ABSTRACT
Since the start of the pandemic, considerable advancements have been made in our understanding of the effects of SARS-CoV-2 infection and the associated COVID-19 on the hepatic system. There is a broad range of clinical symptoms for COVID-19. It affects multiple systems and has a dominant lung illness depending on complications. The progression of COVID-19 in people with pre-existing chronic liver disease (CLD) has also been studied in large multinational groups. Notably, SARS-CoV-2 infection is associated with a higher risk of hepatic decompensation and death in patients with cirrhosis. In this review, the source, composition, mechanisms, transmission characteristics, clinical characteristics, therapy, and prevention of SARS-CoV-2 were clarified and discussed, as well as the evolution and variations of the virus. This review briefly discusses the causes and effects of SARS-CoV-2 infection in patients with CLD. As part of COVID-19, In addition, we assess the potential of liver biochemistry as a diagnostic tool examine the data on direct viral infection of liver cells, and investigate potential pathways driving SARS-CoV-2-related liver damage. Finally, we explore how the pandemic has had a significant impact on patient behaviors and hepatology services, which may increase the prevalence and severity of liver disease in the future. The topics encompassed in this review encompass the intricate relationships between SARS-CoV-2, liver health, and broader health management strategies, providing valuable insights for both current clinical practice and future research directions.
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In the present study, a total of 720 samples were collected from retail raw meat from 13 upazilas in Sylhet District, Bangladesh, of which 225 samples were from cattle meat, 210 samples were from goat meat, and 285 samples were from chicken meat. Salmonella enterica serovars Typhimurium and Enteritidis were screened for extended-spectrum ß-lactamase (ESBL) genes using multiplex PCR. Among the 720 samples, Salmonella spp. was detected in 28.06% (202 out of 720) of the samples, with S. Enteritidis and S. Typhimurium were identified in 11.53% (83 out of 720) and 12.22% (88 out of 720) of the samples, respectively. It was found that all Salmonella enterica serovars isolated from cattle meat displayed multidrug resistance (MDR) based on antimicrobial susceptibility testing. Notably, a significant proportion of S. Enteritidis isolates and all S. Typhimurium isolates from goat meat demonstrated complete resistance to multiple drugs (ampicillin, cefuroxime, and ceftazidime). Regarding chicken meat, out of 89 isolates encompassing both S. Typhimurium and S. Enteritidis, 57 isolates (64.04%) exhibited MDR. Additionally, blaCTX-M-1 exhibited the highest occurrence at 15.69% for S. Typhimurium and 7.89% for S. Enteritidis in chicken meat. Moreover, blaCTX-M-9 was only detected at 3.92% for S. Enteritidis in chicken meat. Furthermore, blaOXA had the highest prevalence rate of 19.04% for S. Enteritidis and 25.80% for S. Typhimurium in cattle meat, followed by chicken meat. These findings highlight the urgency for monitoring ESBL-producing Salmonella in retail raw meat and the need for strict measure to manage antibiotic use to prevent the spread of multidrug-resistant and ESBL-producing Salmonella strains, thereby protecting humans and reducing public health risks.
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The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 23 full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount (mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC50 (0.24 µg/ml) by 8.3 times than F4 (1.99 µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 Mpro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.
ABSTRACT
In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt to improve their biological availability and antiviral activity. Next, both cytotoxicity and anti-SARS-CoV-2 activities of the examined compounds loaded EMLs (F3a-g) were assessed in Vero E6 cells via MTT assay to calculate the CC50 and inhibitory concentration 50 (IC50) values. The most potent 3e-loaded EMLs (F3e) elicited a selectivity index of 18 with an IC50 value of 0.73 µg/mL. Moreover, F3e was selected for further elucidation of a possible mode of action where the results showed that it exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition. Besides, molecular docking and MD simulations towards the SARS-CoV-2 Mpro were performed. Finally, a structure-activity relationship (SAR) study focussed on studying the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide in addition to compound contraction on SARS-CoV-2 activity.HighlightsEmulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g).The most potent 3e-loaded EMLs (F3e) showed an IC50 value of 0.73 µg/mL against SARS-CoV-2.F3e exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition.Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA calculations were performed.Structure-activity relationship (SAR) study was discussed to study the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide on the anti-SARS-CoV-2 activity.
