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P3H4 promotes renal cell carcinoma progression and suppresses antitumor immunity via regulating GDF15-MMP9-PD-L1 axis

  • Tian, Shuo;Huang, Yan;Lai, Dong;Wang, Hanfeng;Du, Songliang;Shen, Donglai;Chen, Weihao;Xuan, Yundong;Lu, Yongliang;Feng, Huayi;Zhang, Xiangyi;Zhao, Wenlei;Wang, Chenfeng;Wang, Tao;Wu, Shengpan;Huang, Qingbo;Niu, Shaoxi;Wang, Baojun;Ma, Xin;Zhang, Xu
    • Advances in nano research
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    • v.12 no.6
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    • pp.639-652
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    • 2022
  • The prolyl 3-hydroxylase family member 4 (P3H4), is associated with post-translational modification of fibrillar collagens and aberrantly activated in cancer leading to tumor progression. However, its role in clear cell renal cell carcinoma (ccRCC) is still unknown. Here we reported that P3H4 was highly expressed in renal cancer tissues and significantly positive correlated with poor prognosis. Knockdown of P3H4 inhibited the proliferation, migration and metastasis of renal cancer cells in vitro and in vivo, and also, overexpression of it enhanced the oncogenic process. Mechanistically, P3H4 depletion decreased the levels of GDF15-MMP9 axis and repressed its downstream signaling. Further functional studies revealed that inhibition of GDF15 suppressed renal cancer cell growth and GDF15 recombinant human protein (rhGDF15) supplementation effectively rescued the inhibitory effect induced by P3H4 knockdown. Moreover, decreased levels of MMP9 caused by inhibition of P3H4-GDF15 signaling constrained the expression of PD-L1 and suppression of P3H4 accordingly promoted anti-tumor immunity via stimulating the infiltration of CD4+ and CD8+ T cells in syngeneic mice model. Taken together, our findings firstly demonstrated that P3H4 promotes ccRCC progression by activating GDF15-MMP9-PD-L1 axis and targeting P3H4-GDF15-MMP9 signaling pathway can be a novel strategy of controlling ccRCC malignancy.

Sperm-Mediated Gene Transfer by Injection of Sperm or Sperm Head into Porcine Oocytes

  • S.Y. Ahn;Lee, H.T.;K. S. Chung
    • Proceedings of the KSAR Conference
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    • 2001.03a
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    • pp.56-56
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    • 2001
  • The exogenous gene transfer by intracytoplasmic sperm injection (ICSI) procedure has been recently used to produce transgenic mice and pigs. Sperm-mediated DNA transfer has the potential to markedly simplify the generation of transgenic animals. This method may serve as an alternative to the pronucleus injection of DNA for the production of transgenic pigs. Therefore, in this study, we investigated the expression of transgene after co-injection of spermatozoon or sperm head with green fluorescent protein (GFP) gene into in vitro matured porcine oocytes. Spermatozoon and sperm head, that was obtained by sonication, were treated with 0.03% Triton X-100 to remove the membrane. They were preincubated with linearized pEGFP-N1 for 1 min, and then embryos cultured NCSU23 medium for 2.5 days after co-injected of sperm and DNA. We monitored expression of GFP in embryos under epifluorescent microscope. The remove of sperm membrane did not alter the developmental competence of embryos after ICSI. At 7 days following injection, the rates of blastocysts following injection of intact sperm (15.0%), and of sperm with disrupted membrane (14.2%) were higher than that following IVF (10.0%). Porcine oocytes injected with sperm which co-cultured with DNA concentration of 1, 0.1, and 0.01 ng were 60, 65.7 and 75% and 18.5, 37.4 and 22.2% for rates of cleavage and GFP expression, respectively. In vitro matured porcine oocytes injected with sperm and isolated sperm head resulted in 69 and 59.7% of cleavage rates, respectively The rates of embryo GFP expressed did not significantly different between sperm (20.4%) and sperm head (20.0%) injection. The transgenic embryos with the clusters of positive blastomeres were observed under fluorescent microscope. Most of embryos expressed GFP gene showed mosaicism. They showed GFP expression at 1/4, 2/4 and 3/4 of blastomeres at the 4-cell stage. Among these 4-cell embryos, the expression rate of 1/4 blastomere group (54.6%) was higher than the other groups (15.3-30.7%). These results indicate that membrane disrupted sperm could attach with exogenous DNA, and that this procedure may be useful to introduce foreign gene into porcine oocytes. Therefore, our data suggest that the ICSI car be a useful tool to efficiently produce transgenic pig as well as other mammals.

