used as a reference throughout the study.

The effects of dexmedetomidine on intraoperative neurophysiologic monitoring modalities during corrective scoliosis surgery in pediatric patients: A systematic review.

BACKGROUND: During scoliosis surgery, motor evoked potentials (MEP), and somatosensory evoked potentials (SSEP) have been reported to be affected by the use of higher doses of anesthetic agents. Dexmedetomidine, a sympatholytic agent, an alpha-2 receptor agonist, has been used as an adjunctive agent to lower anesthetic dose. However, there is conflicting evidence regarding the effects of dexmedetomidine on the intraoperative neurophysiological monitoring of MEP and SSEP during surgery, particularly among pediatric patients. OBJECTIVES: This systematic review aimed to determine whether, during spinal fusion surgery in pediatric patients with scoliosis, dexmedetomidine alters MEP amplitude or SSEP latency and amplitude and, if so, whether different doses of dexmedetomidine display different effects (PROSPERO registration number CRD42022300562). METHODS: We searched PubMed, Scopus, and Cochrane Library on January 1, 2022 and included randomized controlled trials, observational cohort and case-control studies and case series investigating dexmedetomidine in the population of interest and comparing against a standardized anesthesia regimen without dexmedetomidine or comparing multiple doses of dexmedetomidine. Animal and in vitro studies and conference abstracts were excluded. RESULTS: We found substantial heterogeneity in the risk of bias (per Cochrane-preferred tools) of the included articles (n = 5); results are summarized without meta-analysis. Articles with the lowest risk of bias indicated that dexmedetomidine was associated with MEP loss and that higher doses of dexmedetomidine increased risk. In contrast, articles reporting no association between dexmedetomidine and MEP loss suffered from higher risk of bias, including suspected or confirmed problems with confounding, outcome measurement, participant selection, results reporting, and lack of statistical transparency and power. CONCLUSION: Given the limitations of the studies available in the literature, it would be advisable to conduct rigorous randomized controlled trials with larger sample sizes to assess the effects of dexmedetomidine use of in scoliosis surgery in pediatric patients.

Synthesis of novel pyrimido[4,5-b]quinoline derivatives as dual EGFR/HER2 inhibitors as anticancer agents.

A series of novel N-aryl-5-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-4-amines 4a-4l was synthesized as potential anticancer agents through Dimroth rearrangement reaction of intermediates 3a-3c. Pyrimido[4,5-b]quinolines 4a-4l showed promising activity against the Michigan Cancer Foundation-7 (MCF-7) cell line, compared with lapatinib as the reference drug. Compounds 4d, 4h, 4i, and 4l demonstrated higher cytotoxic activity than lapatinib, with IC50 values of 2.67, 6.82, 4.31, and 1.62 µM, respectively. Compounds 4d, 4i, and 4l showed promising epidermal growth factor receptor (EGFR) inhibition with IC50 values of 0.065, 0.116, and 0.052 µM, respectively. These compounds were subjected to human epidermal growth factor receptor 2 (HER2) inhibition and showed IC50 values of 0.09, 0.164, and 0.055 µM, respectively. Compounds 4d, 4i, and 4l are good candidates as dual EGFR/HER2 inhibitors. The most active compound, 4l, was subjected to cell-cycle analysis and induced cell-cycle arrest at the S phase. Compound 4l induced apoptosis 60-fold compared with control untreated MCF-7 cells. 4l can inhibit cancer metastasis. It reduced MCF-7 cell infiltration and metastasis by 45% compared with control untreated cells.

Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFRWT/COX-2 inhibitors with docking studies.