Subject(s)
COVID-19 , Nanoparticles , Humans , Molecular Docking Simulation , SARS-CoV-2 , Antiviral Agents/pharmacology , Molecular Dynamics Simulation , Protease InhibitorsABSTRACT
Human papillomavirus (HPV) is the most prevalent sexually transmitted disease in the world. Even though preventive vaccines against HPV are effective, the effective treatment of HPV infections is much less satisfactory due to multi-drug resistance and secondary adverse effects. Nanotechnology was employed for the delivery of anti-cancer drugs to increase the effectiveness of the treatment and minimize the side effects. Nanodelivery of both preventive and therapeutic HPV vaccines has also been studied to boost vaccine efficacy. Overall, such developments suggest that the nanoparticle-based vaccine might emerge as the most cost-effective way to prevent and treat HPV cancer, assisted or combined with another nanotechnology-based therapy. This review focuses on the current knowledge on pathogenesis and vaccines against HPV, highlighting the current value and perspective regarding the widespread diffusion of HPV vaccines-based nanomaterials. The ongoing advancements in the design of vaccines-based nanomaterials are expanding their therapeutic roles against HPV.
Subject(s)
Alphapapillomavirus , Papillomavirus Infections , Papillomavirus Vaccines , Humans , Nanotechnology , PapillomaviridaeABSTRACT
Resveratrol (RSV), a non-flavonoid stilbene polyphenol, possesses anti-carcinogenic activities against all the major stages of cancer. Zein nanoparticles (ZN NPs) have been utilized successfully in delivery of variant therapeuticals by virtue of their histocompatible nature. The goal of this work was to comparatively explore the antiproliferative, pro-apoptotic and oxidative stress potentials of RSV-ZN NPs versus RSV against human colorectal carcinoma HCT-116 cells. ZN-RSV NPs were developed and assayed for particle size analysis and RSV diffusion. The selected formula obtained 137.6 ± 8.3 nm as mean particle size, 29.4 ± 1.8 mV zeta potential, 92.3 ± 3.6% encapsulation efficiency. IC50 of the selected formula was significantly lower against HCT-116 cells versus Caco-2 cells. Also, significantly enhanced cellular uptake was generated from RSV-ZN NPs versus free RSV. Enhanced apoptosis was concluded due to increased percentage cells in G2-M and pre-G1 phases. The pro-apoptotic potential was explained by caspase-3 and cleaved caspase-3 increased mRNA expression in addition to NF-κB and miRNA125b decreased expression. Biochemically, ZN-RSV NPs induced oxidative stress as demonstrated by enhanced reactive oxygen species (ROS) generation and endothelial nitric oxide synthase (eNOS) isoenzyme increased levels. Conclusively, ZN-RSV NPs obtained cell cycle inhibition supported with augmented cytotoxicity, uptake and oxidative stress markers levels in HCT-116 tumor cells in comparison with free RSV. These results indicated intensified chemopreventive profile of RSV due to effective delivery utilizing ZN nano-dispersion against colorectal carcinoma HCT-116 cells.
Subject(s)
Colorectal Neoplasms , Nanoparticles , Zein , Apoptosis , Caco-2 Cells , Caspase 3/pharmacology , Colorectal Neoplasms/drug therapy , HCT116 Cells , Humans , Oxidants/pharmacology , Resveratrol/pharmacology , Zein/pharmacologyABSTRACT
AIMS: Breast cancer (BC) is the third leading cause of death among other cancer types. Worldwide, it is the most common harmful disease in women, representing 1/4 of all cancers. Treatment of BC remains an ongoing challenge to most researchers. Understanding how cancer cells differ from normal cells can enhance drug targeting and overall disease progression. Endocytosis is a major physiological process modified in cancer cells and affects the cellular uptake of chemotherapeutic agents. MCF-7 breast cancer cells exhibit constitutive macropinocytic activity in comparison to normal non-macropinocytic MCF-10A breast cells. Therefore, we hypothesized that blocking the macropinocytosis mechanism in MCF-7 cells may inhibit the cancer progression while maintaining the safety of normal cells. MAIN METHODS: Using nano-precipitation technique, paclitaxel-PLGA-NPs were successfully prepared in the size range and charge required to opt for macropinocytosis in MCF-7 cells. KEY FINDINGS: Uptake and endocytosis inhibitor assays indicated that the developed NPs acquired size and surface charges that efficiently target macropinocytosis of MCF-7 cells. Paclitaxel-loaded PLGA-NPs showed higher efficacy against MCF-7 cells, while providing no toxicity on normal MCF-10A cells. Metabolomics analysis indicated the nutrients deprivation because of occupying the macropinocytosis. However, treatment of fresh MCF-7 cancer cells by metabolites secreted from PLGA-NPs-treated MCF-7 cells showed a potential metastatic activity. Thus, co- administration with an anti-metastatic drug is advised. SIGNIFICANCE: Collectively, adjusting the size and surface characteristics of a drug can critically control its cellular uptake, affecting the efficacy of drugs and the microenvironment of cancer cells.