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Mutations of Constitutive Activation and Mutations That Impair Signal Transduction Modulate the Agonist-stimulated Internalization of the Lutropin/choriogonadotropin Receptor

  • Park, J.J.;Kim, M.S.;Lee, Y.Y.;H.Y. Kang;Y.M. Chang;Yoon, J.T.;K.S. Min
    • Proceedings of the Korean Society of Developmental Biology Conference
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    • 2003.10a
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    • pp.83-83
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    • 2003
  • The lutropin/choriogonadotropin receptor (LHR) is a member of the rhodopsin-like subfamily of G protein coupled receptor (GPCRs), that has been shown to mediate the internalization of its two naturally occurring agonist, lutropin and choriogonadotropin (CG). The clustered agonist-receptor complex is internalized by a dynamin-dependent pathway and traverses the endosomal compartment without agonist dissociation Dissociation of the agonist-receptor complex occurs in the lysosomes, where both the agonist and receptor are degrade. Recently, constitutively activating mutations of the receptor have been identified that are associated with familial male-precocious puberty (FMPP). A FMPP is a form of sexual precocious puberty in boys in which testosterone levels are elevated independent of changes in luteinizing hormone-releasing hormone and serum luteinizing hormone levels, We have now analyzed two naturally occurring, constitutively active mutants of the human LHR. These mutations were introduced into the rat LHR (rLHR) and are designated L435R and D556Y. Cells expressing rLHR-D556Y bind human choriogonadotropin (hCG) with normal affinity, exhibit a 25-fold increase in basal cAMP and respond to hCG with a normal increase in cAMP accumulation. Cells expressing rLHR-L435R also bind hCG with normal affinity, exhibit a 47-fold increase in basal cAMP, and do not respond to hCG with a further increase in cAMP accumulation. This mutation enhances the internalization of the free and agonist-occupied receptors ~2- and ~17- fold, respectively We conclude that the state of activation of the rLHR can modulate its basal and/or agonist-stimulated internalization. Since the internalization of hCG is involved in the termination of hCG actions, we suggest that the lack of responsiveness detected in cells expressing rLHR-L435R is due to the fast rate of internalization of the bound hCG. The finding that membranes expressing rLHR-L435R respond to hCG with an increase in adenylyl cyclase activity supports this suggestion. Autonomous Leydig cell activity in FMPP is caused by a constitutively activating LH/CGR.

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The complete plastid genome and nuclear ribosomal transcription unit sequences of Spiraea prunifolia f. simpliciflora (Rosaceae)

