Synthesis, biological evaluation and molecular docking studies of novel 1,3,4-thiadiazoles as potential anticancer agents and human carbonic anhydrase inhibitors.

Thiosemicarbazide and also 1,3,4-thiadiazole derivatives have been garnering substantial attention from researchers worldwide due to their expansive range of biological activities, encompassing antimicrobial, anti-inflammatory, and anticancer properties. Herein, we embarked on a comprehensive investigation in this study, introducing a novel series of thiosemicarbazides (3a-3i) and their corresponding 1,3,4-thiadiazole (4a-4i) derivatives. The compounds were meticulously designed, synthesized, and subjected to meticulous characterization using various spectroscopic methods such as FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. Afterward, their potential anti-proliferative effectiveness was assessed using MTT assay against two cancer cell lines (U87 and HeLa) and normal fibroblast cells (L929). Among the compounds, 4d showed the highest cytotoxic activity against U87 and 4i against HeLa. Compound 3b exhibited selective cytotoxic activity against both cancer cells. Among the molecules with selective activity against the U87 cell line; 3a, 3b, 4d and 4e were further evaluated by caspase-3 activity levels, Bax and Bcl-2 protein expression, and total oxidant status assay. Besides, carbonic anhydrase IX activity studies were also performed in order to understand the underlying mechanism of action. The results indicated that compound 4e showed higher efficacy than standard acetazolamide (IC50 = 0.58 ± 0.02 µM) with an IC50 value of 0.03 ± 0.01 µM. Furthermore, molecular docking studies were carried out using carbonic anhydrase IX crystals to determine the compound's interactions with the enzyme's active sites. This comprehensive investigation sheds light on the intricate interplay between molecular structure and biological activity, providing valuable insights into the therapeutic potential of these compounds.

Synthesis and Biological Evaluation of Some Hydrazide-Hydrazone Derivatives as Anticancer Agents.

In this study, a series of hydrazide-hydrazone derivatives (3a-3u) were synthesized and evaluated for their anticancer activities against prostate cancer cell line (PC-3), breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and human umbilical vein endothelial cells (HUVEC) using MTT assay. In particular, compound 3h having a pyrrole ring was found to be the most potent derivative with IC50 = 1.32, 2.99, 1.71 µM against PC-3, MCF-7, HT-29 cancer cell lines respectively using paclitaxel as a standard compound. Furthermore, compound 3h was subjected to further biological studies such as caspase-3 activity and Annexin-V assay to evaluate their inhibitory potentials. The activity results displayed that compound 3h increased caspase-3 activation and the number of cells to early apoptosis. The additional studies like pharmacokinetics, bioavailability scores and drug-likeness properties were also evaluated. The in silico pharmacokinetics predictions displayed that the bioavailability of these compounds may be high.

Design, Synthesis, In Silico ADMET Studies and Anticancer Activity of Some New Pyrazoline and Benzodioxole Derivatives.

A new series of 2-pyrazoline derivatives starting from substituted benzodioxole chalcones were designed and synthesized. IR and 1H NMR spectral data and elemental analysis were used to characterize the structures of the synthesized compounds. The cytotoxic activities on HeLa, MCF-7 cancer cell lines and NIH-3T3 for these compounds were tested by using MTT assay. Among the synthesized compounds 2d, 2j, 3j and 3n against MCF-7 cells, and 3c against HeLa exhibited significant cytotoxic activity with IC50 between 10.08 and 27.63 µM. Compound 3f showed the most potent anticancer activity against both cancer cells with good selectivity (IC50 = 11.53 µM on HeLa with SI = 81.75 and IC50 = 11.37 µM on MCF-7 with SI = 82.90). Furthermore, in silico ADMET analyses were performed and the drug-likeness properties of the compounds were investigated.

Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives.

BACKGROUND: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of Endoplasmic Reticulum (ER) stress and subsequent activation of the Unfolded Protein Response (UPR) has been proposed as a potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. OBJECTIVE: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. METHODS: Cell proliferation assays were performed on HeLa, Capan-1, MCF-7, HCC-1937, and MRC-5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. RESULTS: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of proapoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and -7. The flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). CONCLUSION: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways.