A novel series of pyrimidine-5-carbonitrile derivatives was designed, synthesized, then evaluated for their cytotoxic activity as novel anti-cancer with dual EGFRWT/COX-2 inhibitors. Two compounds 4e and 4f disclosed the highest activity against all NCI60 panel cell lines. They were most potent against Colo 205 (IC50 = 1.66, and 1.83 µM), Sequentially. The most potent two compounds disturbed cell cycle of Colo-205 cells by blocking the G1 phase, coupled with increased annexin-Vstained cells which indicated the increasing in percentage of apoptosis. In addition, 4e and 4f increase the concentration of caspase-3 by 10, and 8-fold compared to control, respectively. Moreover, the two candidate compounds were screened for cytotoxicity on normal epithelial colon cells; fortunately, they were found to be safe. Molecular docking study displayed that these compounds bound to the active site as EGFRWT/COX-2 inhibitors. Furthermore, 3D pharmacophore mapping disclosed many shared features between the most potent candidates 4e and 4f and the standard EGFRWT/COX-2 inhibitors; erlotinib, and celecoxib, respectively. Finally, the physicochemical parameter was calculated for the most potent novel anticancer candidates and the SwissAdme parameter showed that the newly synthesized compounds have good drug-likeness properties.

Improvement of the estimation of the infiltration function in surface irrigation systems.

Surface irrigation systems are widely used on the North China Plain. The design of surface irrigation systems can be improved by developing simulation models including the advanced trajectory, recession trajectory, and infiltration time. Therefore, the objectives of this study were as follows: (1) to evaluate different models to simulate the advanced and recession trajectories, (2) to propose a new method that reduces the required observation data for estimating the infiltration time, and (3) to evaluate the accuracy of the proposed infiltration function based on the modified infiltration time function. Field experiments were conducted. The results indicated that the power function can represent the advanced and recession trajectories well. A modified function that describes the infiltration time has a high correlation and accuracy with the measured data and can be used to estimate the infiltration time. The proposed infiltration function based on the modified infiltration time function is accurate and can be used to estimate the infiltration function.

Factors associated with the laterality of Cardio-Embolic stroke.

OBJECTIVE: Understanding the lateralization factors, including the anatomic and hemodynamic mechanisms, is essential for diagnosing cardio-embolic stroke. This study aims to investigate the elements, for the first time together, that could affect the laterality of stroke. METHODS: We performed a monocentric retrospective case-control study based on prospective registries of acute ischemic stroke patients in the comprehensive stroke center of the RWTH University hospital of Aachen for three years (June 2018-June 2021). We enrolled 222 patients with cardioembolic stroke (136 left stroke and 86 right stroke) admitted for first-ever acute ischemic stroke with unilateral large vessel occlusion of the anterior circulation. The peak systolic velocity (PSV) asymmetry of middle cerebral artery (MCA) was assessed by doppler as well as internal carotid artery (ICA) angle, aortic arch (AA) branching pattern and anatomy were assessed by CT-Angiography. RESULTS: We found that the increasing left ICA angle (p = 0.047), presence of bovine type AA anatomy (p = 0.041) as well as slow PSV of the right MCA with a value of >15% than left (p = 0.005) were the predictors for left stroke lateralization, while the latter was an independent predictor for the left stroke (OR=3.341 [1.415-7.887]). Inter-Rater Reliability ranged from moderate to perfect agreement. CONCLUSION: The predictors for left stroke lateralization include the higher values of left ICA angle, presence of the bovine type AA and the slow right MCA PSV.

Evaluation of the Cutting Seton Technique in Treating High Anal Fistula.

Objectives Fistula-in-ano is a common condition that negatively affects the quality of life of its sufferers. A high anal fistula poses a significant challenge for surgeons due to its proximity to the anorectal ring and the potential risk of incontinence rather than recurrence. Many modalities have been used in a justified search for a satisfactory cure for the condition, but the seton remains a mainstay of surgical treatment. Therefore, the rationale of this study is to assess the outcome of treating a high anal fistula using the cutting seton technique in a hospital in Al Madinah, Saudi Arabia. The evaluation is intended through a retrospective analysis of patients' outcomes, comparing its effectiveness to similar articles. Methods This is a retrospective study that includes 50 patients with high anal fistulas who were treated with a cutting seton at the National Guard Hospital over a four-year period (2019-2022). Information obtained from medical records included clinical and demographic data. The data collected during the study was compiled and statistically analyzed using the SPSS Statistics version 26.0 (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp.). A p-value of <0.05 was considered statistically significant. Results A total of 50 patients with high anal fistula treated with a cutting seton were included: 82% were males and 18% were females, with 66% below 45 years of age. Approximately 92% had inter-sphincteric fistulas, and only 28% had a recurrent fistula. Almost all patients (98%) had an MRI done before surgery. Around 70% of patients were completely cured, 26% had minor complications, 8% of the operated patients experienced mild incontinence, and only one recurrence (2%). Conclusion The cutting seton is still a valid modality in treating patients with a high anal fistula, as it is considerably safe, effective, and yields good outcomes. Standard preoperative assessment and thorough surgical techniques are cornerstones for achieving a satisfactory outcome.