Subject(s)
Breast Neoplasms , Nanoparticles , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Humans , MCF-7 Cells , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Polylactic Acid-Polyglycolic Acid Copolymer , Tumor MicroenvironmentABSTRACT
The field of cancer research has massively grown in recent decades, leading to a better understanding of the underlying causes and greatly improving the therapeutic approaches. Breast cancer (BC) is the third leading cause of mortality among all cancers and the most common malignant disease in women worldwide, representing one in four of all cancers in women. The crosstalk between cancer cells and the surrounding microenvironment is crucial for tumor progression and metastatic process. Tumor cells communicate not only through classical paracrine signaling mechanisms, including cytokines, chemokines, growth factors, but also through "exosomes". Exosomes are nano-vesicles that are released by various types of cells. Over the last decade, researchers have been attracted by the role of exosomes in breast cancer. It has been proven that exosomes influence major tumor-related pathways, including invasion, migration, epithelial-to-mesenchymal transition (EMT), metastasis, and drug resistance. Additionally, exosomes play important roles in clinical applications. Several studies have demonstrated the potential applications of exosomes in cancer therapy and diagnosis. Furthermore, exosomes have been engineered to function as nano-delivery systems of chemotherapeutic drugs. They can also be designed as vaccines to trigger the patient's immune system. This review discusses the recent progress regarding the use of exosomes as drug delivery systems, therapeutic agents, biomarkers, and vaccines against breast cancer.
Subject(s)
Breast Neoplasms , Exosomes , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Female , Humans , Tumor MicroenvironmentABSTRACT
Expansion of COVID-19 worldwide increases interest in unraveling genomic variations of novel SARS-CoV-2 virus. Metadata of 408,493 SARS-CoV-2 genomes submitted to GISAID database were analyzed with respect to genomic clades and their geographic, age, and gender distributions. Of the currently known SARS-CoV-2 clades, clade GR was the most prevalent worldwide followed by GV then GH. Chronological analysis revealed expansion in SARS-CoV-2 clades carrying D614G mutations with the predominance of the newest clade, GV, in the last three months. D614G clades prevail in countries with more COVID-19 cases. Of them, the clades GH and GR were more frequently recovered from severe or deceased COVID-19 cases. In contrast, G and GV clades showed a significantly higher prevalence among asymptomatic patients or those with mild disease. Metadata analysis showed higher (p < 0.05) prevalence of severe/deceased cases among males than females and predominance of GR clade in female patients. Furthermore, severe disease/death was more prevalent (p < 0.05) in elderly than in adults/children. Higher prevalence of the GV clade in children compared to other age groups was also evident. These findings uniquely provide a statistical evidence on the adaptation-driven evolution of SARS-CoV-2 leading to altered infectivity, virulence, and mortality.