  • Jeongjin CHOI;Wonhee KIM;Jee Young PARK;Jong-Soo KANG;Tae-Jin YANG
    • Korean Journal of Plant Taxonomy
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    • v.53 no.1
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    • pp.32-37
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    • 2023
  • Spiraea prunifolia f. simpliciflora Nakai is a perennial shrub widely used for horticultural and medicinal purposes. We simultaneously obtained the complete plastid genome (plastome) and nuclear ribosomal gene transcription units, 45S nuclear ribosomal DNA (nrDNA) and 5S nrDNA of S. prunifolia f. simpliciflora, using Illumina short-read data. The plastome is 155,984 bp in length with a canonical quadripartite structure consisting of 84,417 bp of a large single-copy region, 18,887 bp of a short single-copy region, and 26,340 bp of two inverted repeat regions. Overall, a total of 113 genes (79 protein-coding genes, 30 tRNAs, and four rRNAs) were annotated in the plastome. The 45S nrDNA transcription unit is 5,848 bp in length: 1,809 bp, 161 bp, and 3,397 bp for 18S, 5.8S, and 26S, respectively, and 261 bp and 220 bp for internal transcribed spacer (ITS) 1 and ITS 2 regions, respectively. The 5S nrDNA unit is 512 bp, including 121 bp of 5S rRNA and 391 bp of intergenic spacer regions. Phylogenetic analyses showed that the genus Spiraea was monophyletic and sister to the clade of Sibiraea angustata, Petrophytum caespitosum and Kelseya uniflora. Within the genus Spiraea, the sections Calospira and Spiraea were monophyletic, but the sect. Glomerati was nested within the sect. Chamaedryon. In the sect. Glomerati, S. prunifolia f. simpliciflora formed a subclade with S. media, and the subclade was sister to S. thunbergii and S. mongolica. The close relationship between S. prunifolia f. simpliciflora and S. media was also supported by the nrDNA phylogeny, indicating that the plastome and nrDNA sequences assembled in this study belong to the genus Spiraea. The newly reported complete plastome and nrDNA transcription unit sequences of S. prunifolia f. simpliciflora provide useful information for further phylogenetic and evolutionary studies of the genus Spiraea, as well as the family Rosaceae.

Enhancing the Anti-cancer Activity of Non-steroidal Anti-inflammatory Drug and Down-regulation of Cancer Stemness-related Markers in Human Cancer Cells by DAPT and MHY2245 (DAPT 및 MHY2245의 비스테로이드소염제(NSAID)의 항암 활성 증강 및 종양줄기세포관련 표지자 발현 감소 활성에 대한 분자적 기전)

  • Moon, Hyun-Jung;Kang, Chi-Dug;Kim, Sun-Hee
    • Journal of Life Science
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    • v.32 no.3
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    • pp.210-221
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    • 2022
  • This study investigated the mechanisms underlying the anti-cancer effects of non-steroidal anti-inflammatory drugs (NSAIDs) in human cancer cells in combination with either N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, or MHY2245, a new synthetic sirtuin 1 inhibitor. The results showed both DAPT and MHY2245 as novel chemosensitizers of human colon cancer KM12 and human hepatocellular carcinoma SNU475 cells to NSAIDs involving celecoxib and 2, 5-dimethyl celecoxib. The NSAID-induced cytotoxicity of these cells was significantly increased by DAPT and MHY2245 in a cyclooxygenase-2 independent manner. In addition, DAPT and MHY2245 reduced levels of p62, Notch1 intracellular domain, and multiple cancer stemness (CS)-related markers including Notch1, CD44, CD133, octamer-binding transcription factor 4, mutated p53 and c-Myc. However, the level of activating transcription factor 4 (ATF4) was enhanced, probably indicating the down-regulation of multiple CS-related markers by DAPT or MHY2245-mediated autophagy induction. Moreover, the NSAID-mediated reduction of p62/nuclear factor erythroid-derived 2-like 2 and CS-related marker proteins and the up-regulation of C/EBP homologous protein (CHOP)/ATF4 were accelerated by DAPT and MHY2245. As such, the combination of NSAID and either DAPT or MHY2245 resulted in higher cytotoxicity than NSAID alone by accelerating the down-regulation of multiple CS-related markers and PARP activation, indicating that both inhibitors promote NSAID-mediated autophagic cell death, possibly through the CHOP/ATF4 pathway. In conclusion, either combination strategy may be useful for the effective treatment of human cancer cells expressing CS-related markers.

