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Cancer Research Nov 2015Tetracyclines, a class of antibiotics that target bacterial translation, are commonly used in research for inducible gene expression using Tet-ON/Tet-OFF systems.... (Review)
Review
Tetracyclines, a class of antibiotics that target bacterial translation, are commonly used in research for inducible gene expression using Tet-ON/Tet-OFF systems. However, such tetracycline-inducible systems carry a risk. Given that mitochondria have a "bacterial" ancestry, these antibiotics also target mitochondrial translation and impair mitochondrial function. Indeed, treatment with doxycycline-a tetracycline derivative-disturbs mitochondrial proteostasis and metabolic activity, and induces widespread gene-expression changes. Together, this affects physiology in well-established model systems ranging from cultured cells to simple organisms and to mice and plants. These changes are observed with doxycycline doses that are widely used to regulate gene expression. In light of these findings, and bearing in mind the conserved role of mitochondria in metabolism and whole organism homeostasis, we caution against the use of tetracyclines in experimental approaches. The use of newly developed tetracycline-based systems that are more sensitive could be an alternative; however, even if no overt mitochondrial toxicity is detected, widespread changes in gene expression may sensitize cells to the intended tetracycline-controlled loss or gain of function, thereby introducing a "two-hit model." This is highly relevant for cancer research, as mitochondrial metabolism holds a central position in the reallocation of nutrients for biomass production known as the Warburg effect.
Topics: Animals; Anti-Bacterial Agents; Doxycycline; Humans; Mice; Mitochondria; Protein Biosynthesis; Protein Synthesis Inhibitors
PubMed: 26475870
DOI: 10.1158/0008-5472.CAN-15-1626 -
Parasitology Mar 2021There are available data on in vivo studies of monotherapy of zoonotic cutaneous leishmaniasis with some antibacterial drugs (doxycycline) and their comparison with...
There are available data on in vivo studies of monotherapy of zoonotic cutaneous leishmaniasis with some antibacterial drugs (doxycycline) and their comparison with meglumine antimoniate (glucantime). We used golden Syrian hamsters as a laboratory model. Experimental groups were formed, each of which was treated with one of the tested drugs. Infection of animals was carried out with Leishmania major promastigotes. We selected highly virulent strains of L. major culture isolated from human ulcers or rodents. Meglumine antimoniate monotherapy and doxycycline monotherapy are quite effective and do not differ by the 30th day of their use in such indicators as the average degree of local damage and the average number of Leishmania in the lesions. The main differences were recorded in terms of average body weight gain and average clinical recovery in favour of doxycycline. Leishmania in the lesion on the 60th day were completely absent in treatment with doxycycline. The experiment proved the effectiveness of doxycycline monotherapy: Leishmania in the lesions were absolutely absent by the end of the treatment.
Topics: Animals; Antiprotozoal Agents; Disease Models, Animal; Doxycycline; Leishmaniasis, Cutaneous; Mesocricetus; Zoonoses
PubMed: 33190654
DOI: 10.1017/S0031182020002152 -
Scientific Reports Aug 2023Chlamydiosis remains the leading infectious disease and is one of the key factors responsible for the dramatic reduction of koala populations in South-East Queensland...
Chlamydiosis remains the leading infectious disease and is one of the key factors responsible for the dramatic reduction of koala populations in South-East Queensland (SEQ) and New South Wales (NSW) regions of Australia. Possible infection outcomes include blindness, infertility, painful cystitis, and death if left untreated. Studies have reported the treatment efficacy of chloramphenicol and doxycycline, which are the two most commonly administered treatments in diseased koalas, in clinical settings. However, none have directly compared the treatment efficacy of these antibacterials on koala survival. A retrospective study was essential to identify any relationships between the demographical information, and the animals' responses to the current treatment regimens. Associations were explored between six explanatory (sex; maturity; location; clinical signs, treatment; treatment duration) and two outcome variables (survival; post-treatment PCR). Results showed that female koalas had a statistical trend of lower odds of surviving when compared to males (OR = 0.36, p = 0.05). Koalas treated with chloramphenicol for ≥ 28 days had greater odds of surviving than when treated for < 28 days (OR = 8.8, p = 0.02), and those koalas administered doxycycline had greater odds of testing PCR negative when compared to chloramphenicol treatments (OR = 5.45, p = 0.008). There was no difference between the antibacterial treatments (chloramphenicol, doxycycline, and mixed/other) and the survival of koalas. Female koalas had greater odds of exhibiting UGT signs only (OR = 4.86, p < 0.001), and also greater odds of having both ocular and UGT clinical signs (OR = 5.29, p < 0.001) when compared to males. Of the koalas, 28.5% initially had no clinical signs but were PCR positive for C. pecorum. This study enables further understanding of the complex nature between chlamydial infection and response to antibacterial treatment.