Subject(s)
COVID-19/pathology , SARS-CoV-2/genetics , Adult , Age Factors , Aged , COVID-19/epidemiology , COVID-19/virology , Child , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus RNA-Dependent RNA Polymerase/genetics , Databases, Factual , Europe/epidemiology , Female , Humans , Male , Middle Aged , Mutation , North America/epidemiology , SARS-CoV-2/isolation & purification , Sex Factors , Spike Glycoprotein, Coronavirus/genetics , Viral Nonstructural Proteins/geneticsABSTRACT
Malaria remains the biggest threat to public health, especially among pregnant women and young children in sub-Saharan Africa. Prompt and accurate diagnosis is critical for effective case management and detection of drug resistance. Conventionally, microscopy and rapid diagnostic tests (RDTs) are the tools of choice for malaria diagnosis. RDTs are simple to use and have been extensively used in the diagnosis of malaria among travelers to malaria-endemic regions, routine case management, and surveillance studies. Most RDTs target the histidine-rich protein (PfHRP) which is exclusively found in Plasmodium falciparum and a metabolic enzyme Plasmodium lactate dehydrogenase (pLDH) which is common among all Plasmodium species. Other RDTs incorporate the enzyme aldolase that is produced by all Plasmodium species. Recently, studies have reported false-negative RDTs primarily due to the deletion of the histidine-rich protein (pfhrp2 and pfhrp3) genes in field isolates of P. falciparum. Herein, we review published literature to establish pfhrp2/pfhrp3 deletions, the extent of these deletions in different geographical regions, and the implication in malaria control. We searched for publications on pfhrp2/pfhrp3 deletions and retrieved all publications that reported on this subject. Overall, 20 publications reported on pfhrp2/pfhrp3 deletions, and most of these studies were done in Central and South America, with very few in Asia and Africa. The few studies in Africa that reported on the occurrence of pfhrp2/pfhrp3 deletions rarely evaluated deletions on the flanking genes. More studies are required to evaluate the existence and extent of these gene deletions, whose presence may lead to delayed or missed treatment. This information will guide appropriate diagnostic approaches in the respective areas.
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The current study was conducted to isolate and identify multidrug-resistant Staphylococcus aureus (MDR-SA) from mastitis milk samples and to determine their antimicrobial susceptibility pattern. A total of 48 bovine mastitis (BM) milk samples were collected from different parts of the Rangpur division, Bangladesh. After the collection of milk samples, mastitis was confirmed using the California mastitis test. Isolation and identification of Staphylococcus aureus were performed using conventional cultural and biochemical tests as well as using molecular methods of PCR. Nucleotide sequence analysis of the 23S rRNA gene of Staphylococcus aureus was determined. The antibiogram of the isolated bacteria was conducted using the disc diffusion method. Phylogenetic analysis of 23S rRNA was done using MEGA 7, ClustalW multiple sequence alignment, and NCBI-BLAST tools, where the sequence of the isolate showed 98% to 99% identity. Antibiogram test using 15 antimicrobial agents showed that all of the Staphylococcus aureus isolates were classified as multidrug-resistant (MDR). It was found that the isolates were resistant to tetracycline, novobiocin, methicillin, vancomycin, and cephradine, and the isolates were sensitive to ciprofloxacin, azithromycin, norfloxacin, levofloxacin, gentamicin, and amoxicillin. The detection of MDR-SA in mastitis milk is alarming and represents a great public health concern. The findings of the present study help identify Staphylococcus aureus at the molecular level using 23S rRNA gene sequencing and will help select the appropriate and effective antimicrobial agent to control BM in the northern part of Bangladesh.
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Emerging and re-emerging viral diseases are of great public health concern. The recent emergence of Severe Acute Respiratory Syndrome (SARS) related coronavirus (SARS-CoV-2) in December 2019 in China, which causes COVID-19 disease in humans, and its current spread to several countries, leading to the first pandemic in history to be caused by a coronavirus, highlights the significance of zoonotic viral diseases. Rift Valley fever, rabies, West Nile, chikungunya, dengue, yellow fever, Crimean-Congo hemorrhagic fever, Ebola, and influenza viruses among many other viruses have been reported from different African countries. The paucity of information, lack of knowledge, limited resources, and climate change, coupled with cultural traditions make the African continent a hotspot for vector-borne and zoonotic viral diseases, which may spread globally. Currently, there is no information available on the status of virus diseases in Africa. This systematic review highlights the available information about viral diseases, including zoonotic and vector-borne diseases, reported in Africa. The findings will help us understand the trend of emerging and re-emerging virus diseases within the African continent. The findings recommend active surveillance of viral diseases and strict implementation of One Health measures in Africa to improve human public health and reduce the possibility of potential pandemics due to zoonotic viruses.
