Study of some morphometric and meristic characteristics of Alepes vari (Cuvier, 1833) collected from the Arabian coast / Estudo de características morfométricas e merísticas de Alepes vari (Cuvier, 1833) coletados na costa da Arábia

The present study examines the correlations between fifteen morphometric and ten meristic characters and total length (TL) of males, females, and combined sexes of Alepes vari (Cuvier, 1833) collected from Karachi fish harbor, West Wharf of Karachi Coast. Statistical analyses of linear regression relationships show mostly strong correlations (r≥0.70; p<0.05) between total length (TL) and most morphometric characters in males, females, and combined sexes, except the height of pectoral-fin (PFH), and pelvic-fin base length (PelFL); whereas, meristic characters were found to be constant and indicate weak or negative type correlations (r≤0.50; p>0.05) with total length (TL). Hence, according to our present results, there is a direct relationship between the total length of fish and all morphometric characters, which were found to be the best indicators of positive allometric pattern growth in fish. Moreover, analysis of the 2-sample t-test revealed (t-test; p>0.05) that no sexual dimorphism was reported in Alepes vari. Thus, our present study could be valuable in systematic classification, sexual dimorphism, and management of this species on the Karachi coast.

O presente estudo examina as correlações entre 15 caracteres morfométricos e 10 caracteres merísticos e comprimento total (CT) de machos, fêmeas e sexos combinados de Alepes vari (Cuvier, 1833), coletados do porto de Karachi, West Wharf, na costa de Karachi. As análises estatísticas das relações de regressão linear mostraram, principalmente, correlações fortes (r ≥ 0,70; p < 0,05) entre o CT e a maioria dos caracteres morfométricos em machos, fêmeas e sexos combinados, exceto a altura da nadadeira peitoral e o comprimento da base da nadadeira pélvica, enquanto os caracteres merísticos foram constantes, indicando correlações fracas ou negativas (r ≤ 0,50; p > 0,05) com o CT. Portanto, de acordo com nossos resultados, existe uma relação direta entre o CT dos peixes e todos os caracteres morfométricos, que foram considerados os melhores indicadores de crescimento do padrão alométrico positivo em peixes. Além disso, a análise do teste t de duas amostras revelou (teste t; p > 0,05) que nenhum dimorfismo sexual foi relatado em A. vari.

Biodiversity, distributions and isolation of microplastics pollution in finfish species in the Panjkora River at Lower and Upper Dir districts of Khyber Pakhtunkhwa province of Pakistan / Biodiversidade, distribuição e isolamento de poluições por microplásticos em espécies de peixes no rio Panjkora nos distritos de Lower e Upper Dir da província de Khyber Pakhtunkhwa do Paquistão

The basic aim of this study was aimed to determine the ichthyofaunal diversity of River Panjkora in both upper and lower Dir districts in Khyber Pakhtunkhwa province of Pakistan.Fish samples were collected by using fishnets from March to September 2020. A total of 724 specimens were collected and classified into 5 families, 14 genera, and 18 species. The overall results revealed that most fish fauna of river Panjkora contains 8 species of family Cyprinidae (56.49%) followed by 4 species of Nemacheilidae (24.44%), 2 species of Channidae (10.63%), and Sisoridae (7.04%), and 1 species of Mastacembelidae (1.38%), respectively. Among all kinds of fish species, Schizothorax plagiostomus (16.57%) was highly dominated and followed by Carassius auratus (11.87%) and Racoma labiata (9.66%) and were reported as highly abundant, especially during April, May, and June. The least abundant species were Glyptothorax punjabensis, Glyptothorax sufii, and Mastacembelus armatus, that constituting 2.48%, 2.20%, and 1.38% of the total fish samples. The Overall Simpson's diversity (1-D= 0.919) and Simpson's Reciprocal index values (1/D= 12.3876), and Shannon's index (H= 2.68) were indicating that river Panjkora contains a quite rich and diverse group of fish species. The highest microplastics observed in site 7 compared to other study area. Conservation steps should be taken as a top priority to protect and conserve the marine environment and natural heritage from further loss, extinction and stop or minimize losses incurred through irresponsible fishery practices

