Objective: Prokineticin-1 (PROK1) is a recently described protein with a wide range of functions including tissue specific angiogenesis, modulation of inflammatory responses and regulation of haematopoiesis. PROK1 has...Objective: Prokineticin-1 (PROK1) is a recently described protein with a wide range of functions including tissue specific angiogenesis, modulation of inflammatory responses and regulation of haematopoiesis. PROK1 has been found in the steroidogenic organs like ovary, testis, adrenal and specially placenta and they have been found to have a role in development of the olfactory system and GnRH system. The aim was to update the role of PROK1 and PROK2 inhuman reproduction since the review was provided by Maldono-Perez (2007) on the potentials of prokineticins in reproduction. Design: A review of international scientific literature by a search of Pubmed and the authors files was done for citation of articles relevant to prokineticins in reproduction, be it its role in ovary, testis, uterus with special emphasis on implantation, normal pregnancy, in labour, pathophysiological states like tubal pregnancy, pcos, various genital tumours, and cases of isolated hypogonadotropic hypogonadism with mutations with PROK2/ PROKR2 and studies detailing functional mechanisms. Results: In the normal cycle, PROK1 has been found to have important roles in implantation, regulating several genes like COX-2, IL-8, IL-11, CTGF related to implantation. Initially murine studies revealed a critical role of PROK2 pathway on olfactory bulb morphogenesis and GnRH secretion which was accidentally discovered and since then several studies on mutations in PROK2/PROKR2 showed that they underlie some case of KS in humans. Although in mouse heterozygote state is not associated with clinical phenotype, most of human mutations are heterozygous. Conclusions: Role of PROK-1 in the process of implantation, with a deeper understanding of the process success rates in IVF and ART can be improved, besides understanding the pathophysiology of tubal pregnancy. Further presence in ovarian follicles of PROK1 can be used to plan a strategy for treating pcos. Development of antagonism of PROK’S may be a helpful strategy in treating preterm labour.展开更多
We earlier reviewed how obesity has assumed an endemic/pandemic proportions that has resulted in escalating incidence and prevalence of associated escalating worldwide incidence of Metabolic Syndrome(MetS)with non alc...We earlier reviewed how obesity has assumed an endemic/pandemic proportions that has resulted in escalating incidence and prevalence of associated escalating worldwide incidence of Metabolic Syndrome(MetS)with non alcoholic fatty liver disease(NAFLD),that is correlated with enhanced morbidity.Later we tried to detail how probiotics,L-Carnitine(LC),Nicotinamide Ribose(NR)Combination,along with Apical Sodium Dependent Bile Acids Transporter(ASBT)or Volixibat and Silybin,Vitamin D,Allyl Isothiocyanate(AITC),might aid in treating and understand the etiopathogenesis of NAFLD.The prevalence of NAFLD all over the world is approximately 25%,with that of non alcoholic steatohepapititis(NASH),varying from 1.5%=6.45%.Particularly NASH,specifically the ones associated with fibrosis possess a greater chance of generation of side effects that include progression to cirrhosis as well as liver-associated mortality.Despite an improvement was observed with vitamin E,Pioglitazone.liraglutide in histological appearance in liver randomized controlled clinical trials(RCT),at present no drugs exists that have received FDI approval for NASH.The aim of this review was to update the newer drugs getting evaluated,undergoing phase 2-3 trials.Currently there are Obeticholic acid,elafibranor,cenicriviroc,resmetriom,in addition to aramchol,that are the five agents that are getting analysed in big,histology dependent phase 3 trials.Hopefully within another 2-4 years,newer,efficacious drugs will be available for the therapy of NASH.Besides that a lot of phase 2 trials are continuing for different drugs.Further depending on outcomes of phase 2-3 trials,combination treatments are getting evaluated.For future therapeutic approaches would be made up of variations in NASH phenotypes,besides personalized approaches based on various NASH phenotypes in addition to response of every single patient.Further recently there were reports of utilization of curcumin with nonselective beta blocker for regression from cirrhosis(reviewed by us).Hopefully once there are approved therapies for NAFLD/NASH,we can work in that direction.展开更多