Bone Density, Nutrient Intake, Blood Composition and Food Habits in Non-Smoking and Non-Alcohol Drinking Male University Students (금연.금주 남자대학생의 골밀도, 영양소 섭취, 혈액 성상 및 식습관)

  • Choi, Soon-Nam;Chung, Nam-Yong
    • Journal of the Korean Society of Food Culture
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    • v.25 no.4
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    • pp.389-399
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    • 2010
  • This study was conducted in order to investigate and compare anthropometric measurements, bone density, nutrient intake, blood composition and food habits between non-smoking, non-alcohol drinking and smoking, alcohol drinking male university students in Seoul, South Korea. The data for food habits and health-related behaviors were obtained by selfadministered questionnaires. The BQIs of the subjects were measured by Quantitative Ultrasound (QUS). The subjects were divided into two groups: NSND (non-smoking and non-alcohol drinking, n=62) group and General (smoking and alcohol drinking, n=160) group. The results were analyzed using the SPSS program and were as follows: The average heights, weights, and BMIs of the two groups were 173.3 cm, 66.5 kg and 22.1 and 173.4 cm, 68.7 kg and 22.9, respectively. There were no differences between the groups regarding height, weight or BMI. SBP and DBP, however, were significantly higher in the general group than in the NSND group (p<0.01). The BQIs, Z-scores and T-scores of the two groups were 99.83, -0.23, and -0.31 and 98.24, -0.27 and -0.39, respectively, producing no significant differences between the two groups. The percentages for normal bone status, osteopenia and osteoporosis were 83.88%, 16.12% and 0.0% and 74.37%, 25.62% and 0.01%, respectively. Mean intakes of animal protein (p<0.05), animal fat (p<0.05), fiber (p<0.05), animal Ca(p<0.05), animal Fe (p<0.001), Zn(p<0.05), vitamin B1 (p<0.05) and niacin (p<0.05) were significantly different between the two groups, and mean serum levels of SGOT (p<0.01), SGPT (p<0.001), ${\gamma}$-GTP (p<0.001), triglycerides (p<0.01), total cholesterol (p<0.05) and hematocrit (p<0.05) were also significantly different between the two groups. Overall, there were no differences in meal regularity, frequency of snacking, reasons for overeating, exercise and defecation between the groups. However, favorite foods (p<0.05) and night-time meals (p<0.05) were significantly different. In conclusion, the health status of the NSND group was superior compared to the general group. Thus, students who smoke and alcohol drink should receive a practical and systematically-organized education regarding the increased health benefits of quitting smoking and alcohol drinking.

A Study on the Vegetables Mentioned in the Bible (성서에 언급된 채소류에 관한 연구)

  • Woo, Ja-Won
    • Journal of the Korean Society of Food Culture
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    • v.22 no.1
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    • pp.1-9
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    • 2007
  • This paper is intended to study what kinds of the vegetables are mentioned in the Bible and how they were used in those days. While one hundred and twenty-eight different plants are mentioned in the Bible, there are today 2,384 plant species in modem Israel, most of which have been introduced in recent centuries. These plants obviously did not exist there in biblical times and were only recently introduced from Australia and South America, respectively. This article will study only the vegetables mentioned in the Bible and known to have existed in the old and new testament times. Since the first book devoted exclusively to biblical botany was that of Levinus Lemmens in 1566, the modem systematic study of biblical plants, began with F. Hasselquist, a student of Linnaeus, the founder of modem botany. In 1928, Immanuel Loew approached the subject differently, reviewing all known data pertaining to biblical plants. His work not only discussed biblical plants, but also plants in later Jewish literature, particularly the Talmud. The British scholar G. E. Post provided a broad field study of modem plants in Palestine, Syria, Lebanon, and Jordan. More recent major treatments of the subject include those of A. and H. Moldenke (1952), M. Zohary (1982), N. Hareuveni (1984), and Y. J. Choi(1996). Today, articles on specific biblical plants listed in the Bible can be found in any number of encyclopedias. This study attempts to provide a synthesis of the work of a number of scholars who studied the vegetables and plants mentioned in the Bible. As a preliminary study on the culture of food in the biblical period, this study has focused on the identity and features of the vegetables of the Bible. In only a limited number of instances, because of the paucity of the informations and the broad and generic descriptions of the plants, we can't be certain about the identification of the vegetables named in the Bible. In many instances the traditions established by the Greek, Aramaic, and English translations are helpful, although sometimes they are misleading. This paper subdivides the vegetables into broad areas, the general vegetables and the flavoring herbs. Vegetables formed very important part of the diet in the biblical times. Two main types were used: those whose nutritious seeds could be easily stored and those which were eaten freshly gathered from gardens. Pulse seeds provided a useful source of vegetable protein, while fresh green vegetables were vitamin rich. Pulses could be eaten boiled, or their dried seeds could be ground up into flour and then made into nutritious soups. Fresh vegetables were eaten either raw or lightly cooked, usually by boiling in water. The general vegetables in the Bible are herbs(garden rocket), cucumber(snake cucumber), watermelon, leeks, chicory, and onions. Also the flavoring herbs in the Bible are rue, dill, cummin, black cummin, frankincense, cinnamon, cassia, myrrh, black mustard, coriander, mint, saffron, ginger grass, syrian hyssop, aloes(eagle wood), manna which have the flavor, aroma, and medical values.