O objetivo básico deste estudo foi determinar a diversidade ictiofaunística do rio Panjkora nos distritos de Lower e Upper de Dir, na província de Khyber Pakhtunkhwa, no Paquistão. Amostras de peixes foram coletadas com redes de arrasto de março a setembro de 2020. Foram coletados 724 espécimes, classificados em 5 famílias, 14 gêneros e 18 espécies. Os resultados gerais revelaram que a maioria da ictiofauna do rio Panjkora contém 8 espécies da família Cyprinidae (56,49%), seguidas por 4 espécies de Nemacheilidae (24,44%), 2 espécies de Channidae (10,63%) e Sisoridae (7,04%) e 1 espécie de Mastacembelidae (1,38%). Entre todas as espécies de peixes, Schizothorax plagiostomus (16,57%) foi altamente predominante, seguida por Carassius auratus (11,87%) e Racoma labiata (9,66%), e elas foram relatadas como altamente abundantes, especialmente nos meses de abril, maio e junho. As espécies menos abundantes foram Glyptothorax punjabensis, Glyptothorax sufii e Mastacembelus armatus, que constituíram 2,48%, 2,20% e 1,38%, respectivamente, do total de peixes amostrados. O índice de diversidade de Simpson (1-D = 0,919), o índice recíproco de Simpson (1/D = 12,3876) e o índice de Shannon (H = 2,68) indicaram que o rio Panjkora contém um grupo bastante rico e diversificado de espécies de peixes. Os microplásticos mais altos foram observados no local 7 em comparação com outra área de estudo. Medidas de conservação devem ser tomadas como prioridade máxima para proteger e conservar o ambiente marinho e o patrimônio natural de novas perdas e extinção e para parar ou minimizar as perdas ocorridas por práticas de pesca irresponsáveis.

Growth performance and survivability of the Asian seabass Lates calcarifer (Bloch, 1790) reared under hyper-saline, hypo-saline and freshwater environments in a closed aquaculture system / Desempenho de crescimento e sobrevivência do robalo asiático Lates calcarifer (Bloch, 1790) criado em ambientes hipersalinos, hipossalinos e de água doce em um sistema de aquicultura fechado

Salinity is one of the most critical environmental parameters regarding fish physiology, modifying food intake and growth performance in many fish species. The present study has investigated the effects of different salinity levels on growth performance, feeding and survival of Asian seabass Lates calcarifer juveniles. Asian seabass juveniles were reared at 0 (T1), 5 (T2), 22 (T3), 36 (T4), and 42 (T5) ppt salinity. Approximately eight hundred thirty fish individuals with an average weight of 1.24±0.52 g were randomly distributed (166 fish/Tank) in 5 concrete tanks (each tank 30×6×4 ft, volume 19,122 L) for forty days. Juveniles were initially fed 42% crude protein-containing diets at a rate of 6% of their body weight per day. The results showed that salinity level had a significant effect on the weight gain (WG), average daily weight gain (ADWG), specific growth rate (SGR), feed conversion ratio (FCR), survival rate (SR), total biomass and health indices (p<0.05). The highest WG (39.11±1.49 g), ADWG (1.00±0.12 g), SGR (8.74±0.03% d-1) and lowest FCR (0.96±0.20) were observed with T3 treatment, which was significantly higher compared to other treatment groups (p<0.05). Among the health indices, the highest hepatosomatic index and viscerosomatic index were found with T3 treatment, significantly higher than the other groups (p<0.05). No significant differences were found among the treatments in terms of survival rate (p>0.05), but the maximum survival rate (98.89±0.0%) was observed in the T3 and T2 treatments. The maximum level of crude proteins (19.99±1.4%) was found in the whole-body biochemical composition of Asian seabass juveniles in the T3 treatment group. The second-order polynomial regression showed that 20 ppt salinity is optimum for the best growth of Asian seabass. Thus, the present study recommends 20 to 36 ppt salinity for the commercial farming of Asian seabass under a closed aquaculture system.

