Urinary tract infections(UTIs)are among the most prevalent pediatric bacterial infections,and undertreated episodes may lead to renal scarring,hypertension,or chronic kidney disease.Multidrug-resistant(MDR)Enterobacte...Urinary tract infections(UTIs)are among the most prevalent pediatric bacterial infections,and undertreated episodes may lead to renal scarring,hypertension,or chronic kidney disease.Multidrug-resistant(MDR)Enterobacterales have been increasingly reported in children,with higher rates in Asian and Middle Eastern settings than in high-income countries[1,2].展开更多
A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which dec...A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which decrease drug penetration into the central nervous system and ultimately into tumors.It is noteworthy that the ABC transporters,ABCB1[known as P-glycoprotein(P-gp)]and ABCG2[known as breast cancer resistance protein(BCRP)],are overexpressed in brain tumors,including common gliomas.The co-presence of these transporters may negate the inhibition of either transporter,particularly if both transport the same anticancer drug.The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs.However,the clinical relevance as a therapeutic target in human tumors remains a matter of contention.Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance,none are currently approved.Furthermore,the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy,significant toxicities,and unsuitable pharmacokinetic profiles.Therefore,innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance.This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments.The molecular alterations in BBB following brain tumor development,which are linked to various cancer therapies,are discussed.The overexpression of ABCB1 and ABCG2 at the BBB is discussed,potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed,and the implementation of novel approaches is considered.展开更多
Objective:To explore the effect of a hydrogel of Piper longum(P.longum)root against biofilm-forming multidrug-resistant(MDR)Staphylococcus aureus(S.aureus)through in vitro,in silico,and in vivo studies.Methods:We isol...Objective:To explore the effect of a hydrogel of Piper longum(P.longum)root against biofilm-forming multidrug-resistant(MDR)Staphylococcus aureus(S.aureus)through in vitro,in silico,and in vivo studies.Methods:We isolated the P.longum root ethanolic extract and the compounds using p-HPLC.In vitro antibacterial and antibiofilm activities of P.longum root extract and isolated alkamide compounds against biofilm-forming MDR S.aureus(ATCC 33591)were assessed using agar diffusion and broth microdilution methods,respectively.In silico investigations were conducted to investigate the interaction of alkamide compounds with three target proteins glycogen synthase kinase 3β(GSK3β),matrix metalloproteinases-8(MMP-8),and inducible nitric oxide synthase(iNOS).In addition,the wound healing effect of P.longum root extract 2%and 5%(w/v)-containing hydrogels was determined in mice.Results:The ethanolic root extract of P.longum and its compounds exhibited in vitro antibacterial activity with minimum inhibitory concentrations between 50µg/mL and 700µg/mL,as well as significantly reduced biofilm formation.Piperdardine isolated from P.longum root extract had the best molecular docking score(-9.7,-9.8,and-9.2 kcal/mol)with target proteins GSK3β,MMP-8,and iNOS.In vivo studies showed that P.longum hydrogels significantly lowered the number of colony-forming units(P<0.05).The P.longum 5%(w/v)hydrogel-treated group showed enhanced wound healing activity,achieving a wound contraction rate of 99.34%on day 14.Furthermore,histopathological analysis confirmed increased re-epithelialization and reduced inflammation in mice treated with P.longum 5%(w/v)hydrogel.Conclusions:P.longum root extract has pharmacological potential as an antibacterial and wound-healing agent,and further research is required to confirm its efficacy and clinical application.展开更多
Acinetobacter(A.)baumannii is a Gram-negative,non-fermenting opportunistic pathogen increasingly implicated in nosocomial infections,particularly in intensive care units(ICUs).Its ability to acquire multidrug resistan...Acinetobacter(A.)baumannii is a Gram-negative,non-fermenting opportunistic pathogen increasingly implicated in nosocomial infections,particularly in intensive care units(ICUs).Its ability to acquire multidrug resistance(MDR),including to carbapenems,poses a major public health threat.Infections caused by A.baumannii-ranging from pneumonia to bloodstream and wound infections-are difficult to treat and associated with high mortality,especially in critically ill patients[1].展开更多
P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) family of transporters, plays a crucial role in the development of multi-drug resistance (MDR) in cancer treatment. P-gp actively pumps chemotherapeuti...P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) family of transporters, plays a crucial role in the development of multi-drug resistance (MDR) in cancer treatment. P-gp actively pumps chemotherapeutic drugs out of cancer cells, reducing their intracellular concentrations and thereby diminishing their efficacy. This review explores the mechanisms by which P-gp contributes to MDR, including intrinsic and acquired resistance. It also discusses various strategies to inhibit P-gp, such as blocking drug binding sites, interfering with ATP hydrolysis, and altering cell membrane integrity. The potential of fourth-generation P-gp inhibitors and other novel approaches to enhance the effectiveness of cancer therapies is also examined. Understanding and overcoming P-gp-mediated MDR is essential for improving therapeutic outcomes in cancer patients.展开更多
文摘Urinary tract infections(UTIs)are among the most prevalent pediatric bacterial infections,and undertreated episodes may lead to renal scarring,hypertension,or chronic kidney disease.Multidrug-resistant(MDR)Enterobacterales have been increasingly reported in children,with higher rates in Asian and Middle Eastern settings than in high-income countries[1,2].
