Gramine sensitizes Klebsiella pneumoniae to tigecycline killing.

BACKGROUND: The presence of plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 and its related variants has been associated with heightened resistance to tigecycline, thus diminishing its effectiveness. In this study, we explored the potential of gramine, a naturally occurring indole alkaloid, as an innovative adjuvant to enhance the treatment of infections caused by K. pneumoniae carrying tmexCD-toprJ-like gene clusters. METHODS: The synergistic potential of gramine in combination with antibiotics against both planktonic and drug-tolerant multidrug-resistant Enterobacterales was evaluated using the checkerboard microbroth dilution technique and time-killing curve analyses. Afterwards, the proton motive force (PMF) of cell membrane, the function of efflux pump and the activity of antioxidant system were determined by fluorescence assay and RT-PCR. The intracellular accumulation of tigecycline was evaluated by HPLC-MS/MS. The respiration rate, bacterial ATP level and the NAD+/NADH ratio were investigated to reveal the metabolism state. Finally, the safety of gramine was assessed through hemolytic activity and cytotoxicity assays. Two animal infection models were used to evaluate the in vivo synergistic effect. RESULTS: Gramine significantly potentiated tigecycline and ciprofloxacin activity against tmexCD1-toprJ1 and its variants-positive pathogens. Importantly, the synergistic activity was also observed against bacteria in special physiological states such as biofilms and persister cells. The mechanism study showed that gramine possesses the capability to augment tigecycline accumulation within cells by disrupting the proton motive force (PMF) and inhibiting the efflux pump functionality. In addition, the bacterial respiration rate, intracellular ATP level and tricarboxylic acid cycle (TCA) were promoted under the treatment of gramine. Notably, gramine effectively restored tigecycline activity in multiple animal infection models infected by tmexCD1-toprJ1 positive K. pneumoniae (RGF105-1). CONCLUSION: This study provides the first evidence of gramine's therapeutic potential as a novel tigecycline adjuvant for treating infections caused by K. pneumoniae carrying tmexCD-toprJ-like gene clusters.

Utilizing the photodynamic properties of curcumin to disrupt biofilms in Cutibacterium acnes: A promising approach for treating acne.

BACKGROUND: The treatment of acne vulgaris is often challenging due to the antibiotic resistance frequently observed in Cutibacterium acnes (C.acnes), a prevalent bacterium linked to this condition. OBJECTIVE: The objective of this research was to examine the impact of curcumin photodynamic therapy (PDT) on the survival of C.acnes and activity of biofilms produced by this microorganism. METHODS: Following the Clinical and Laboratory Standards Institute (CLSI) guidelines, we assessed the drug sensitivity of 25 clinical C.acnes strains to five antibiotics (erythromycin, clindamycin, tetracycline, doxycycline, minocycline) and curcumin by implementing the broth microdilution technique. In addition, we established C.acnes biofilms in a laboratory setting and subjected them to curcumin-PDT(curcumin combined with blue light of 180 J/cm2). Afterwards, we evaluated their viability using the XTT assay and observed them using confocal laser scanning microscopy. RESULTS: The result revealed varying resistance rates among the tested antibiotics and curcumin, with erythromycin, clindamycin, tetracycline, doxycycline, minocycline, and curcumin exhibiting resistance rates of 72 %, 44 %, 36 %, 28 %, 0 %, and 100 %, respectively. In the curcumin-PDT inhibition tests against four representative antibiotic-resistant strains, it was found that the survival rate of all strains of planktonic C. acnes was reduced, and the higher the concentration of curcumin, the lower the survival rate. Furthermore, in the biofilm inhibition tests, the vitality and three-dimensional structure of the biofilms were disrupted, and the inhibitory effect became more significant with higher concentrations of curcumin. CONCLUSION: The results emphasize the possibility of using curcumin PDT as an alternative approach for the treatment of C.acnes, especially in instances of antibiotic-resistant variations and infections related to biofilms.

Comparison of Doxycycline or Minocycline to Sulfamethoxazole-Trimethoprim for Treatment of Stenotrophomonas maltophilia Pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant organism with limited antibiotic treatment options. Minocycline and doxycycline may be appropriate, but clinical data are limited. OBJECTIVE: To compare tetracyclines (minocycline and doxycycline [TCN]) with standard of care, sulfamethoxazole-trimethoprim (TMP-SMZ), in S. maltophilia pneumonia treatment. METHODS: This retrospective, 2-center study evaluated patients treated for S. maltophilia pneumonia with TCN or TMP-SMZ for clinical success, defined as resolution of leukocytosis, fever, and tachypnea. Patients were classified as treatment with TCN or TMP-SMZ based on definitive agent used for ≥50% of the treatment course and ≥4 days. Inclusion criteria were age ≥18 years, S. maltophilia confirmed on respiratory culture from January 2013 to November 2020, and appropriate definitive antibiotic dosing. Pregnancy, incarceration, S. maltophilia-resistant or intermediate to definitive therapy, and combination therapy for treatment of S. maltophilia pneumonia were exclusion criteria. Secondary outcomes were microbiologic success and recurrence or reinfection within 30 days requiring treatment. RESULTS: A total of 80 patients were included (21 TCN [15 minocycline, 6 doxycycline], 59 TMP-SMZ). There was no difference in clinical success (28.6% vs 25.4%; P = 0.994), microbiologic success (n = 28, 55.6% vs 66.4%; P = 0.677), or recurrence or reinfection (n = 24, 66.7% vs 26.7%; P = 0.092) between TCN and TMP-SMZ, respectively. CONCLUSION AND RELEVANCE: Clinical and microbiologic success rates were similar in patients treated with TCN compared with TMP-SMZ for S. maltophilia pneumonia. These data suggest minocycline and doxycycline may be options to treat S. maltophilia pneumonia, but conclusive clinical data continue to be lacking.