A salinidade é um dos parâmetros ambientais mais críticos em relação à fisiologia dos peixes, modificando a ingestão de alimentos e o desempenho de crescimento em muitas espécies. O presente estudo investigou os efeitos de diferentes níveis de salinidade no desempenho de crescimento, alimentação e sobrevivência de jovens espécies de robalos asiáticos Lates calcarifer, as quais foram criadas sob salinidade 0 (T1), 5 (T2), 22 (T3), 36 (T4) e 42 (T5) ppt. Aproximadamente 830 indivíduos de peixes com peso médio de 1,24 ± 0,52 g foram distribuídos aleatoriamente (166 peixes / tanque) em cinco tanques de concreto (cada tanque tinha 30 × 6 × 4 pés (9,1 x 1,8 x 1,2 metros), com volume de 19,12 litros) por 40 dias. Os peixes foram inicialmente alimentados com uma dieta contendo 42% de proteína bruta a uma taxa de 6% do seu peso corporal por dia. Os resultados mostraram que o nível de salinidade teve um efeito significativo no ganho de peso (GP), ganho de peso médio diário (GPMD), taxa de crescimento específico (TCE), taxa de conversão alimentar (TCA), taxa de sobrevivência (TS), biomassa total e índices de saúde (p < 0,05). O maior GP (39,11 ± 1,49 g), GPMD (1,00 ± 0,12 g), TCE (8,74 ± 0,03% d-1) e o menor TCA (0,96 ± 0,20) foram observados com o tratamento T3, que foi significativamente superior em comparação com os outros tratamentos (p < 0,05). Entre os índices de saúde, os maiores índices hepatossomáticos e viscerossomáticos foram encontrados no tratamento T3, significativamente superior do que os demais grupos (p < 0,05). Não foram encontradas diferenças significativas entre os tratamentos quanto à TS (p > 0,05), mas a TS máxima (98,89 ± 0,0%) foi observada nos tratamentos T3 e T2. O nível máximo de proteína bruta (19,99 ± 1,4%) foi encontrado na composição bioquímica dos corpos dos jovens robalos asiáticos no grupo T3. A regressão polinomial de segunda ordem mostrou que a salinidade de 20 ppt é ótima para o melhor crescimento do robalo asiático. Assim, o presente estudo recomenda salinidade de 20 a 36 ppt para o cultivo comercial de robalo asiático em sistema de aquicultura fechado.

Study of some morphometric and meristic characteristics of Alepes vari (Cuvier, 1833) collected from the Arabian coast

Abstract The present study examines the correlations between fifteen morphometric and ten meristic characters and total length (TL) of males, females, and combined sexes of Alepes vari (Cuvier, 1833) collected from Karachi fish harbor, West Wharf of Karachi Coast. Statistical analyses of linear regression relationships show mostly strong correlations (r0.70; p 0.05) between total length (TL) and most morphometric characters in males, females, and combined sexes, except the height of pectoral-fin (PFH), and pelvic-fin base length (PelFL); whereas, meristic characters were found to be constant and indicate weak or negative type correlations (r0.50; p>0.05) with total length (TL). Hence, according to our present results, there is a direct relationship between the total length of fish and all morphometric characters, which were found to be the best indicators of positive allometric pattern growth in fish. Moreover, analysis of the 2-sample t-test revealed (t-test; p>0.05) that no sexual dimorphism was reported in Alepes vari. Thus, our present study could be valuable in systematic classification, sexual dimorphism, and management of this species on the Karachi coast.

Resumo O presente estudo examina as correlações entre 15 caracteres morfométricos e 10 caracteres merísticos e comprimento total (CT) de machos, fêmeas e sexos combinados de Alepes vari (Cuvier, 1833), coletados do porto de Karachi, West Wharf, na costa de Karachi. As análises estatísticas das relações de regressão linear mostraram, principalmente, correlações fortes (r 0,70; p 0,05) entre o CT e a maioria dos caracteres morfométricos em machos, fêmeas e sexos combinados, exceto a altura da nadadeira peitoral e o comprimento da base da nadadeira pélvica, enquanto os caracteres merísticos foram constantes, indicando correlações fracas ou negativas (r 0,50; p > 0,05) com o CT. Portanto, de acordo com nossos resultados, existe uma relação direta entre o CT dos peixes e todos os caracteres morfométricos, que foram considerados os melhores indicadores de crescimento do padrão alométrico positivo em peixes. Além disso, a análise do teste t de duas amostras revelou (teste t; p > 0,05) que nenhum dimorfismo sexual foi relatado em A. vari. Assim, o presente estudo pode ser valioso na classificação sistemática, dimorfismo sexual e manejo dessa espécie na costa de Karachi.