Methods: Asystematic literature search was performed using PUBMED for all English articles up to April 2014. Although this review mainly focuses on published human studies, it also draws attention to where future rese...Methods: Asystematic literature search was performed using PUBMED for all English articles up to April 2014. Although this review mainly focuses on published human studies, it also draws attention to where future research should be directed based on animal studies. Results: Besides the 9 known mutations widely quoted for KS namely KAL1, Fibroblast growth factor 8 (FGF8), fibroblast growth factor receptor 1 (FGFR1), prokineticin 2 (PROK2), PROK receptor 2 (PROKR2), WDR11, heparin sulfate-6-O-Transferase (HS6T1), chromodomain helicase DNA binding protein 7 (CHD7) and semaphorin 3A (SEMA 3A), additional mutations in “FGF8 synexpression” group e.g., FGF 17, ILRD, DUSP 6, SPRY4 and FLRT3 have been shown to be involved in CHH, mostly KS besides SEMA 7A. Although traditionally division has been based on anosmic/normosnic criteria, further genes found to cause so called nIHH like Gonadotropin releasing hormone receptor (GNRHR). KISS1, TAC3, TACR3 have also been found to be associated with hyposmia on detailed testing on UPSIT and MRI for olfactory structures revealed absent OB. Further detailed examination of transcription factor genes have revealed involvement of HESX1, TSHZ1, AXL, SOX10 with a strong overlap of in transcription factors in development of septooptic dysplasia (SOD), combined pituitary hormone deficiency (CHPD) and KS. Treatment with rFSH/-hCG gives almost similar results to pulsatile GnRH therapy and should be based on cost factor, availability and in occasional cases specific treatment like kisspeptin therapy. Conclusions: Contrary to the traditional thinking, one shoud reconsider classifying cases of IHH simply on basis of anosmia/normosmia. Deafness calls for looking for mutations in Sox 10/CHD7/ILRD7 considering 38% association of former. Therapy should be individualized based on availability of pulsatile GnRH, cost factor and in recalcitrant cases kp therapy may be of use with kp mutations and NKB mutations.展开更多
文摘Objective: Prokineticin-1 (PROK1) is a recently described protein with a wide range of functions including tissue specific angiogenesis, modulation of inflammatory responses and regulation of haematopoiesis. PROK1 has been found in the steroidogenic organs like ovary, testis, adrenal and specially placenta and they have been found to have a role in development of the olfactory system and GnRH system. The aim was to update the role of PROK1 and PROK2 inhuman reproduction since the review was provided by Maldono-Perez (2007) on the potentials of prokineticins in reproduction. Design: A review of international scientific literature by a search of Pubmed and the authors files was done for citation of articles relevant to prokineticins in reproduction, be it its role in ovary, testis, uterus with special emphasis on implantation, normal pregnancy, in labour, pathophysiological states like tubal pregnancy, pcos, various genital tumours, and cases of isolated hypogonadotropic hypogonadism with mutations with PROK2/ PROKR2 and studies detailing functional mechanisms. Results: In the normal cycle, PROK1 has been found to have important roles in implantation, regulating several genes like COX-2, IL-8, IL-11, CTGF related to implantation. Initially murine studies revealed a critical role of PROK2 pathway on olfactory bulb morphogenesis and GnRH secretion which was accidentally discovered and since then several studies on mutations in PROK2/PROKR2 showed that they underlie some case of KS in humans. Although in mouse heterozygote state is not associated with clinical phenotype, most of human mutations are heterozygous. Conclusions: Role of PROK-1 in the process of implantation, with a deeper understanding of the process success rates in IVF and ART can be improved, besides understanding the pathophysiology of tubal pregnancy. Further presence in ovarian follicles of PROK1 can be used to plan a strategy for treating pcos. Development of antagonism of PROK’S may be a helpful strategy in treating preterm labour.