Topics: Animals; Male; Female; Phascolarctidae; Retrospective Studies; Doxycycline; Chlamydia; Chlamydia Infections; Anti-Bacterial Agents; Chloramphenicol
PubMed: 37542093
DOI: 10.1038/s41598-023-39832-w -
Annals of Surgery Jul 2020To investigate the effects of local doxycycline administration on skin scarring.
OBJECTIVE
To investigate the effects of local doxycycline administration on skin scarring.
BACKGROUND
Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo.
METHODS
Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue.
RESULTS
A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005).
CONCLUSIONS
Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.
Topics: Animals; Cicatrix; Collagen; Disease Models, Animal; Doxycycline; Female; Injections, Intralesional; Mice; Mice, Inbred C57BL; Tensile Strength; Wound Healing
PubMed: 30585822
DOI: 10.1097/SLA.0000000000003172 -
International Journal of Molecular... Dec 2018Doxycycline (DOX), a derivative of tetracycline, is a broad-spectrum antibiotic that exhibits a number of therapeutic activities in addition to its antibacterial...
Doxycycline (DOX), a derivative of tetracycline, is a broad-spectrum antibiotic that exhibits a number of therapeutic activities in addition to its antibacterial properties. For example, DOX has been used in the management of a number of diseases characterized by chronic inflammation. One potential mechanism by which DOX inhibits the progression of these diseases is by reducing oxidative stress, thereby inhibiting subsequent lipid peroxidation and inflammatory responses. Herein, we tested the hypothesis that DOX directly scavenges reactive oxygen species (ROS) and inhibits the formation of redox-mediated malondialdehyde-acetaldehyde (MAA) protein adducts. Using a cell-free system, we demonstrated that DOX scavenged reactive oxygen species (ROS) produced during the formation of MAA-adducts and inhibits the formation of MAA-protein adducts. To determine whether DOX scavenges specific ROS, we examined the ability of DOX to directly scavenge superoxide and hydrogen peroxide. Using electron paramagnetic resonance (EPR) spectroscopy, we found that DOX directly scavenged superoxide, but not hydrogen peroxide. Additionally, we found that DOX inhibits MAA-induced activation of Nrf2, a redox-sensitive transcription factor. Together, these findings demonstrate the under-recognized direct antioxidant property of DOX that may help to explain its therapeutic potential in the treatment of conditions characterized by chronic inflammation and increased oxidative stress.
Topics: Cell-Free System; Doxycycline; Free Radical Scavengers; HEK293 Cells; Humans; Hydrogen Peroxide; Inflammation; Malondialdehyde; NF-E2-Related Factor 2; Oxidative Stress; Superoxides
PubMed: 30562944
DOI: 10.3390/ijms19124078 -
Trials Jan 2023Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology (CKDu), have been treated with oral prednisolone and doxycycline by physicians in Sri Lanka. This trial assessed the effectiveness of prednisolone and doxycycline based on eGFR changes at 6 months in patients with AIN of unknown aetiology.
METHOD
A randomized clinical trial with a 2 × 2 factorial design for patients presenting with AIN of unknown aetiology (n = 59) was enacted to compare treatments with; A-prednisolone, B-doxycycline, C-both treatments together, and D-neither. The primary outcome was a recovery of patients' presenting renal function to eGFR categories: 61-90 ml/min/1.73m (complete remission- CR) to 31-60 ml/min/1.73m (partial remission- PR) and 0-30 ml/min/1.73m no remission (NR) by 6 months. A secondary outcome was progression-free survival (not reaching < 30 ml/min/1.73m eGFR), by 6-36 months. Analysis was by intention to treat.