Growth performance and survivability of the Asian seabass Lates calcarifer (Bloch, 1790) reared under hyper-saline, hypo-saline and freshwater environments in a closed aquaculture system

Abstract Salinity is one of the most critical environmental parameters regarding fish physiology, modifying food intake and growth performance in many fish species. The present study has investigated the effects of different salinity levels on growth performance, feeding and survival of Asian seabass Lates calcarifer juveniles. Asian seabass juveniles were reared at 0 (T1), 5 (T2), 22 (T3), 36 (T4), and 42 (T5) ppt salinity. Approximately eight hundred thirty fish individuals with an average weight of 1.24±0.52 g were randomly distributed (166 fish/Tank) in 5 concrete tanks (each tank 30×6×4 ft, volume 19,122 L) for forty days. Juveniles were initially fed 42% crude protein-containing diets at a rate of 6% of their body weight per day. The results showed that salinity level had a significant effect on the weight gain (WG), average daily weight gain (ADWG), specific growth rate (SGR), feed conversion ratio (FCR), survival rate (SR), total biomass and health indices (p 0.05). The highest WG (39.11±1.49 g), ADWG (1.00±0.12 g), SGR (8.74±0.03% d-1) and lowest FCR (0.96±0.20) were observed with T3 treatment, which was significantly higher compared to other treatment groups (p 0.05). Among the health indices, the highest hepatosomatic index and viscerosomatic index were found with T3 treatment, significantly higher than the other groups (p 0.05). No significant differences were found among the treatments in terms of survival rate (p>0.05), but the maximum survival rate (98.89±0.0%) was observed in the T3 and T2 treatments. The maximum level of crude proteins (19.99±1.4%) was found in the whole-body biochemical composition of Asian seabass juveniles in the T3 treatment group. The second-order polynomial regression showed that 20 ppt salinity is optimum for the best growth of Asian seabass. Thus, the present study recommends 20 to 36 ppt salinity for the commercial farming of Asian seabass under a closed aquaculture system.

Resumo A salinidade é um dos parâmetros ambientais mais críticos em relação à fisiologia dos peixes, modificando a ingestão de alimentos e o desempenho de crescimento em muitas espécies. O presente estudo investigou os efeitos de diferentes níveis de salinidade no desempenho de crescimento, alimentação e sobrevivência de jovens espécies de robalos asiáticos Lates calcarifer, as quais foram criadas sob salinidade 0 (T1), 5 (T2), 22 (T3), 36 (T4) e 42 (T5) ppt. Aproximadamente 830 indivíduos de peixes com peso médio de 1,24 ± 0,52 g foram distribuídos aleatoriamente (166 peixes / tanque) em cinco tanques de concreto (cada tanque tinha 30 × 6 × 4 pés (9,1 x 1,8 x 1,2 metros), com volume de 19,12 litros) por 40 dias. Os peixes foram inicialmente alimentados com uma dieta contendo 42% de proteína bruta a uma taxa de 6% do seu peso corporal por dia. Os resultados mostraram que o nível de salinidade teve um efeito significativo no ganho de peso (GP), ganho de peso médio diário (GPMD), taxa de crescimento específico (TCE), taxa de conversão alimentar (TCA), taxa de sobrevivência (TS), biomassa total e índices de saúde (p 0,05). O maior GP (39,11 ± 1,49 g), GPMD (1,00 ± 0,12 g), TCE (8,74 ± 0,03% d-1) e o menor TCA (0,96 ± 0,20) foram observados com o tratamento T3, que foi significativamente superior em comparação com os outros tratamentos (p 0,05). Entre os índices de saúde, os maiores índices hepatossomáticos e viscerossomáticos foram encontrados no tratamento T3, significativamente superior do que os demais grupos (p 0,05). Não foram encontradas diferenças significativas entre os tratamentos quanto à TS (p > 0,05), mas a TS máxima (98,89 ± 0,0%) foi observada nos tratamentos T3 e T2. O nível máximo de proteína bruta (19,99 ± 1,4%) foi encontrado na composição bioquímica dos corpos dos jovens robalos asiáticos no grupo T3. A regressão polinomial de segunda ordem mostrou que a salinidade de 20 ppt é ótima para o melhor crescimento do robalo asiático. Assim, o presente estudo recomenda salinidade de 20 a 36 ppt para o cultivo comercial de robalo asiático em sistema de aquicultura fechado.

