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Circulation Dec 2023The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of...
BACKGROUND
The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation.
METHODS
We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed.
RESULTS
We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5 mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5/Atf4), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes.
CONCLUSIONS
These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.
Topics: Humans; Mice; Animals; Myocytes, Cardiac; Doxycycline; Cells, Cultured; Induced Pluripotent Stem Cells; RNA, Small Interfering; Protein Biosynthesis; Cell Proliferation; Regeneration; Mitochondrial Proteins
PubMed: 37905452
DOI: 10.1161/CIRCULATIONAHA.122.061192 -
The New England Journal of Medicine Dec 2023Doxycycline postexposure prophylaxis (PEP) has been shown to prevent sexually transmitted infections (STIs) among cisgender men and transgender women, but data from... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Doxycycline postexposure prophylaxis (PEP) has been shown to prevent sexually transmitted infections (STIs) among cisgender men and transgender women, but data from trials involving cisgender women are lacking.
METHODS
We conducted a randomized, open-label trial comparing doxycycline PEP (doxycycline hyclate, 200 mg taken within 72 hours after condomless sex) with standard care among Kenyan women 18 to 30 years of age who were receiving preexposure prophylaxis against human immunodeficiency virus (HIV). The primary end point was any incident infection with , , or . Hair samples were collected quarterly for objective assessment of doxycycline use.
RESULTS
A total of 449 participants underwent randomization; 224 were assigned to the doxycycline-PEP group and 225 to the standard-care group. Participants were followed quarterly over 12 months. A total of 109 incident STIs occurred (50 in the doxycycline-PEP group [25.1 per 100 person-years] and 59 in the standard-care group [29.0 per 100 person-years]), with no significant between-group difference in incidence (relative risk, 0.88; 95% confidence interval [CI], 0.60 to 1.29; P = 0.51). Among the 109 incident STIs, chlamydia accounted for 85 (78.0%) (35 in the doxycycline-PEP group and 50 in the standard-care group; relative risk, 0.73; 95% CI, 0.47 to 1.13). No serious adverse events were considered by the trial investigators to be related to doxycycline, and there were no incident HIV infections. Among 50 randomly selected participants in the doxycycline-PEP group, doxycycline was detected in 58 of 200 hair samples (29.0%). All -positive isolates were resistant to doxycycline.
CONCLUSIONS
Among cisgender women, the incidence of STIs was not significantly lower with doxycycline PEP than with standard care. According to hair-sample analysis, the use of doxycycline PEP among those assigned to receive it was low. (Funded by the National Institutes of Health; dPEP ClinicalTrials.gov number, NCT04050540.).
Topics: Female; Humans; Chlamydia Infections; Chlamydia trachomatis; Doxycycline; HIV Infections; Kenya; Neisseria gonorrhoeae; Pre-Exposure Prophylaxis; Sexually Transmitted Diseases; Unsafe Sex; Anti-Infective Agents; Adolescent; Young Adult; Adult; Gonorrhea; Treponema pallidum; Syphilis; Drug Monitoring; Hair
PubMed: 38118022
DOI: 10.1056/NEJMoa2304007 -
Pediatrics Jul 2023The use of antibiotics in young children is widespread and may lead to adverse effects on dental health, including staining, developmental defects, and dental caries.
CONTEXT
The use of antibiotics in young children is widespread and may lead to adverse effects on dental health, including staining, developmental defects, and dental caries.
OBJECTIVE
To systematically review the effects of early childhood antibiotic exposure on dental health.
DATA SOURCES
Medline (Ovid/PubMed), Embase (Ovid) and Cochrane databases. Study bias was assessed using the Newcastle-Ottawa Scale.
STUDY SELECTION
English language articles that reported antibiotic exposure before 8 years of age and 1 or more of the relevant outcomes (dental caries, intrinsic tooth staining, or developmental defects of enamel) were included.
DATA EXTRACTION
Data on study population, design, type of antibiotic, outcome measurement, and results were extracted from the identified studies.
RESULTS
The initial search yielded 1003 articles of which 34 studies were included. Five of the 18 studies on tetracycline described a dose response relationship between exposure to tetracycline doses of > 20 mg/kg per day and dental staining. Early childhood exposure to doxycycline (at any dose) was not associated with dental staining. There was no clear association between any early childhood antibiotic exposure and dental caries or enamel defects.
LIMITATIONS
In all included studies, the main limitations and sources of bias were the lack of comparison groups, inconsistent outcome measures, and lack of adjustment for relevant confounders.
CONCLUSIONS
There was no evidence that newer tetracycline formulations (doxycycline and minocycline) at currently recommended dosages led to adverse effects on dental health. Findings regarding antibiotic exposure and developmental defects of enamel or dental caries were inconsistent. Further prospective studies are warranted.