Design, synthesis and biological evaluation of some new 2-Pyrazoline derivatives as potential anticancer agents.

A new series of N-(4-(1-Phenyl-5-aryl-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-4-substitutedbenzamide derivatives were designed and synthesized from new chalcone derivatives. All newly synthesized compounds were determined by using IR, 1H-NMR, 13C-NMR spectroscopic methods, elemental analysis and evaluated for their in vitro antiproliferative activities on HeLa, MCF-7, MKN-45 cancer cell lines and NIH-3T3 cell line using MTT assay. Expression of Bax and Bcl-2 proteins was detected by Western-blot analysis and caspase-3 enzyme activity was measured. Notably, compounds 1f and 2f showed a significant cytotoxic effect in all three cancer cells and did not display cytotoxicity on NIH-3T3 normal cells. (IC50 = 26.66 ± 2.73 µM on HeLa, IC50 = 9.41 ± 2.19 µM on MCF-7, IC50 = 5.17 ± 3.54 µM on MKN-45 for 1f. IC50 = 17.96 ± 3.34 µM on HeLa, IC50 = 0.69 ± 0.13 µM on MCF-7, IC50 = 0.88 ± 0.16 µM on MKN-45 for 2f.) Moreover, 1f and 2f upregulated protein expression level of Bax and downregulated protein expression level of Bcl-2 in cells. Similarly, caspase-3 activity was increased in cells via 1f and 2f. It can be concluded that 1f and 2f activated apoptosis by inducing mitochondrial apoptotic proteins in HeLa, MCF-7, MKN-45. This could be potentially new anti-cancer derivatives and used to contribute to new therapeutic development.

Design, Synthesis and Evaluation of the Biological Activities of Some New Carbohydrazide and Urea Derivatives.

OBJECTIVES: Urea and carbohydrazide derivatives are important compounds exhibiting cytotoxic activities. In this study, a series of new urea and carbohydrazide derivatives containing an pyridine ring were synthesized and evaluated for cytotoxic activity. MATERIALS AND METHODS: The proposed structures of the synthesized compounds were confirmed using elemental analysis, IR, and 1H-NMR spectroscopic techniques. The cytotoxic potencies of synthesized compounds were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) on BRCA mutant-carrying HCC1937 and Capan-1 cell lines, as well as on MCF7, HeLa, and MRC5 cells. RESULTS: 3a, 3b, 3c and 3d showed cytotoxic activity against all cancer cell lines. CONCLUSION: Our data indicate that compounds 3a-d are more selective to cancer cells compared with nontumoral fibroblasts; however, these compounds are not more potent on HR defective cells with BRCA mutants.

The effects of acupuncture versus sham acupuncture in the treatment of fibromyalgia: a randomized controlled clinical trial.

OBJECTIVE: The aim of this manuscript is to determine and to compare the efficacy of real acupuncture with sham acupuncture on fibromyalgia (FM) treatment. METHODS: 50 women with FM were randomized into 2 groups to receive either true acupuncture or sham acupuncture. Subjects were evaluated with VAS (at night, at rest, during activity), SF-36, Fibromyalgia Impact Questionnaire (FIQ), Beck Depression scale (BDI), Fatigue Severity Scale (FSS) at baseline, 1 month and 2 months after the 1st session. Patients in both groups received 3 sessions in the 1st week, 2 sessions/week during 2 weeks and 1 session/week in the following 5 weeks (totally 12 sessions). RESULTS: 25 subjects with a mean age of 47,28±7,86 years were enrolled in true acupuncture group and 25 subjects with a mean age of 43,60±8,18 years were enrolled in sham acupuncture group. Both groups improved significantly in all parameters 1 month after the 1st session and this improvement persisted 2 months after the 1st session (p<0,05). However, real acupuncture group had better scores than sham acupuncture score in terms of all VAS scores, BDI and FIQ scores either 1 or 2 months after the 1st session (all p<0,05). CONCLUSION: Acupuncture significantly improved pain and symptoms of FM. Although sham effect was important, real acupuncture treatment seems to be effective in treatment of FM.