Biodiversity, distributions and isolation of microplastics pollution in finfish species in the Panjkora River at Lower and Upper Dir districts of Khyber Pakhtunkhwa province of Pakistan

Abstract The basic aim of this study was aimed to determine the ichthyofaunal diversity of River Panjkora in both upper and lower Dir districts in Khyber Pakhtunkhwa province of Pakistan.Fish samples were collected by using fishnets from March to September 2020. A total of 724 specimens were collected and classified into 5 families, 14 genera, and 18 species. The overall results revealed that most fish fauna of river Panjkora contains 8 species of family Cyprinidae (56.49%) followed by 4 species of Nemacheilidae (24.44%), 2 species of Channidae (10.63%), and Sisoridae (7.04%), and 1 species of Mastacembelidae (1.38%), respectively. Among all kinds of fish species, Schizothorax plagiostomus (16.57%) was highly dominated and followed by Carassius auratus (11.87%) and Racoma labiata (9.66%) and were reported as highly abundant, especially during April, May, and June. The least abundant species were Glyptothorax punjabensis, Glyptothorax sufii, and Mastacembelus armatus, that constituting 2.48%, 2.20%, and 1.38% of the total fish samples. The Overall Simpsons diversity (1-D= 0.919) and Simpsons Reciprocal index values (1/D= 12.3876), and Shannons index (H= 2.68) were indicating that river Panjkora contains a quite rich and diverse group of fish species. The highest microplastics observed in site 7 compared to other study area. Conservation steps should be taken as a top priority to protect and conserve the marine environment and natural heritage from further loss, extinction and stop or minimize losses incurred through irresponsible fishery practices

Resumo O objetivo básico deste estudo foi determinar a diversidade ictiofaunística do rio Panjkora nos distritos de Lower e Upper de Dir, na província de Khyber Pakhtunkhwa, no Paquistão. Amostras de peixes foram coletadas com redes de arrasto de março a setembro de 2020. Foram coletados 724 espécimes, classificados em 5 famílias, 14 gêneros e 18 espécies. Os resultados gerais revelaram que a maioria da ictiofauna do rio Panjkora contém 8 espécies da família Cyprinidae (56,49%), seguidas por 4 espécies de Nemacheilidae (24,44%), 2 espécies de Channidae (10,63%) e Sisoridae (7,04%) e 1 espécie de Mastacembelidae (1,38%). Entre todas as espécies de peixes, Schizothorax plagiostomus (16,57%) foi altamente predominante, seguida por Carassius auratus (11,87%) e Racoma labiata (9,66%), e elas foram relatadas como altamente abundantes, especialmente nos meses de abril, maio e junho. As espécies menos abundantes foram Glyptothorax punjabensis, Glyptothorax sufii e Mastacembelus armatus, que constituíram 2,48%, 2,20% e 1,38%, respectivamente, do total de peixes amostrados. O índice de diversidade de Simpson (1-D = 0,919), o índice recíproco de Simpson (1/D = 12,3876) e o índice de Shannon (H = 2,68) indicaram que o rio Panjkora contém um grupo bastante rico e diversificado de espécies de peixes. Os microplásticos mais altos foram observados no local 7 em comparação com outra área de estudo. Medidas de conservação devem ser tomadas como prioridade máxima para proteger e conservar o ambiente marinho e o patrimônio natural de novas perdas e extinção e para parar ou minimizar as perdas ocorridas por práticas de pesca irresponsáveis.

[Long Noncoding RNAs MEG3, TUG1, and hsa-miR-21-3p Are Potential Diagnostic Biomarkers for Coronary Artery Disease].

