Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently.

There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.

Bisphosphonate therapy associated with bilateral atypical femoral fracture and delayed union.

OBJECTIVES: The aim of this study was to identify the risk factors for developing atypical femoral fractures (AFF) and to examine the effect of bisphosphonate (BP) therapy on delayed bone union and bilateral fractures. PATIENTS AND METHODS: Between January 1st, 2012 and December 31st, 2020, a total of 74 AFF patients (8 males, 66 females; mean age: 75.4±7.2 years; range, 51 to 94 years) were recorded in two centers and retrospectively analyzed. A control fragility fracture group (n=143) was compared to the AFF group according to fracture characteristics, surgical fixation methods, comorbidities, and medications. The AFF patients were selected and subdivided according to their BP therapy: Group 1 (without BP) and Group 2 (with BP). Group 2 was further classified into Group 2a (<5 years of BP) and Group 2b (<5 years of BP). RESULTS: The multivariate logistic regression model showed that, BP drug use was the most significant risk factor in development of AFF (p<0.001, odds ratio= 10.749, 95% confidence interval: 3.886-29.733). The patients on BP showed longer bone union (Group 2 - 8.3±3.5 vs. Group 1 - 6.4±3.1 months, p=0.02; Group 2b - 9±3.8 vs. Group 2a - 7.3 ±3.9 months, p=0.09). Of all 19 cases of bilateral fractures, 14 were in Group 2 with BP use (p=0.11). Of 74 cases, 26 (35%) contralateral femoral X-rays were taken on admission and 24 (92%) showed AFF minor criteria signs. Of these 24 patients, 10 (42%) developed contralateral AFF. CONCLUSION: The most significant risk factor in development of AFF was BP drug use. Longer BP therapy (>5 years) showed longer delayed bone union, which was not significant. There was a relatively high risk of developing AFFs and bilateral fractures on BP therapy. In case of an AFF, a contralateral femoral X-ray must be always performed for signs of an impending fracture.

Multidisciplinary treatment of a complicated crural degloving injury in a diabetic patient.

Diabetes is a common disease that potentially interferes with healing processes after lower limb trauma. In our presented case a trimalleolar ankle fracture with undiscovered serious soft-tissue injuries resulted in chronic soft-tissue complications in a diabetic patient, requiring three and a half months of hospitalization in a higher level center and the application of state-of-the-art wound treatment, including vacuum-assisted closure therapy, Integra bioengineered skin substitute, split-thickness skin-grafting, and methods enhancing wound healing, such as polarized light therapy and transdermal CO2 delivery. The presented case emphasizes the importance of soft-tissue care and multidisciplinary approach in diabetic trauma patients with poor compliance.

Novel perspectives of target-binding by the evolutionarily conserved PP4 phosphatase.

Protein phosphatase 4 (PP4) is an evolutionarily conserved and essential Ser/Thr phosphatase that regulates cell division, development and DNA repair in eukaryotes. The major form of PP4, present from yeast to human, is the PP4c-R2-R3 heterotrimeric complex. The R3 subunit is responsible for substrate-recognition via its EVH1 domain. In typical EVH1 domains, conserved phenylalanine, tyrosine and tryptophan residues form the specific recognition site for their target's proline-rich sequences. Here, we identify novel binding partners of the EVH1 domain of the Drosophila R3 subunit, Falafel, and demonstrate that instead of binding to proline-rich sequences this EVH1 variant specifically recognizes atypical ligands, namely the FxxP and MxPP short linear consensus motifs. This interaction is dependent on an exclusively conserved leucine that replaces the phenylalanine invariant of all canonical EVH1 domains. We propose that the EVH1 domain of PP4 represents a new class of the EVH1 family that can accommodate low proline content sequences, such as the FxxP motif. Finally, our data implicate the conserved Smk-1 domain of Falafel in target-binding. These findings greatly enhance our understanding of the substrate-recognition mechanisms and function of PP4.