Effects of Body Composition, Nutrient Intakes and Biochemical Indices on Skin Health Status of Female University Students with Sensitive Skin (체성분, 영양소 섭취상태 및 생화학적 지표가 민감성 피부 여대생의 피부건강상태에 미치는 영향)

  • Kim, Mi-Young;Cho, Kyung-Dong;Baek, Ok-Hee;Lee, Bog-Hieu
    • Journal of the Korean Society of Food Culture
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    • v.23 no.2
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    • pp.258-267
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    • 2008
  • The purpose of this study was to investigate the effects that body composition, nutrient intake, and biochemical indices have on skin status, as well as their associations with skin health status, by assessing 44 female university students. The subjects were classified into 3 groups according to skin sensitivity: sensitive skin (n=11), slightly sensitive skin (n=24), and normal skin (n=9). The study included anthropometric measurements and body composition analyses, dietary intake evaluations, blood chemical analyses, and skin health status assessments. Based on % body fat, the results indicated the subjects were moderately obese (29.6%). Obesity indices were not different among the groups, but the sensitive skin group tended to have higher skinfold thickness. Dry skin was determined as the skin type of all subjects. In the sensitive skin groups, U-zone and T-zone sebum were significantly lower (p<0.05), and spots were significantly higher (p<0.05) than in the normal skin group. In terms of nutrient intakes, the sensitive skin groups consumed significantly lower amounts of P and vitamins A and E (p<0.05). There were no significant differences in serum lipid fractions or total antioxidant status among the groups. In correlation coefficients analysis, skin elasticity had significant negative correlations with subscapular and midaxillary skinfold thickness, body protein, and body minerals (p<0.05). Wrinkling had positive correlations with triceps and thigh skinfold thickness (p<0.05). Skin evenness had negative correlations with energy intake, vitamins A, $B_1,\;B_2$, C, E, niacin, and zinc (p<0.05), as well as folate and P (p<0.01) and vitamin $B_6$ (p<0.001). A similar correlation tendency was observed for spots and nutrient intake, showing negative correlations with vitamins A, $B_6$, and E, as well as folate, Fe, and P. U-zone sebum showed significant positive correlations with serum levels of total cholesterol and triglycerides. From these findings, skin health status appears to be affected by both nutrient intake and body composition. Therefore, having a proper balance between dietary intake and body composition may influence skin health status in females with sensitive skin.