RESULTS
Seventy patients compatible with a clinical diagnosis of AIN were biopsied for eligibility; 59 AIN of unknown aetiology were enrolled, A = 15, B = 15, C = 14 and D = 15 randomly allocated to each group. Baseline characteristics were similar between groups. The number of patients with CR, PR and NR, respectively, by 6 months, in group A 3:8:2, group B 2:8:3 and group C 8:5:0 was compared with group D 8:6:1. There were no significant differences found between groups A vs. D (p = 0.2), B vs. D (p = 0.1) and C vs. D (p = 0.4). In an exploratory analysis, progression-free survival in prednisolone-treated (A + C) arms was 0/29 (100%) in comparison to 25/30 (83%) in those not so treated (B + D) arms, and the log-rank test was p = 0.02, whereas no such difference found (p = 0.60) between doxycycline-treated (B + C) arms 27/29 (93%) vs those not so treated (A + D) arms 27/30 (90%).
CONCLUSION
Prednisolone and doxycycline were not beneficial for the earliest presentation of CKDu at 6 months. However, there is a potential benefit of prednisolone on the long-term outcome of CKDu. An adequately powered steroid trial using patients reaching < 30 ml/min/1.73m eGFR by 3 years, as an outcome is warranted for AIN of unknown aetiology.
TRIAL REGISTRATION
Sri Lanka Clinical Trial Registry SLCTR/2014/007, Registered on the 31st of March 2014.
Topics: Humans; Doxycycline; Glucocorticoids; Nephritis, Interstitial; Prednisolone; Renal Insufficiency, Chronic; Sri Lanka
PubMed: 36600250
DOI: 10.1186/s13063-022-07056-4 -
Molecules (Basel, Switzerland) Jul 2021Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus...
Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus replication by cleaving viral polyprotein at various junctions to release viral proteins and cause cytotoxic effects in ZIKV-infected cells. This study characterized the inhibitory effects of doxycycline against ZIKV NS2B-NS3 protease and viral replication in human skin cells. The in silico data showed that doxycycline binds to the active site of ZIKV protease at a low docking energy (-7.8 Kcal/mol) via four hydrogen bonds with the protease residues TYR1130, SER1135, GLY1151, and ASP83. Doxycycline efficiently inhibited viral NS2B-NS3 protease at average human temperature (37 °C) and human temperature with a high fever during virus infection (40 °C). Interestingly, doxycycline showed a higher inhibitory effect at 40 °C (IC50 = 5.3 µM) compared to 37 °C (9.9 µM). The virus replication was considerably reduced by increasing the concentration of doxycycline. An approximately 50% reduction in virus replication was observed at 20 µM of doxycycline. Treatment with 20 µM of doxycycline reduced the cytopathic effects (CPE), and the 40 µM of doxycycline almost eliminated the CPE of human skin cells. This study showed that doxycycline binds to the ZIKV protease and inhibits its catalytic activity at a low micro-molecular concentration range. Treatment of human skin fibroblast with doxycycline eliminated ZIKV infection and protected the cells against the cytopathic effects of the infection.
Topics: Animals; Chlorocebus aethiops; Doxycycline; Fibroblasts; Humans; Serine Endopeptidases; Skin; Vero Cells; Viral Nonstructural Proteins; Viral Proteins; Virus Replication; Zika Virus
PubMed: 34299596
DOI: 10.3390/molecules26144321 -
Advances in Therapy Sep 2016Rosacea is a common, chronic inflammatory skin disease that can present with a variety of signs and symptoms. The potentially simultaneous occurrence of different signs... (Review)
Review
Rosacea is a common, chronic inflammatory skin disease that can present with a variety of signs and symptoms. The potentially simultaneous occurrence of different signs and symptoms is due to different underlying inflammatory pathways, emphasizing the need for complementary treatment approaches. Topical ivermectin cream (10 mg/g) and systemic, oral anti-inflammatory doxycycline (40 mg modified-release) are both approved for the treatment of papulopustular rosacea (PPR). Whether or not a combined therapeutic approach may be more beneficial than monotherapy for patients with PPR remains to be tested. Here, we summarize underlying inflammatory pathways implicated in rosacea and clarify the impact of these two agents on selective pathways during inflammation, due to specific characteristics of their individual mechanisms of action (MoA). Based on the complementary MoA of doxycycline modified-release and ivermectin, a scientific rationale for a combined therapy targeting inflammatory lesions in rosacea is given. We propose that topical ivermectin cream is a promising new candidate as first-line treatment to target the inflammatory lesions of rosacea, which can be used in combination with systemic doxycycline modified-release to provide an optimal treatment approach considering all inflammatory pathways involved in PPR. Funding Galderma.