Sigma-1 Receptor Engages an Anti-Inflammatory and Antioxidant Feedback Loop Mediated by Peroxiredoxin in Experimental Colitis.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Since the treatment of IBD is still an unresolved issue, we designed our study to investigate the effect of a novel therapeutic target, sigma-1 receptor (σ1R), considering its ability to activate antioxidant molecules. As a model, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to induce colitis in Wistar-Harlan male rats. To test the beneficial effects of σ1R, animals were treated intracolonically (i.c.): (1) separately with an agonist (fluvoxamine (FLV)), (2) with an antagonist of the receptor (BD1063), or (3) as a co-treatment. Our results showed that FLV significantly decreased the severity of inflammation and increased the body weight of the animals. On the contrary, simultaneous treatment of FLV with BD1063 diminished the beneficial effects of FLV. Furthermore, FLV significantly enhanced the levels of glutathione (GSH) and peroxiredoxin 1 (PRDX1) and caused a significant reduction in 3-nitrotyrosine (3-NT) levels, the effects of which were abolished by co-treatment with BD1063. Taken together, our results suggest that the activation of σ1R in TNBS-induced colitis through FLV may be a promising therapeutic strategy, and its protective effect seems to involve the antioxidant pathway system.

Atypical periprosthetic femoral fracture associated with long-term bisphosphonate therapy.

BACKGROUND: Atypical femoral fracture is one of the many complications after the long-term use of bisphosphonates. The American Society for Bone and Mineral Research has officially excluded periprosthetic femoral fractures (PFFs) from the definition of atypical femoral fractures (AFFs). Several case reports found that PFFs can occur with characteristics similar to those of AFFs. The purpose of our study was to evaluate the proportion of atypical fractures among Vancouver type B1 fractures, and to determine the association between the long-term use of bisphosphonates and the occurrence of atypical periprosthetic femoral fractures (APFFs). METHODS: In this retrospective study, we reviewed 41 patients with Vancouver type B1 periprosthetic fractures between January 1, 2011 and December 31, 2018. We classified them into two groups, namely atypical and typical PFFs, based on the fracture morphology. We noted the proportion of atypical periprosthetic fractures among B1 fractures and identified risk factors. RESULTS: Among the 41 PFFs, 5 (13%) fractures were classified as atypical PFF based on the radiological characteristics. The longer duration of bisphosphonate use was probably the only independent risk factor that significantly increases the occurrence of APFF (p = 0.03, 0.08 (CI 0.008 - 0.16)). There were no significant differences in age, gender, body mass index, comorbidities, corticosteroid use, positioning of the femoral stem, the method of fixation (cemented or cementless) and time lapse from before the primary prosthesis implantation to the PFF in the development of atypical fracture type. CONCLUSIONS: There seems to be a correlation between the long-term intake of bisphosphonates and the atypical periprosthetic fracture. Atypical femoral fracture can also occur in the periprosthetic form. TRIAL REGISTRATION: Study number: 22/2019-SZTE, http://www.klinikaikutatas.hu/hu/kutatasetika/jovahagyott-vizsgalatok-koezerdeku-adatai/category/25-jovahagyott-vizsgalatok-kozerdeku-adatai-rkeb-2019.html?download=985:22-2019 .

Phenothiazines and Selenocompounds: A Potential Novel Combination Therapy of Multidrug Resistant Cancer.

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.

Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway.

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar-Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [3H](+)-pentazocine binding sites, and FLV treatment increased the reduced σ1R maximum binding capacity in TNBS-induced colitis. Furthermore, FLV significantly attenuated the colonic damage, the effect of which was abolished by the administration of BD1063. Additionally, FLV potentially increased the expression of ubiquitin C-terminal hydrolase ligase-1 (UCHL-1) and the levels of endothelial nitric oxide synthase (eNOS), and decreased the levels of interleukin-6 (IL-6) and inducible NOS (iNOS) expression. In summary, our study offers evidence for the anti-inflammatory potential of FLV and σ1R in experimental colitis, and our results present a promising approach to the development of new σ1R-targeted treatment options against IBD.

[The prognostic value of the hip screw position in intertrochanteric fractures]. / A combfejcsavar helyzetének prognosztikai jelentosége a csípotáji törések esetén.