Epidemiologic data of trauma-related lower limb amputees: A single center 10-year experience.

OBJECTIVE: The aim of this study is three fold: 1) to introduce epidemiologic data of patients with trauma-related amputations as a 10-year experience of a rehabitation center; 2) to determine comorbidities and secondary conditions of lower limb loss; 3) to determine the rehospitalization reasons for lower limb amputee patients. MATERIALS AND METHODS: This retrospective study was conducted in a tertiary rehabilitation center in Turkey. Clinical and demographic data of amputees including sex, age, employment status, time since amputation, time after amputation to first hospitalization, length of hospitalization, how many times the patient was hospitalized, reason for hospitalization, stump complications, comorbid conditions, amputation level and K classifacation were documented. RESULTS: Three hundred ninetynine patients with a mean age of 23,48±6,04 (4-74) years were included in this study. Mean duration after amputation was 119,71±68,86months. Patients were 3,43±2,53 times hospitalized. Landmine explosion was the most common etiology of amputation with 370 patients (92.7%). Below knee amputation was the most common amputation level with 230 (50,77%) amputations. 399 patients were hospitalized 1369 times and the most common hospitalization reason were stump complications (356 times, 26,00%). Spur formation (202 times) was the most common stump complications. Pyscologic disorders were the most common comorbidity with 68 patient (37,56%). CONCLUSION: Patients with traumatic limb amputations are likely to experience several complications and comorbidities. Prevention of secondary conditions affecting those living with the loss of a limb is an important part of amputee rehabilitation and may prevent rehospitalization.

Ultrasonographic evaluation of the femoral cartilage thickness in patients with chronic renal failure.

OBJECTIVE: To investigate the effects of chronic renal failure (CRF) on the distal femoral cartilage thickness by using ultrasonography and to determine the relationship between cartilage thickness and certain disease-related parameters. DESIGN: Fifty-seven CRF patients (41 male and 16 female) (mean [SD] age, 44.7 [12.1] years) and 60 healthy controls (41 male and 19 female) (mean [SD] age, 43.5 [13.3] years) were enrolled in this study. Demographic and clinical characteristics were recorded. Cartilage thickness measurements were taken from the medial and lateral condyles, and intercondylar areas of both knees. RESULTS: Groups were similar in terms of age, weight, height, body mass index and gender (all p>0.05). The mean cartilage thickness was found to be less in CRF patients than in controls (statistically significant for medial condyles and intercondylar areas both in right and the left knees [all p<0.05]). Cartilage thickness showed no correlation with eGFR, and with the levels of serum urea, creatinine, calcium, magnesium, phosphor, hemoglobin, uric acid and as well as steroid use (all p>0.05) in CRF patients. CONCLUSION: In the light of our findings, we imply that patients with CRF have thinner femoral cartilage than healthy controls. This result may support the view that patients with CRF are at increased risk for developing early knee osteoarthritis. Last but not least, clinicians should be aware of the importance of rehabilitation strategies aimed at decreasing onset and progression of knee osteoarthritis in patients with CRF.

Nineteen reasons why physiatrists should do musculoskeletal ultrasound: EURO-MUSCULUS/USPRM recommendations.

This article is an eventual consensus of experts from the European Musculoskeletal Ultrasound Study Group (EURO-MUSCULUS) and the Ultrasound Study Group in Physical and Rehabilitation Medicine (USPRM) pertaining to the use of musculoskeletal ultrasound in physical and rehabilitation medicine. Nineteen important reasons (as regards general advantages, specific conditions in physical and rehabilitation medicine, as well as comparisons with other imaging tools) have been highlighted to consolidate the scenario of how/why the probe of ultrasound needs to become the stethoscope, the extended hand, and the pen of physiatrists.

Femoral cartilage thickness measurements in healthy individuals: learning, practicing and publishing with TURK-MUSCULUS.