Peripheral blood biomarkers are of particular importance to diagnose certain diseases including coronary artery disease (CAD) due to their non-invasiveness. Investigating the expression of noncoding RNAs (ncRNAs) paves the way to early disease diagnosis, prognosis, and treatment. Consequently, in this research, we aimed to investigate a panel of ncRNAs as potential biomarkers in patients with coronary artery disease. Two different groups have been designed (control and CAD). All participants were subjected to interviews and clinical examinations. Peripheral blood samples were collected, and plasma was extracted. At the same time, target ncRNAs have been selected based on literature review and bioinformatic analysis, and later they underwent investigation using quantitative real-time PCR. The selected panel encompassed the long non-coding RNAs (lncRNAs) MEG3, TUG1, and SRA1, and one related microRNA (miRNA): hsa-miR-21-3p. We observed statistically significant upregulation in MEG3, TUG1, and hsa-miR21-3p in CAD patients compared to control participants (p-value < 0.01). Nevertheless, SRA1 exhibited downregulation with no statistical significance (p-value > 0.05). All ncRNAs under study displayed a significantly strong correlation with disease incidence, age, and smoking. Network construction revealed a strong relationship between MEG3 and TUG1. ROC analysis indicated high potentiality for hsa-miR-21-3p to be a promising biomarker for CAD. Moreover, MEG3 and TUG1 displayed distinguished diagnostic discrimination but less than hsa-miR-21-3p, all of them exhibited strong statistical significance differences between CAD and control groups. Conclusively, this research pinpointed that MEG3, TUG1, and hsa-miR-21-3p are potential biomarkers of CAD incidence and diagnosis.

Immunomodulatory and anti-cancer potential of cloves (Syzygium aromaticum) bud extract and its phytogenic silver nanoparticles.

Clove plant (Syzygium aromaticum) is one of the Myrtaceae family. It's a common flavor in food and the traditional medicine. The study's objective was to ascertain whether the clove bud aqueous extract (CAE) and CAE + nanosilver have any biological effects on immune cells and HT-29 colon cancer cell line. Nanosilver was produced through green synthesis approach using CAE. Produced nanosilver was characterized via electron microscope (scanning, SEM) and ultraviolet-visible spectroscopy. CAE and CAE + nanosilver were examined for their active biomolecules using FTIR analysis, p53 contents using real-time PCR, apoptosis and cell cycle arrest power on HT-29 cancer cell line via flow cytometerty and immunomodulatory potential utilizing MTT assay. Results cleared that a spherical nanosilver with a diameter range of 53 nm was formed by CAE. There were several active biomolecules in CAE and CAE + nanosilver. CAE and CAE + nanosilver increased the p53 protein expression and apoptotic cell number in HT-29 colon cancer cells. CAE and CAE + nanosilver could arrest HT-29 cells at the phase G2/M. CAE and CAE + nanosilver stimulated quiescent and PHA-pre-treated splenic cells at higher concentrations, and CAE suppressed quiescent splenic cell when diluted. In conclusion, the safe edible Syzygium aromaticum plant can be utilized to make anti-tumor agent, essentially for colon tumor. As Syzygium aromaticum plant could stimulate immune cells, it can be used as immune-stimulatory agent that can help fight tumor and tumor development.

Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity.

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling.

Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals.

Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1ß. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique.

Ambroxol, a mucolytic agent, boosts HO-1, suppresses NF-κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that increases the risk of developing colorectal cancer and imposes a lifelong healthcare burden on millions of patients worldwide. Current treatment strategies are associated with significant risks and have been shown to be fairly effective. Hence, discovering new therapies that have better efficacy and safety profiles than currently exploited therapeutic strategies is challenging. It has been well delineated that NF-κB/Nrf2 crosstalk is a chief player in the interplay between oxidative stress and inflammation. Ambroxol hydrochloride, a mucolytic agent, has shown antioxidant and anti-inflammatory activity in humans and animals and has not yet been examined for the management of UC. Therefore, our approach was to investigate whether ambroxol could be effective to combat UC using the common acetic acid rat model. Interestingly, a high dose of oral ambroxol (200 mg/kg/day) reasonably improved the microscopic and macroscopic features of the injured colon. This was linked to low disease activity and a reduction in the colonic weight/length ratio. In the context of that, ambroxol boosted Nrf2 activity and upregulated HO-1 and catalase to augment the antioxidant defense against oxidative damage. Besides, ambroxol inactivated NF-κB signaling and its consequent target pro-inflammatory mediators, IL-6 and TNF-α. In contrast, IL-10 is upregulated. Consistent with these results, myeloperoxidase activity is suppressed. Moreover, ambroxol decreased the susceptibility of the injured colon to apoptosis. To conclude, our findings highlight the potential application of ambroxol to modify the progression of UC by its anti-inflammatory, antioxidant, and antiapoptotic properties.