INTRODUCTION: In our study, we analyzed one of the Hungarian population's most frequent injuries, the hip fracture, focusing mainly on the lateral femoral neck and the pertrochanteric fractures. According to the classification of the Swiss Association for Ostheosynthesis (AO), we focused on 31-A1 and 31-A2 fractures, the incidence of which increases by ageing. METHOD: Between 2010 and 2016, we analyzed the data of 1179 patients. All of the fractures were stabilized with intramedullary nails. 992 patients received Stryker Gamma3®, whereas 187 patients' fractures were solved with Synthes PFNA® nail. In all cases, closed reduction method was used with fluoroscopy on an extension table. The surgeries were done in general or epidural anesthesia and performed by traumatology residents or specialists using standard lateral exploration. Data were collected using GEPACS software and statistical analysis was done with MS Excel. RESULTS: Cut-out occurred in 33 cases (2,79%): out of that 21 (1.78%) were left sided and 12 were (1,01%) right sided. 29 (87.87%) patients were treated with Gamma3 nail, and in 4 (12,12%) cases PFNA nail was used. The average TAD-index was 18 mm. CONCLUSION: According to recommendations of the TAD-index value, when using dynamic hip screw, it should be 20 mm or lower. The average index value was 18 mm which was equal in the complicated and non-complicated groups. Our study shows that the cut-out is independent from the TAD-index value, thus this recommendation cannot be applied for intramedullary nails. Orv Hetil. 2019; 160(9): 338-342.

[Drainage data analysis of chest-injured patients]. / Mellkasi sérültek drenázsadatainak vizsgálata.

INTRODUCTION: Chest injuries cause a significant number of pneumothorax (PTX) and hemothorax (HTX). The most commonly used treatment is chest-tube drainage. The position of the tube is a prime necessity to achieve adequate drainage. AIM: To analyze the duration of chest drainage at the occurrence of PTX and HTX. To find what the underlying cause of drainage insufficiency is and whether there is any relation between the surgical qualification needed to the procedure. METHOD: Clinical data of 110 injured patients from 2011 to 2015 were collected and retrospectively analyzed. In the case of tube breaking or drainage insufficiency it was investigated if repositioning, usage of new tubes or insertion of additional tubes resolved the drainage insufficiency. Authors investigated the location of the tube on x-ray and CT, and the connection between the drainage insufficiency and the surgical qualifications needed to the procedure. RESULTS: The average duration of chest drainage was 6.5 days. The duration of drainage was shorter by 1.9 days regarding the tube inserted in the middle section of the chest compared to the upper one and shorter by 1.2 days regarding the tube inserted in the lower section of the chest compared to the upper one. In the case of HTX, the duration of drainage was shorter by 2.8 days regarding the lower and by 3.6 days regarding the middle section compared to the upper position. Drainage insufficiency occurred in 30% of all cases. The duration of chest drainage was shorter after application of new tubes (9.5 days) than after reposition (10.2 days), but there was no significant difference. CONCLUSION: Chest injury is a wide entity, thus one standard protocol cannot be developed on the management of these injuries. Authors concluded that drainage duration decreases significantly if the position of the tube is in the middle or lower section of the chest. The high occurrence of drainage insufficiency was caused by inadequate tube positioning and tube breaking. The practical qualification of trauma surgeons did not play a significant role regarding the prevalence of drainage insufficiency rather if the tube positioning was appropriate. Orv Hetil. 2019; 160(5): 172-178.

Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus.

A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks.

Bioactive compounds from the African medicinal plant Cleistochlamys kirkii as resistance modifiers in bacteria.

Cleistochlamys kirkii (Benth) Oliv. (Annonaceae) is a medicinal plant traditionally used in Mozambique to treat infectious diseases. The aim of this study was to find resistance modifiers in C. kirkii for Gram-positive and Gram-negative model bacterial strains. One of the most important resistance mechanisms in bacteria is the efflux pump-related multidrug resistance. Therefore, polycarpol (1), three C-benzylated flavanones (2-4), and acetylmelodorinol (5) were evaluated for their multidrug resistance-reverting activity on methicillin-susceptible and methicillin-resistant Staphylococcus aureus and Escherichia coli AG100 and AG100 A strains overexpressing and lacking the AcrAB-TolC efflux pump system. The combined effects of antibiotics and compounds (2 and 4) were also assessed by using the checkerboard microdilution method in both S. aureus strains. The relative gene expression of the efflux pump genes was determined by real-time reverse transcriptase quantitative polymerase chain reaction. The inhibition of quorum sensing was also investigated. The combined effect of the antibiotics and compound 2 or 4 on the methicillin-sensitive S. aureus resulted in synergism. The most active compounds 2 and 4 increased the expression of the efflux pump genes. These results suggested that C. kirkii constituents could be effective adjuvants in the antibiotic treatment of infections.