Dual amylin and calcitonin receptor agonist treatment reduces biomarkers associated with kidney fibrosis in diabetic rats.

Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight, glucose control, and insulin action. However, whether DACRAs protect against diabetes-related kidney damage remains unknown. We characterize the potential of long-acting DACRAs (KBP-A, Key Bioscience Peptide-A) as a treatment for T2D-related pathological alterations of the kidney extracellular matrix (ECM) in Zucker diabetic fatty rats (ZDF). We examined levels of endotrophin (profibrotic signaling molecule reflecting collagen type VI formation) and tumstatin (matrikine derived from collagen type IVα3) in serum and evaluated kidney morphology and collagen deposition in the kidneys. We included a study in obese Sprague-Dawley rats to further investigate the impact of KBP-A on ECM biomarkers. In ZDF vehicles, levels of endotrophin and tumstatin increased, suggesting disease progression along with an increase in blood glucose levels. These rats also displayed damage to their kidneys, which was evident from the presence of collagen formation in the medullary region of the kidney. Interestingly, KBP-A treatment attenuated these increases, resulting in significantly lower levels of endotrophin and tumstatin than the vehicle. Levels of endotrophin and tumstatin were unchanged in obese Sprague-Dawley rats, supporting the relation to diabetes-related kidney complications. Furthermore, KBP-A treatment normalized collagen deposition in the kidney while improving glucose control. These studies confirm the beneficial effects of DACRAs on biomarkers associated with kidney fibrosis. Moreover, these antifibrotic effects are likely associated with improved glucose control, highlighting KBP-A as a promising treatment of T2D and its related late complications.NEW & NOTEWORTHY These studies describe the beneficial effects of using a dual amylin and calcitonin receptor agonist (DACRA) for diabetes-related kidney complications. DACRA treatment reduced levels of serological biomarkers associated with kidney fibrosis. These reductions were further reflected by reduced collagen expression in diabetic kidneys. In general, these results validate the use of serological biomarkers while demonstrating the potential effect of DACRAs in treating diabetes-related long-term complications.

Synergistic effect of doxycycline and aqueous extract of irradiated khella on structure of nanobacteria isolated from kidney stones: In vitro and in vivo studies.

Kidney stones have been associated with an increased risk of chronic kidney diseases, end-stage renal failure. This study is devoted to isolate nanobacteria from patients with active urolithiasis and investigate the in vitro and in vivo antinanobacterial activity of some antibiotics alone or in combination with extracts of irradiated herbs from certain medicinal plants. Nanobacteria were detected using scanning (SEM) and transmission (TEM) electron microscopy, protein electrophoresis (SDS-PAGE) and DNA profile. The antimicrobial susceptibility of some biofilm-producing nanobacterial isolates was evaluated. The effect of medicinal plant extracts on growth was tested. A combination treatment between the most potent extracts and antibiotics was tested on biofilm production, protein profile, release of 260 nm absorbing material, protein content, and ultrastructure of the strongest biofilm producers. In vivo study of nanobacteria and its treatment by the most potent agents was evaluated on male rats. Renal function was measured in serum; histological examination and oxidative stress parameters were determined in kidney tissues. Results showed that streptomycin, trimethoprim/sulfamethoxazole, doxycycline, and water extracts of irradiated khella at 6 kGy had antinanobacterial activity. Meanwhile, the synergistic effect of the aqueous extract of irradiated Khella and doxycycline showed higher inhibition activity on microbial growth and biofilm production. They affected dramatically the strength of its cell membrane and subsequently its ultrastructure. Moreover, these results are confirmed by ameliorations in renal function and histological alterations. It could be concluded that the combination of DO and an aqueous extract of irradiated khella has an antinephrotoxic effect against nanobacteria-induced renal toxicity.