基金supported by Arkansas Bioscience Institute funds (ABI-GR020025) from University of Arkansas for Medical Sciences
文摘A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which decrease drug penetration into the central nervous system and ultimately into tumors.It is noteworthy that the ABC transporters,ABCB1[known as P-glycoprotein(P-gp)]and ABCG2[known as breast cancer resistance protein(BCRP)],are overexpressed in brain tumors,including common gliomas.The co-presence of these transporters may negate the inhibition of either transporter,particularly if both transport the same anticancer drug.The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs.However,the clinical relevance as a therapeutic target in human tumors remains a matter of contention.Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance,none are currently approved.Furthermore,the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy,significant toxicities,and unsuitable pharmacokinetic profiles.Therefore,innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance.This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments.The molecular alterations in BBB following brain tumor development,which are linked to various cancer therapies,are discussed.The overexpression of ABCB1 and ABCG2 at the BBB is discussed,potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed,and the implementation of novel approaches is considered.
基金supported by NPDF fellowship grants from the Central Council for Research in Ayurvedic Sciences,Ministry of AYUSH,Govt.of India(HQ-ESTT012/60/2022-ESTT/6783).
文摘Objective:To explore the effect of a hydrogel of Piper longum(P.longum)root against biofilm-forming multidrug-resistant(MDR)Staphylococcus aureus(S.aureus)through in vitro,in silico,and in vivo studies.Methods:We isolated the P.longum root ethanolic extract and the compounds using p-HPLC.In vitro antibacterial and antibiofilm activities of P.longum root extract and isolated alkamide compounds against biofilm-forming MDR S.aureus(ATCC 33591)were assessed using agar diffusion and broth microdilution methods,respectively.In silico investigations were conducted to investigate the interaction of alkamide compounds with three target proteins glycogen synthase kinase 3β(GSK3β),matrix metalloproteinases-8(MMP-8),and inducible nitric oxide synthase(iNOS).In addition,the wound healing effect of P.longum root extract 2%and 5%(w/v)-containing hydrogels was determined in mice.Results:The ethanolic root extract of P.longum and its compounds exhibited in vitro antibacterial activity with minimum inhibitory concentrations between 50µg/mL and 700µg/mL,as well as significantly reduced biofilm formation.Piperdardine isolated from P.longum root extract had the best molecular docking score(-9.7,-9.8,and-9.2 kcal/mol)with target proteins GSK3β,MMP-8,and iNOS.In vivo studies showed that P.longum hydrogels significantly lowered the number of colony-forming units(P<0.05).The P.longum 5%(w/v)hydrogel-treated group showed enhanced wound healing activity,achieving a wound contraction rate of 99.34%on day 14.Furthermore,histopathological analysis confirmed increased re-epithelialization and reduced inflammation in mice treated with P.longum 5%(w/v)hydrogel.Conclusions:P.longum root extract has pharmacological potential as an antibacterial and wound-healing agent,and further research is required to confirm its efficacy and clinical application.
基金supported by ICMR-RMRC intramural fund(RMRC/IM/2022/26).
文摘Acinetobacter(A.)baumannii is a Gram-negative,non-fermenting opportunistic pathogen increasingly implicated in nosocomial infections,particularly in intensive care units(ICUs).Its ability to acquire multidrug resistance(MDR),including to carbapenems,poses a major public health threat.Infections caused by A.baumannii-ranging from pneumonia to bloodstream and wound infections-are difficult to treat and associated with high mortality,especially in critically ill patients[1].
文摘P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) family of transporters, plays a crucial role in the development of multi-drug resistance (MDR) in cancer treatment. P-gp actively pumps chemotherapeutic drugs out of cancer cells, reducing their intracellular concentrations and thereby diminishing their efficacy. This review explores the mechanisms by which P-gp contributes to MDR, including intrinsic and acquired resistance. It also discusses various strategies to inhibit P-gp, such as blocking drug binding sites, interfering with ATP hydrolysis, and altering cell membrane integrity. The potential of fourth-generation P-gp inhibitors and other novel approaches to enhance the effectiveness of cancer therapies is also examined. Understanding and overcoming P-gp-mediated MDR is essential for improving therapeutic outcomes in cancer patients.