文摘We earlier reviewed how obesity has assumed an endemic/pandemic proportions that has resulted in escalating incidence and prevalence of associated escalating worldwide incidence of Metabolic Syndrome(MetS)with non alcoholic fatty liver disease(NAFLD),that is correlated with enhanced morbidity.Later we tried to detail how probiotics,L-Carnitine(LC),Nicotinamide Ribose(NR)Combination,along with Apical Sodium Dependent Bile Acids Transporter(ASBT)or Volixibat and Silybin,Vitamin D,Allyl Isothiocyanate(AITC),might aid in treating and understand the etiopathogenesis of NAFLD.The prevalence of NAFLD all over the world is approximately 25%,with that of non alcoholic steatohepapititis(NASH),varying from 1.5%=6.45%.Particularly NASH,specifically the ones associated with fibrosis possess a greater chance of generation of side effects that include progression to cirrhosis as well as liver-associated mortality.Despite an improvement was observed with vitamin E,Pioglitazone.liraglutide in histological appearance in liver randomized controlled clinical trials(RCT),at present no drugs exists that have received FDI approval for NASH.The aim of this review was to update the newer drugs getting evaluated,undergoing phase 2-3 trials.Currently there are Obeticholic acid,elafibranor,cenicriviroc,resmetriom,in addition to aramchol,that are the five agents that are getting analysed in big,histology dependent phase 3 trials.Hopefully within another 2-4 years,newer,efficacious drugs will be available for the therapy of NASH.Besides that a lot of phase 2 trials are continuing for different drugs.Further depending on outcomes of phase 2-3 trials,combination treatments are getting evaluated.For future therapeutic approaches would be made up of variations in NASH phenotypes,besides personalized approaches based on various NASH phenotypes in addition to response of every single patient.Further recently there were reports of utilization of curcumin with nonselective beta blocker for regression from cirrhosis(reviewed by us).Hopefully once there are approved therapies for NAFLD/NASH,we can work in that direction.
文摘Methods: Asystematic literature search was performed using PUBMED for all English articles up to April 2014. Although this review mainly focuses on published human studies, it also draws attention to where future research should be directed based on animal studies. Results: Besides the 9 known mutations widely quoted for KS namely KAL1, Fibroblast growth factor 8 (FGF8), fibroblast growth factor receptor 1 (FGFR1), prokineticin 2 (PROK2), PROK receptor 2 (PROKR2), WDR11, heparin sulfate-6-O-Transferase (HS6T1), chromodomain helicase DNA binding protein 7 (CHD7) and semaphorin 3A (SEMA 3A), additional mutations in “FGF8 synexpression” group e.g., FGF 17, ILRD, DUSP 6, SPRY4 and FLRT3 have been shown to be involved in CHH, mostly KS besides SEMA 7A. Although traditionally division has been based on anosmic/normosnic criteria, further genes found to cause so called nIHH like Gonadotropin releasing hormone receptor (GNRHR). KISS1, TAC3, TACR3 have also been found to be associated with hyposmia on detailed testing on UPSIT and MRI for olfactory structures revealed absent OB. Further detailed examination of transcription factor genes have revealed involvement of HESX1, TSHZ1, AXL, SOX10 with a strong overlap of in transcription factors in development of septooptic dysplasia (SOD), combined pituitary hormone deficiency (CHPD) and KS. Treatment with rFSH/-hCG gives almost similar results to pulsatile GnRH therapy and should be based on cost factor, availability and in occasional cases specific treatment like kisspeptin therapy. Conclusions: Contrary to the traditional thinking, one shoud reconsider classifying cases of IHH simply on basis of anosmia/normosmia. Deafness calls for looking for mutations in Sox 10/CHD7/ILRD7 considering 38% association of former. Therapy should be individualized based on availability of pulsatile GnRH, cost factor and in recalcitrant cases kp therapy may be of use with kp mutations and NKB mutations.