Possible Biological and Clinical Applications of Phenothiazines.

Phenothiazines have been used in many areas of medicine, mainly in psychopharmacology. These compounds are able to effectively inhibit dopamine, histamine, serotonin, acetylcholine, and α-adrenergic receptors; thus, their effect and side-effect profiles are extremely diverse. Besides their antipsychotic activity, phenothiazines have a significant antimicrobial effect as well, since they can enhance the bactericidal function of macrophages and inhibit efflux pumps. They are also able to eliminate bacterial resistance plasmids and destroy bacteria by their membrane-destabilizing effect. Their antiviral, antiprotozoal, antifungal, and antiprion activities have also been described. Phenothiazines have also been proven to destroy cancer cells and sensitize them to chemotherapy. Anti-angiogenesis and anticancer stem cell activities have also been reported, and they might be applied as adjuvants in the treatment of infections and tumors in the future. Finally, phenothiazines can also be effective in the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

Isolation of Chlorogenic Acid from Soil Borne Fungi Screlotium rolfsii, their Reversal of Multidrug Resistance and Anti-proliferative in Mouse Lymphoma Cells.

BACKGROUND: Fungi performing a wide range of function in soil by secreting low molecular weight compound known as secondary metabolites. S. rolfsii is a soil borne phytopathogenic fungi was used for the production of bioactive compounds. OBJECTIVE: The present study belongs to evaluate the anticancer potentials of a secondary metabolites isolated from S. rolfsii, their multidrug resistance (MDR), and molecular docking study. METHOD: (1S,3R,4R,5R,E)-3-(3-(3,4-Dihydroxyphenyl)acryloyloxy)-1,4,5 trihydroxycyclohexanecarboxylic acid (1), or best known as chlorogenic acid, was isolated from the ethyl acetate fraction of crude secondary metabolites produced by the soil borne Fungus Screlotium rolfsii. Structure of chlorogenic acid (1) was confirmed by means of FT-IR, 1H NMR, 13C NMR, and mass spectrometry as well as by melting point. RESULTS: Effect of compound 1 on the reversion of multidrug resistant (MDR) mediated by Pglycoprotein (P-gp) against cancer cells was evaluated with a rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma. Compound 1 was also evaluated for Anti-proliferative effect on the L5178 mouse Tcell lymphoma cell line. CONCLUSION: Results from the present investigation revealed that compound 1 exhibits excellent MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Compound 1 also showed anti-proliferative effect on L5178Y mouse T-lymphoma cell line.

The Anticancer Activity of the Old Neuroleptic Phenothiazine-type Drug Thioridazine.

Thioridazine (TZ), an antipsychotic drug, renders multidrug-resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has anti-prolilferative activity and apoptosis-inducing properties in various tumor cell lines and cancer stem cells. Whereas the anti-proliferative activity takes place at high concentrations that ensure the intercalation of the compound between nucleic bases (especially rich in G/C bases), much lower concentrations inhibit the export function of the ABCB1 (P-glycoprotein), which is responsible for the MDR phenotype of the cancer cell. The co-administration of TZ with doxorubicin inhibits efflux of doxorubicin and, hence, increases the intracellular concentration of anticancer drug. The (+) and (-) enantiomers of TZ have the same activities as TZ. The main focus of this review is to present extensive evidence provided by our work, confirmed by much later studies, as it supports adjuvant use of TZ with an anticancer drug for MDR cancer therapy.

[Comparison of the effect of multidrug resistance modifiers on prostate cancer, mouse lymphoma and colon cancer cells]. / Rezisztenciamódosítók összehasonlítása multidrog-rezisztens prosztata-, egérlymphoma- és vastagbélrák-sejtvonalakon.