Expanded IL-22+ Group 3 Innate Lymphoid Cells and Role of Oxidized LDL-C in the Pathogenesis of Axial Spondyloarthritis with Dyslipidaemia

  • Hong Ki Min;Jeonghyeon Moon;Seon-Yeong Lee;A Ram Lee;Chae Rim Lee;Jennifer Lee;Seung-Ki Kwok;Mi-La Cho;Sung-Hwan Park
    • IMMUNE NETWORK
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    • v.21 no.6
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    • pp.43.1-43.14
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    • 2021
  • Group 3 innate lymphoid cells (ILC3), which express IL-22 and IL-17A, has been introduced as one of pathologic cells in axial spondyloarthritis (axSpA). Dyslipidaemia should be managed in axSpA patients to reduce cardiovascular disease, and dyslipidaemia promotes inflammation. This study aimed to reveal the role of circulating ILC3 in axSpA and the impact of dyslipidaemia on axSpA pathogenesis. AxSpA patients with or without dyslipidaemia and healthy control were recruited. Peripheral blood samples were collected, and flow cytometry analysis of circulating ILC3 and CD4+ T cells was performed. The correlation between Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-reactive protein (CRP) and circulating immune cells was evaluated. The effect of oxidized low-density lipoprotein cholesterol (oxLDL-C) on immune cell differentiation was confirmed. AxSpA human monocytes were cultured with with oxLDL-C, IL-22, or oxLDL-C plus IL-22 to evaluate osteoclastogenesis using tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative PCR of osteoclast-related gene expression. Total of 34 axSpA patients (13 with dyslipidaemia and 21 without) were included in the analysis. Circulating IL-22+ ILC3 and Th17 were significantly elevated in axSpA patients with dyslipidaemia (p=0.001 and p=0.034, respectively), and circulating IL-22+ ILC3 significantly correlated with ASDAS-CRP (Rho=0.4198 and p=0.0367). Stimulation with oxLDL-C significantly increased IL-22+ ILC3, NKp44- ILC3, and Th17 cells, and these were reversed by CD36 blocking agent. IL-22 and oxLDL-C increased TRAP+ cells and osteoclast-related gene expression. This study suggested potential role of circulating IL-22+ ILC3 as biomarker in axSpA. Furthermore, dyslipidaemia augmented IL-22+ ILC3 differentiation, and oxLDL-C and IL-22 markedly increased osteoclastogenesis of axSpA.

Effects of the Mating System on Retail Cut Yield and Meat Quality in Commercial Pigs (비육돈의 교배조합이 부분육 생산수율 및 육질에 미치는 영향)

  • Kim, H.S.;Yang, H.S.;Lee, J.I.;Joo, S.T.;Jeon, J.T.;Lee, Jung-Gyu
    • Journal of Animal Science and Technology
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    • v.49 no.3
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    • pp.379-386
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    • 2007
  • This study was conducted to investigate the effect of the mating system on the retail cut yield and meat quality in pigs. A total of 210 samples were used to estimate meat productivity and meat quality two blocks of two boarlines Duroc (D) and Berkshire (B) were mated to sows of the sowlines Yorkshire×Landrace (YL) and Berkshire (B). Results showed that YLD (YL♀×D♂) and BD (B♀×D♂) had higher percentages of Boston butt and belly than YLB while it has higher percentages of lean meat yield than YLB (YL♀×B♂). There were no significant differences in crude protein and ash content of pork from different breeds (P>0.05). However, YLB and YLD had higher moisture content in loin and Boston butt than BD (P<0.05). The pH of BD was highest in pork loin and belly (P<0.05). There differences in meat yield, pH and moisture content among the genotypes suggested that pork quality might be affected by the lightness and cooking loss. BD was lowest lightness value (CIE L*) and cooking loss in pork loin among the genotypes (P<0.05). The percentage of saturated palmitic acid (C16:0) in Boston butt (P<0.05) of BD had significant lower, while the percentage of unsaturated palmitoleic (C16:1) and oleic acid (C18:1) had higher in pork loin and belly (P<0.05). Drip and marbling score were found significantly different in genotypes and BD had lower drip and higher marbling score in pork loin and belly (P<0.05). The sensory evaluations indicated that the highest overall acceptability in BD was attained. From the results, BD breed had highest meat quality among crossbred pigs.