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Multidrug resistant (MDR) Salmonella are a leading cause of foodborne diseases and serious human health concerns worldwide. In this study we detected MDR Salmonella in broiler chicken along with the resistance genes and class 1 integron gene intl1. A total of 100 samples were collected from broiler farms comprising 50 cloacal swabs, 35 litter and 15 feed samples. Overall prevalence of Salmonella was 35% with the highest detected in cloacal swabs. Among the Salmonella, 30 isolates were confirmed as S. enterica serovar Typhimurium using molecular methods of PCR. Disk diffusion susceptibility test revealed that all the Salmonella were classified as MDR with the highest resistance to tetracycline (97.14%), chloramphenicol (94.28%), ampicillin (82.85%) and streptomycin (77.14%). The most prevalent resistance genotypes were tetA (97.14%), floR (94.28%), blaTEM-1 (82.85%) and aadA1 (77.14%). In addition, among the MDR Salmonella, 20% were positive for class 1 integron gene (intl1). As far as we know, this is the first study describing the molecular basis of antibiotic resistance in MDR Salmonella from broiler farms in Bangladesh. In addition to tetA, floR, blaTEM-1, aadA1 and intl1 were also detected in the isolated MDR Salmonella. The detection of MDR Salmonella in broiler chicken carrying intl1 is of serious public health concern because of their zoonotic nature and possibilities to enter into the food chain.
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BACKGROUND: Echinococcus granulosus is causative agent of cystic echinococcosis (CE), which has a cosmopolitan distribution. The current methods for the treatment of human CE include surgery. Therefore, the development of new scolicidal agents with low side effects and more efficacies is an urgent need. PURPOSE: The present study aimed to compare the scolicidal efficacies of silver, iron, copper, silica and zinc oxide nanoparticles (NPs) against hydatid cyst protoscolices in vitro. METHODS: Hydatid cysts of sheep liver and lung were collected. The cyst fluid containing protoscolices was aspirated aseptically. The scolicidal activities of the silver, iron, copper, silica and zinc nanoparticles (Ag-NP, Fe-NP, Cu-NP, Si-NP and Zn-NP) were tested at different concentrations of 0.25, 0.5 and 1 mg/mL following 10, 30 and 60 min of incubation in triplicate. Viability of protoscolices was confirmed by 0.1% eosin staining. RESULTS: Results showed that Ag-NPs at all concentrations tested had the highest scolicidal effect. Ag-NPs at 1 mg/mL concentration after 60 min of exposure time showed 80% mortality rate. Si-NPs had the high scolicidal activity at 1 mg/mL concentration (52.33%), Cu-NPs at 0.5 mg/mL concentration (41%), Fe-NPs at 1mg/mL concentration (28%) and Zn-NPs at concentration of 1mg/mL after 60 mins (15.67%). CONCLUSION: The findings of the present study showed that Ag-NPs, Fe-NPs, Cu-NPs, Si-NPs and Zn-NPs had potent scolicidal effects and that Ag-NPs are recommended as effective scolicidal agents. However, further in vivo studies are required to evaluate the efficacy of these nanoparticles.
Subject(s)
Anticestodal Agents/pharmacology , Echinococcosis/drug therapy , Echinococcus granulosus/drug effects , Metal Nanoparticles/therapeutic use , Animals , Anticestodal Agents/chemistry , Echinococcosis/parasitology , Echinococcosis, Hepatic/drug therapy , Echinococcosis, Hepatic/parasitology , Echinococcosis, Pulmonary/drug therapy , Echinococcosis, Pulmonary/parasitology , Echinococcus granulosus/pathogenicity , Metal Nanoparticles/chemistry , SheepABSTRACT
Houseflies (Musca domestica) are well-known mechanical vectors for spreading multidrug-resistant bacteria. Fish sold in open markets are exposed to houseflies. The present study investigated the prevalence and antibiotypes of multidrug-resistant (MDR) Salmonella spp. in houseflies captured from a fish market. Direct interviews with fish vendors and consumers were also performed to draw their perceptions about the role of flies in spreading antibiotic-resistant bacteria. A total of 60 houseflies were captured from a local fish market in Bangladesh. The presence of Salmonella spp. was confirmed using PCR method. Antibiogram was determined by the disk diffusion method, followed by the detection of tetA, tetB, and qnrA resistance genes by PCR. From the interview, it was found that most of the consumers and vendors were not aware of antibiotic resistance, but reported that flies can carry pathogens. Salmonella spp. were identified from the surface of 34 (56.7%) houseflies, of which 31 (91.2%) were found to be MDR. This study revealed 25 antibiotypes among the isolated Salmonella spp. All tested isolates were found to be resistant to tetracycline. tetA and tetB were detected in 100% and 47.1% of the isolates, respectively. Among the 10 isolates phenotypically found resistant to ciprofloxacin, six (60%) were found to be positive for qnrA gene. As far as we know, this is the first study from Bangladesh to report and describe the molecular detection of multidrug-resistant Salmonella spp. in houseflies in a fish market facility. The occurrence of a high level of MDR Salmonella in houseflies in the fish market is of great public health concerns.