Topics: Administration, Oral; Administration, Topical; Anti-Inflammatory Agents; Delayed-Action Preparations; Doxycycline; Drug Therapy, Combination; Humans; Inflammation; Ivermectin; Rosacea; Treatment Outcome
PubMed: 27432381
DOI: 10.1007/s12325-016-0380-z -
Annals of Clinical Microbiology and... Sep 2023Urogenital Mycoplasma infections are considered an important public health problem, owing to the presence of antibiotic resistance or decreased susceptibility, the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Urogenital Mycoplasma infections are considered an important public health problem, owing to the presence of antibiotic resistance or decreased susceptibility, the treatment options are limited.
OBJECTIVE
Therefore, this meta-analysis aimed to estimate resistance rates of genital Mycoplasmas to tetracyclines (tetracycline, doxycycline, and minocycline).
METHODS
We searched the relevant published studies in PubMed, Scopus, and Embase until 3, March 2022. All statistical analyses were carried out using the statistical package R.
RESULTS
The 26 studies included in the analysis were performed in 15 countries. In the metadata, the proportions of tetracycline, doxycycline, and minocycline resistance in Mycoplasma and Ureaplasma urogenital isolates were reported 14.2% (95% CI 8.2-23.2%), 5% (95% CI 3-8.1%), and 11.9% (95% CI 6.3-21.5%), respectively. According to the meta-regression, the tetracycline and minocycline resistance rate decreased over time. Although, the doxycycline resistance rate increased over time. There was a statistically significant difference in the tetracyclines resistance rates between different continents/countries (P < 0.05).
CONCLUSION
The prevalence rate and antibiotic susceptibility profiles vary geographically. Therefore, rigorous or improved antimicrobial stewardship, contact tracing, and enhanced intensive surveillance systems are necessitated for preventing the emergence and further spreading of tetracyclines resistance in genital Mycoplasmas.
Topics: Humans; Mycoplasma; Tetracycline; Doxycycline; Minocycline; Anti-Bacterial Agents
PubMed: 37697380
DOI: 10.1186/s12941-023-00628-5 -
Journal of Dentistry Jan 2021To evaluate the incorporation of doxycycline (DOX) into a commercial dental adhesive regarding physicochemical properties, microtensile bond strength (μTBS),...
OBJECTIVES
To evaluate the incorporation of doxycycline (DOX) into a commercial dental adhesive regarding physicochemical properties, microtensile bond strength (μTBS), nanoleakage (NL), nanohardness (NH) and Young's modulus (YM), metalloproteinases (MMP) inhibition, and antibiofilm activity.
METHODS
DOX was incorporated into the adhesive at 0.05, 0.1, 0.5, and 1 wt%. Restored teeth were evaluated for μTBS, NL, NH, and YM after 24 -hs and 1-year of water storage. Biofilms of Streptococcus mutans were grown on top of these adhesives and determined for bacterial viability and amount of biomass. The inhibitory effect on MMP was analyzed by in situ zymography under confocal microscopy.
RESULTS
Adhesives with 0.5 and 1 wt% of DOX presented reduced pH and degree of conversion. The incorporation of DOX did not affect μTBS and hybrid layer YM. The control group (no DOX) had a decrease in μTBS and the densest silver nitrate areas after 1-year storage. Hybrid layer NH values increased with 0.1 wt% DOX compared to control and 1 wt% DOX groups, at 24 -hs. After 1-year storage, NH of 1 wt% DOX adhesive decreased compared to the control group. The 0.5 and 1 wt% concentrations of DOX decreased the bacterial viability and the biofilm biomass. Confocal images suggest an increased MMP inhibition proportional to the percentage of DOX.
CONCLUSION
At any concentration, DOX-doped dental adhesives were able to inhibit MMP activity, diminish nanoleakage, and maintain the resin-dentin bond-strength after 1 year of artificial aging.
CLINICAL SIGNIFICANCE
Doxycycline-doped dental adhesive inhibited metalloproteinases activity and preserved interface bond strength. This formulation has a potential to improve adhesive restorations clinical longevity.
Topics: Biofilms; Dental Bonding; Dental Cements; Dentin; Dentin-Bonding Agents; Doxycycline; Humans; In Vitro Techniques; Materials Testing; Metalloproteases; Molar; Resin Cements; Tensile Strength
PubMed: 33276081
DOI: 10.1016/j.jdent.2020.103550