Topics: Child; Child, Preschool; Humans; Infant; Anti-Bacterial Agents; Doxycycline; Dental Caries; Bias; Databases, Factual
PubMed: 37264510
DOI: 10.1542/peds.2023-061350 -
European Journal of Pharmacology Oct 2023In recent years, research on tetracycline antibiotics has gradually shifted from their antibacterial effects to anticancer effects. Doxycycline, minocycline, and... (Review)
Review
In recent years, research on tetracycline antibiotics has gradually shifted from their antibacterial effects to anticancer effects. Doxycycline, minocycline, and tigecycline as the US Food and Drug Administration (FDA) approved tetracycline antibiotics have been the main subjects of studies. Evidence indicated that they have anticancer properties and are able to control cancer progression through different mechanisms, such as anti-proliferation, anti-metastasis, and promotion of autophagy or apoptosis. In addition, studies have shown that these three tetracycline antibiotics can be utilized in conjunction with chemotherapeutic and targeted drugs to inhibit cancer progression and improve the quality of patient survival. Therefore, doxycycline, minocycline, and tigecycline are taken as examples in this work. Their mechanisms of action in different cancers and related combination therapies are introduced. Their current roles in alleviating the suffering of patients undergoing chemotherapy when used as adjuvant drugs in clinical treatment are also described. Finally, the research gaps and potential research directions at this stage are briefly summarized.
Topics: Humans; Doxycycline; Minocycline; Tigecycline; Anti-Bacterial Agents; Antineoplastic Agents; Neoplasms; Heterocyclic Compounds
PubMed: 37541377
DOI: 10.1016/j.ejphar.2023.175949 -
International Journal of STD & AIDS Feb 2024Tyson's glands are sebaceous glands located on each side of the frenulum that communicate with the preputial sac, and their inflammation can be an infrequent...
Tyson's glands are sebaceous glands located on each side of the frenulum that communicate with the preputial sac, and their inflammation can be an infrequent complication of urethritis. We describe a rare case that presented with urethral discharge and parafrenular swelling with mucopurulent discharge a week after an unprotected sexual encounter. The patient was empirically treated with 500 mg of ceftriaxone intramuscularly and 100 mg of doxycycline every 12 h for 14 days with symptomatic resolution. The urethral swab culture and the urine polymerase chain reaction (PCR) were negative for and , therefore, and given the response to treatment, nongonococcal tysonitis was diagnosed.
Topics: Humans; Chlamydia Infections; Urethritis; Chlamydia trachomatis; Neisseria gonorrhoeae; Doxycycline; Gonorrhea
PubMed: 37852285
DOI: 10.1177/09564624231208241 -
Indian Dermatology Online Journal 2023Lyme disease, a tick-borne multisystem disease, is caused by spirochete . It is a common illness in temperate countries, especially the United States, but the incidence... (Review)
Review
Lyme disease, a tick-borne multisystem disease, is caused by spirochete . It is a common illness in temperate countries, especially the United States, but the incidence is increasing across continents due to increasing reforestation, travel and adventure tourism, increased intrusion in the vector habitat, and changing habitat of the vector. Transmission primarily occurs via bite of an infected tick ( spp.). The appearance of an erythema migrans rash following a tick bite is diagnostic of early Lyme disease even without laboratory evidence. Borrelia lymphocytoma and acrodermatitis chronica atrophicans along with multisystem involvement occur in late disseminated and chronic stages. A two-step serologic testing protocol using an enzyme-linked immunosorbent assay (ELISA) followed by confirmation of positive and equivocal results by Western immunoblot is recommended for the diagnosis. Transplacental transmission to infant occurs in the first trimester with possible congenital Lyme disease making treatment imperative during antenatal period. The treatment is most effective in the early stages of the disease, whereas rheumatological, neurological, or other late manifestations remain difficult to treat with antibiotics alone. Treatment with oral doxycycline is preferred for its additional activity against other tick-borne illnesses which may occur concurrently in 10%-15% of cases. New-generation cephalosporins and azithromycin are alternative options in patients with doxycycline contraindications. No vaccine is available and one episode of the disease will not confer life-long immunity; thus, preventive measures remain a priority. The concept of post-Lyme disease syndrome versus chronic Lyme disease remains contested for want of robust evidence favoring benefits of prolonged antibiotic therapy.
PubMed: 37727539
DOI: 10.4103/idoj.idoj_418_22 -
Revista Espanola de Enfermedades... Oct 2023Doxycycline is a bacteriostatic antibiotic of the tetracycline group widely indicated in the treatment of numerous infections (skin, soft tissues...). Given its acid...
Doxycycline is a bacteriostatic antibiotic of the tetracycline group widely indicated in the treatment of numerous infections (skin, soft tissues...). Given its acid nature, doxycycline is able to potentially generate mucous damage acting as a caustic; therefore, when the capsule of doxycycline (high concentrated substance) is taken inappropriately (with a small quantity of liquid or just before laying down) and remains for a longer time in contact with the esophagus, doxycycline may cause esophagitis-type lesions and ulcerations.
PubMed: 37882175
DOI: 10.17235/reed.2023.9989/2023