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We report the genome sequence of Brucella abortus biovar 3 strain BAU21/S4023, isolated from a dairy cow that suffered an abortion in Savar, Dhaka, Bangladesh. The genome sequence length is 3,244,234 bp with a 57.2% GC content, 3,147 coding DNA sequences (CDSs), 51 tRNAs, 1 transfer messenger RNA (tmRNA), and 3 rRNA genes.
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Zoonoses present a major public health threat and are estimated to account for a substantial part of the infectious disease burden in low-income countries. The severity of zoonotic diseases is compounded by factors such as poverty, living in close contact with livestock and wildlife, immunosuppression as well as coinfection with other diseases. The interconnections between humans, animals and the environment are essential to understand the spread and subsequent containment of zoonoses. We searched three scientific databases for articles relevant to the epidemiology of bacterial zoonoses/zoonotic bacterial pathogens, including disease prevalence and control measures in humans and multiple animal species, in various African countries within the period from 2008 to 2018. The review identified 1966 articles, of which 58 studies in 29 countries met the quality criteria for data extraction. The prevalence of brucellosis, leptospirosis, Q fever ranged from 0-40%, 1.1-24% and 0.9-28.2%, respectively, depending on geographical location and even higher in suspected outbreak cases. Risk factors for human zoonotic infection included exposure to livestock and animal slaughters. Dietary factors linked with seropositivity were found to include consumption of raw milk and locally fermented milk products. It was found that zoonoses such as leptospirosis, brucellosis, Q fever and rickettsiosis among others are frequently under/misdiagnosed in febrile patients seeking treatment at healthcare centres, leading to overdiagnoses of more familiar febrile conditions such as malaria and typhoid fever. The interactions at the human-animal interface contribute substantially to zoonotic infections. Seroprevalence of the various zoonoses varies by geographic location and species. There is a need to build laboratory capacity and effective surveillance processes for timely and effective detection and control of zoonoses in Africa. A multifaceted 'One Health' approach to tackle zoonoses is critical in the fight against zoonotic diseases. The impacts of zoonoses include.
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Estrogen (E2) plays a central role in the development and progression of hormone-responsive cancers. Estrogen metabolites exhibit either stimulatory or inhibitory roles on breast and prostate cells. The catechol metabolite 4-hydroxyestradiol (4-OHE2) enhances cell proliferation, while 2-methoxyestradiol (2â¯ME) possesses anticancer activity. The major metabolizing enzyme responsible for detoxifying the deleterious metabolite 4-OHE2 and forming the anticancer metabolite 2â¯ME is Catechol-O-Methyl Transferase (COMT). The current work investigated the relationship between the expression level of COMT and the cell proliferation of hormone-responsive cancers. The results showed that COMT silencing enhanced the cell proliferation of ER-α positive cancer cells MCF-7 and PC-3 but not the cells that lack ER-α expression as MDA-MB231 and DU-145. The data generated from our study provides a better understanding of the effect of COMT on critical signaling pathways involved in the development and progression of breast cancer (BC) and prostate cancer (PC) including ER-α, p21cip1, p27kip1, NF-κB (P65) and CYP19A1. These findings suggest that COMT enzyme plays a tumor suppressor role in hormone receptor-positive tumors which opens the door for future studies to validate COMT expression as a novel biomarker for the prediction of cancer aggressiveness and treatment efficacy.