The dynamic interplay between AMPK/NFκB signaling and NLRP3 is a new therapeutic target in inflammation: Emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury.

Acute lung injury (ALI) is one the most common causes of morbidity and mortality in critically ill patients. In this study, we examined for first time the role of dapagliflozin (DPGZ) in lipopolysaccharide (LPS)-induced ALI in rats and determined the underlying molecular mechanisms by evaluating the effects of DPGZ on adenosine monophosphate kinase (AMPK), nuclear transcription factor kappa B, nucleotide-binding and oligomerization domain-like receptor 3 inflammasome activation. Treatment of acute lung injured rats with either low dose (5 mg/kg) or high dose (10 mg/kg) DPGZ significantly decreased oxidative stress by decreasing malondialdehyde and nitric oxide tissue levels with a significant increase in spectrophotometric measurements of superoxide dismutase, catalase, and reduced glutathione levels. DPGZ treatment resulted in a significant anti-inflammatory effect as indicated by suppression in myeloperoxidase activity, MCP-1, IL-1ß, IL-18, and TNF-α levels. DPGZ treatment also increased p-AMPK/t-AMPK with a significant reduction in NF-kB P65 binding activity and NFĸB p65 (pSer536) levels. These effects of DPGZ were accompanied by a significant reduction in NLRP3 levels and NLRP3 gene expression and a significant decrease in caspase-1 activity, which were also confirmed by histopathological examinations. We conclude that DPGZ antioxidant and anti-inflammatory activity may occur through regulation of AMPK/NFĸB pathway and inhibition of NLRP3 activation. These results suggest that DPGZ represents a promising intervention for the treatment of ALI, particularly in patients with type 2 diabetes.

Design, Synthesis, Cytotoxic Screening and Molecular Docking Studies of Novel Hybrid Thiosemicarbazone Derivatives as Anticancer Agents.

Thiosemicarbazones have been the focus of scientists owing to their broad clinical anticancer range. Herein, A Series of new thiosemicarbazone derivatives 5-9 were synthesized and confirmed through the use of different spectroscopic techniques along with elemental analysis. The in vitro cytotoxic activity of compounds 5-9 against MCF-7 and A549 cell lines and normal breast cells were assessed. Several compounds were found to be active. The most active compound 7 caused MCF-7 cell cycle arrest at G1/ S phases; and induced apoptosis at the pre-G1 phase. The apoptosis-inducing activity of compound 7 was proofed by the elevation of caspase 3/7 activity and also by up-regulation of the expression of Bax and p53 proteins together with the down-regulation of the expression of the Bcl-2 protein. It also had a strong inhibitory effect topoisomerase IIß enzyme. Molecular Docking study revealed that the synthesized compounds had good docking scores compared to the standard drug Etoposide towards the topoisomerase IIß protein (3QX3). Overall, these findings confirmed that the new thiosemicarbazone derivatives could aid in the development of promising cancer drug candidates.

Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.

Eprosartan: A closer insight into its neuroprotective activity in rats with focal cerebral ischemia-reperfusion injury.

Eprosartan (EPRO), an angiotensin receptor type-1 (AT-1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)-induced ischemic stroke in rats. Fifty-six male Wistar rats were divided into four groups (n = 14 per group): sham-operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia-reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase-3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti-inflammatory activity of EPRO was revealed by downregulation of nuclear factor-kappa B and tumor necrosis factor-ß levels and (C-X-C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia-inducible factor-1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin-1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO-induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways.

EGFR/VEGFR-2 dual inhibitor and apoptotic inducer: Design, synthesis, anticancer activity and docking study of new 2-thioxoimidazolidin-4one derivatives.