BACKGROUND AND OBJECTIVES: Measurement of the femoral cartilage thickness by using in-vivo musculoskeletal ultrasonography (MSUS) has been previously shown to be a valid and reliable method in previous studies; however, to our best notice, normative data has not been provided before in the healthy population.The aim of our study was to provide normative data regarding femoral cartilage thicknesses of healthy individuals with collaborative use of MSUS. METHODS: This is across-sectional study run at Physical and Rehabilitation Medicine Departments of 18 Secondary and Tertiary Centers in Turkey. 1544 healthy volunteers (aged between 25-40 years) were recruited within the collaboration of TURK-MUSCULUS (Turkish Musculoskeletal Ultrasonography Study Group). Subjects who had a body mass index value of less than 30 and who did not have signs and symptoms of any degenerative/inflammatory arthritis or other rheumatic diseases, history of knee trauma and previous knee surgery were enrolled. Ultrasonographic measurements were performed axially from the suprapatellar window by using linear probes while subjects' knees were in maximum flexion. Three (mid-point) measurements were taken from both knees (lateral condyle, intercondylar area, medial condyle). RESULTS: A total of 2876 knees (of 817 M, 621 F subjects) were taken into analysis after exclusion of inappropriate images. Mean cartilage thicknesses were significantly lower in females than males (all p< 0.001). Thickness values negatively correlated with age; negatively (females) and positively (males) correlated with smoking. Men who regularly exercised had thicker cartilage than who did not exercise (all p < 0.05). Increased age (in both sexes) and absence of exercise (males) were found to be risk factors for decreased cartilage thicknesses. CONCLUSION: Further data pertaining to other countries would be interesting to uncover whether ethnic differences also affect cartilage thickness. Collaborative use of MSUS seems to be promising in this regard.

The efficacy of hyperbaric oxygen therapy in the management of chronic fatigue syndrome.

OBJECTIVE: Chronic fatigue syndrome (CFS) is a chronic disease with social components that ensue secondary to the incapacity of the person to fulfill work, social and family responsibilities. Currently, there is no consensus regarding its treatment. The aim of this study was to determine the efficacy of hyperbaric oxygen (HBO2) therapy in CFS. DESIGN: Sixteen patients included in the study were diagnosed with CFS according to the Fukuda criteria. Patients received 15 treatment sessions of HBO2 therapy over a period of three consecutive weeks (five days per week). The outcome measures (visual analog fatigue scale (VAFS). Fatigue Severity Scale (FSS) and Fatigue Quality of Life Score (FQLS) were assessed before the treatment and after completion of the 15 sessions. RESULTS: HBO2 therapy was well tolerated, with no complications. After treatment, patients' scores were found to have improved with respect to VAFS, FSS and FQLS (all p<0.005). CONCLUSIONS: We ,may infer that HBO2 therapy decreases the severity of symptoms and increases the life quality of CFS patients. It may be a new treatment modality for the management of CFS. However, further studies with larger sample sizes and control groups are definitely awaited.

Epidemiologic data of the patients with spinal cord injury: seven years' experience of a single center.

BACKGROUND: We aimed to present the demographic and epidemiologic data on spinal cord injury (SCI) patients who were rehabilitated at our hospital, to identify high-risk groups and etiological factors, and to evaluate the factors that affect the duration of hospitalization (DOH). METHODS: Data on 905 SCI patients treated on an inpatient basis between December 2000 and June 2007 at our hospital were retrospectively evaluated. Patient age, sex, etiology of injury, DOH, neurologic level, and functional grouping were analyzed. Additionally, the effects of age and sex on DOH were evaluated. RESULTS: In total, 661 (73%) of the patients were male and 244 (27%) were female. The mean age of the patients was 33.4±15.0 years; 51.27% of the patients were 20-33 years of age. The mean DOH was 73.6±49.8 days. In all, 304 (33.5%) of the patients were tetraplegic and 601 (66.5%) were paraplegic. Motor vehicle collisions were the most common cause of injury (n=318, 35.1%), followed by falls from an elevated height (n=170, 18.8%). DOH was significantly higher among the tetraplegia American Spinal Injury Association (ASIA) A-B patients than among the other patients (p<0.01). CONCLUSION. It is clear that most of the SCIs we observed were preventable. Comprehensive identification of the epidemiologic, demographic and pathologic features of SCIs contributes to identifying high-risk groups, thereby making it possible to pay personal and communal attention to precautions for SCIs.