Subject(s)
Breast Neoplasms/pathology , Catechol O-Methyltransferase/metabolism , Gene Knockdown Techniques , Hormones/pharmacology , Prostatic Neoplasms/pathology , 2-Methoxyestradiol/pharmacology , Aromatase/genetics , Aromatase/metabolism , Catechols/pharmacology , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Docetaxel/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing/drug effects , Humans , Male , Nitriles/pharmacology , Phosphorylation/drug effects , RNA, Small Interfering/metabolism , Receptors, Estrogen/metabolism , Transcription Factor RelA/metabolismABSTRACT
Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other ß-lactam antibiotics, the principal antibacterial/bactericidal activity of cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its siderophore-like property and has enhanced stability to ß-lactamases. The chemical structure of cefiderocol is similar to both ceftazidime and cefepime, which are third- and fourth-generation cephalosporins, respectively, but with high stability to a variety of ß-lactamases, including AmpC and extended-spectrum ß-lactamases (ESBLs). Cefiderocol has a pyrrolidinium group in the side chain at position 3 like cefepime and a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus like ceftazidime. The major difference in the chemical structures of cefiderocol, ceftazidime and cefepime is the presence of a catechol group on the side chain at position 3. Together with the high stability to ß-lactamases, including ESBLs, AmpC and carbapenemases, the microbiological activity of cefiderocol against aerobic Gram-negative bacilli is equal to or superior to that of ceftazidime-avibactam and meropenem, and it is active against a variety of Ambler class A, B, C and D ß-lactamases. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem versus Acinetobacter baumannii, including meropenem non-susceptible and multidrug-resistant (MDR) isolates. Cefiderocol's activity against meropenem-non-susceptible and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriales is comparable or superior to ceftazidime-avibactam. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem against all resistance phenotypes of Pseudomonas aeruginosa and against Stenotrophomonas maltophilia. The current dosing regimen being used in phase III studies is 2 g administered intravenously every 8 h (q8 h) using a 3-h infusion. The pharmacokinetics of cefiderocol are best described by a three-compartment linear model. The mean plasma half-life (t½) was ~ 2.3 h, protein binding is 58%, and total drug clearance ranged from 4.6-6.0 L/h for both single- and multi-dose infusions and was primarily renally excreted unchanged (61-71%). Cefiderocol is primarily renally excreted unchanged and clearance correlates with creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC). In vivo efficacy of cefiderocol has been studied in a variety of humanized drug exposure murine and rat models of infection utilizing a variety of MDR and extremely drug resistant strains. Cefiderocol has performed similarly to or has been superior to comparator agents, including ceftazidime and cefepime. A phase II prospective, multicenter, double-blind, randomized clinical trial assessed the safety and efficacy of cefiderocol 2000 mg q8 h versus imipenem/cilastatin 1000 mg q8 h, both administered intravenously for 7-14 days over 1 h, in the treatment of complicated urinary tract infection (cUTI, including pyelonephritis) or acute uncomplicated pyelonephritis in hospitalized adults. A total of 452 patients were initially enrolled in the study, with 303 in the cefiderocol arm and 149 in the imipenem/cilastatin arm. The primary outcome measure was a composite of clinical cure and microbiological eradication at the test-of-cure (TOC) visit, that is, 7 days after the end of treatment in the microbiological intent-to-treat (MITT) population. Secondary outcome measures included microbiological response per pathogen and per patient at early assessment (EA), end of treatment (EOT), TOC, and follow-up (FUP); clinical response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concentrations of cefiderocol; and the number of participants with adverse events. The composite of clinical and microbiological response rates was 72.6% (183/252) for cefiderocol and 54.6% (65/119) for imipenem/cilastatin in the MITT population. Clinical response rates per patient at the TOC visit were 89.7% (226/252) for cefiderocol and 87.4% (104/119) for imipenem/cilastatin in the MITT population. Microbiological eradication rates were 73.0% (184/252) for cefiderocol and 56.3% (67/119) for imipenem/cilastatin in the MITT population. Additionally, two phase III clinical trials are currently being conducted by Shionogi & Co., Ltd., Japan. The two trials are evaluating the efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens and evaluating the efficacy of cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-associated pneumonia or healthcare-associated pneumonia caused by Gram-negative pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. Cefiderocol appears to be well positioned to help address the increasing number of infections caused by carbapenem-resistant and MDR Gram-negative bacilli, including ESBL- and carbapenemase-producing strains (including metallo-ß-lactamase producers). A distinguishing feature of cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.