AIMS: EGFR and VEGFR-2 have emerged as promising targets for cancer management as they play a crucial role in tumor growth, angiogenesis and metastasis. A novel series of 2-thioxoimidazolidin-4-one derivatives were synthesized and evaluated as apoptotic inducers and EGFR/VEGFR-2 dual inhibitors. MAIN METHODS: The cytotoxic activities of all synthesized compounds were tested against MCF-7, HepG2 and A549 cell lines. The molecular mechanism of the most promising cytotoxic compounds was investigated via a series of assays including in vitro EGFR and VEGFR-2 inhibitory activity in MCF-7 cell line. Additionally, levels of p53, Bax, Bcl-2, caspase 7, 9 as well as cell cycle analysis were assessed in MCF-7 cell line to gain better understanding of their apoptotic activity. Molecular docking study was carried out to predict binding pattern of these compounds with EGFR and VEGFR-2 active sites. Finally, in silico ADME and drug-likeness profiling were calculated. KEY FINDINGS: Compounds 6 and 8a exhibited superior cytotoxic activity compared to sorafenib and erlotinib, against the three tested cell lines. In the same context, 6 and 8a showed better EGFR and VEGFR-2 inhibitory activity compared to the reference compounds. The later effect was further supported by the docking study. Furthermore, these compounds displayed potent apoptotic activity as evident by cell accumulation at pre-G1 phase and cell cycle arrest at G2/M phase together with increased p53, caspae-7 and caspase-9 levels and Bax/Bcl-2 ratio. Finally, synthesized compounds have acceptable drug likeness. SIGNIFICANCE: Compounds 6 and 8a act as potent dual EGFR/VEGFR-2 inhibitors with evident apoptotic activity.

AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma.

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKß, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-ß. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

Novel HDAC/Tubulin Dual Inhibitor: Design, Synthesis and Docking Studies of α-Phthalimido-Chalcone Hybrids as Potential Anticancer Agents with Apoptosis-Inducing Activity.

INTRODUCTION: In order to develop novel anticancer HDAC/tubulin dual inhibitors, a novel series of α-phthalimido-substituted chalcones-based hybrids was synthesized and characterized by IR, 1H NMR, 13C NMR, mass spectroscopy and X-ray analysis. METHODS: All the synthesized compounds were evaluated for their in vitro anticancer activity against MCF-7 and HepG2 human cancer cell lines using MTT assay. To explore the mechanism of action of the synthesized compounds, in vitro ß-tubulin polymerization and HDAC 1 and 2 inhibitory activity were measured for the most potent anticancer hybrids. Further, cell cycle analysis was also evaluated. RESULTS: The trimethoxy derivative 7j showed the most potent anticancer activity, possessed the most potent ß-tubulin polymerase and HDAC 1 and 2 inhibitory activity and efficiently induced cell cycle arrest at both G2/M and preG1phases in the MCF-7 cell line.

Flow cytometry for cell cycle parameters in healthcare workers potentially exposed to ionizing radiation.

INTRODUCTION: There is much controversy about the effects of chronic low dose exposure to ionizing radiation and the possible consequences particularly in occupational exposures. OBJECTIVES: This study aims at the assessment of cell cycle in healthcare workers (HCWs) occupationally exposed to radiation. Subjects and Methods. Participants in the study included 106 HCWs, of them 79 were potentially exposed to ionizing radiation during their routine work, while the other 27 were non-exposed subjects taken as controls. Exposure was monitored by thermo-luminescent dosimeters. Peripheral blood lymphocytes were separated, fixed and stained with propidium iodide followed by analysis via flow cytometry for DNA content as a marker of cell cycle and apoptosis pattern. RESULTS: Compared to controls, exposed subjects showed a significant higher mean percentage of G2/M cell (4.01+/-4.19 vs. 1.88+/-3.02, p<0.05) and higher mean percentage of coefficient of variation (CV) (4.41+/-1.37 vs. 3.81+/-1.07, p<0.05). Furthermore, HCWs with older age, longer duration of exposure and higher cumulative radiation dose had significant higher G2/M % and CV% with lower G0/G1 % than other workers. Significant correlation was found between cumulative dose of radiations and the mean percentage of cells in the phases of G0/G1 and G2/M as well as their mean CV% (p<0.05). CONCLUSION AND RECOMMENDATIONS: Healthcare workers exposed to radiation had cellular changes that could be detected by flow cytometry that probably can be used as a follow up marker for potential major harmful effects.