INTRODUCTION: The reason for unsuccessful tumor chemotherapy is related to multidrug resistance. An important factor is the overexpression of efflux pumps, such as P-glycoprotein. AIM: Amino- and amide-substituted steroid compounds and phenothiazine derivatives were investigated in tumor models in vitro. METHOD: The inhibition of P-glycoprotein was evaluated by flow cytometry and the interaction of these compounds with doxorubicin was investigated as well. Molecular docking was used to estimate the binding energies of the compounds to P-glycoprotein. RESULTS: The aminosteroids showed anticancer activity on multidrug resistant mouse T-lymphoma and prostate cancer cell lines. The combination of steroids and doxorubicin potentiated its effect in hormone resistant prostate cancer cells. Among the N-hydroxyalkyl-2-aminophenothiazines, secondary amines exhibited anticancer effects on multidrug resistant colon adenocarcinoma cells. CONCLUSIONS: The tested phenothiazine and steroid derivatives showed potent anticancer activity, furthermore, the stereoisomerism of thioridazine did not play a role in the antitumor properties. Neither steroids nor thioridazine influenced apoptosis in hormone resistant cells. Orv. Hetil., 2016, 157(37), 1489-1495.

Reversal of Multidrug Resistance and Computational Studies of Pistagremic Acid Isolated from Pistacia integerrima.

Pistagremic acid (PA) is a bioactive triterpenoid isolated from various parts of Pistacia integerrima plants. The aim of this research was to investigate PA for reversion of multidrug resistant (MDR) mediated by P-glycoprotein using rhodamine-123 exclusion study on a multidrug resistant human ABCB1 (ATP-binding cassette, sub-family B, member 1) gene-transfected mouse T-lymphoma cell line in vitro. Results were similar to those with verapamil as a positive control. Docking studies of PA and standard Rhodamine123 were carried out against a P-gp crystal structure which showed satisfactory results. Actually, PA cannot bind exactly where co-crystallized ligand of P-gp is already present. However, the docking study predicted that if a compound gives a lesser score then it may have some potency. The docking scores of PA and Rhodamine were similar. Therefore, we can conclude that there are certain important chemical features of PA which are responsible for the inhibiting potency of P-gp.

Isolation and Structure Elucidation, Molecular Docking Studies of Screlotiumol from Soil Borne Fungi Screlotium rolfsii and their Reversal of Multidrug Resistance in Mouse Lymphoma Cells.

A new compound namely (13-(3,3-dihydroxypropyl)-1,6-dihydroxy-3,4-dihydro-1H-isochromen-8(5H)-one (1) was isolated from an ethyl acetate extract of the borne fungi Screlotium rolfsii. Its chemical structure was elucidated by spectroscopic analysis. Screlotiumol 1 were evaluated for their effects on the reversion of multidrug resistant (MDR) mediated by P-glycoprotein (P-gp) of the soil borne fungi. The multidrug resistant P-glycoprotein is a target for chemotherapeutic drugs in cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma which showed excellent MDR reversing effect in a dose dependent manner against mouse T-lymphoma cell line. Moreover, molecular docking studies of compound-1 also showed better results as compared with the standard. Therefore the preliminary results obtained from this study suggest that screlotiumol 1 could be used as a potential agent for the treatment of cancer.

Operative management of bilateral Salter-Harris type III fractures of the proximal phalanges of the great toes of a 10-year-old female ballet dancer: a case report.

Differentiation between the normal variant cleft epiphysis and Salter-Harris type III fracture of the first proximal phalanges of the foot in children might be challenging. The authors describe a case of a 10-year-old ballet dancer girl with bilateral epiphyseal segmentation of the first proximal phalanges of the foot, unresponsive to conservative treatment. Considered a nonhealing stress-induced fracture, operative treatment with closed reduction and Herbert screw insertion was chosen on both sides. Complete union was achieved, with significant reduction of pain. The presented case suggests that internal fixation can be a viable option in the treatment of the problem.

Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia integerrima.

Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine- 123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.