A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BACKGROUND: Inflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan. METHODS: 10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months. FINDINGS: Forty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p < 0.01 in those exposed to omega-3. Minocycline did not affect CAARMS or depression scores. INTERPRETATION: In keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation. FUNDING: The study was funded by the Stanley Research Medical Institute.

Tetracycline antibiotics: Potential anticancer drugs.

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.

Clinical Efficacy of Minocycline Hydrochloride for the Treatment of Peri-Implant Disease: A Systematic Review With Meta-Analysis of Randomized Controlled Trials.

This systematic review aimed to assess the clinical efficacy of the local application of minocycline hydrochloride for treating peri-implantitis. Four databases-PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure-were searched from their inception through December 2020. English and Chinese randomized controlled trials (RCTs) that compared minocycline hydrochloride with control regimes, including negative control, iodine solution or glycerin, and chlorhexidine, for patients with peri-implant diseases were retrieved. Three outcomes-plaque index (PLI), probing depth (PD), and sulcus bleeding index (SBI)-were assessed using meta-analysis based on the random-effects model. Fifteen RCTs were included in the present meta-analysis, and results suggested that minocycline hydrochloride significantly affected PLI, PD, or SBI reduction regardless of the type of comparator regime. However, subgroup analyses suggested that minocycline hydrochloride was not superior to chlorhexidine in terms of reduction of PLI (1 week: MD = -0.18, 95% CI = -0.55 to 0.20, P = .36; 4 weeks: MD = -0.08, 95% CI = -0.23 to 0.07, P = .28; 8 weeks: MD = -0.01, 95% CI = -0.18 to 0.16, P = .91) and PD (1 week: MD = 0.07, 95% CI = -0.27 to 0.41, P = .68; 4 weeks: MD = -0.10, 95% CI = -0.43 to 0.24, P = .58; 8 weeks: MD = -0.30, 95% CI = -0.68 to 0.08, P = .12), and minocycline hydrochloride was also not better than chlorhexidine regarding reduction of SBI at 1 week after treatment (MD = -0.10; 95% CI = -0.21 to 0.01; P = .08). This study concludes that minocycline hydrochloride as adjuvant therapy of nonsurgical treatment enhances the clinical results when compared to control regimes. However, the difference between minocycline hydrochloride and chlorhexidine should be further investigated by designing additional high-quality studies with large sample sizes.

In vitro and in vivo efficacy of minocycline-based therapy for Elizabethkingia anophelis and the impact of reduced minocycline susceptibility.

OBJECTIVES: Elizabethkingia anophelis is inherently resistant to multiple antibiotics, except minocycline. This study aimed to determine the in vitro and in vivo efficacy of minocycline monotherapy and combination therapy against susceptible strains and the impact of reduced minocycline susceptibility. METHODS: Three clinical isolates and one laboratory-induced mutant with reduced minocycline susceptibility were included. Time-kill and checkerboard assays were used to assess in vitro efficacy and synergy, respectively. Galleria mellonella infection and mouse pneumonia models were used to assess in vivo efficacy, and a mouse thigh infection model was used to determine the bacterial load. RESULTS: Minocycline monotherapy exerted a modest inhibitory effect on three clinical minocycline-susceptible E. anophelis isolates in vitro, but delayed G. mellonella death and improved infected mouse survival; it also significantly reduced the in vivo bacterial load. Minocycline had decreased efficacy on G. mellonella and mice infected by the mutant with reduced minocycline susceptibility. Genome comparison revealed several spontaneous mutations associated with reduced minocycline susceptibility. Among eight antibiotics tested in combination with minocycline, rifampin consistently showed in vitro synergy. The addition of rifampin (1 mg/L) reduced the mutant prevention concentration of minocycline from 2-4 mg/L to < 0.5 mg/L. However, compared with monotherapy, the combination of rifampin and minocycline did not further reduce the bacterial load or improve the survival of G. mellonella or mice. CONCLUSION: Minocycline monotherapy was in vivo effective against susceptible E. anophelis. Reduced minocycline susceptibility due to spontaneous mutation decreased its therapeutic efficacy. In combination with rifampin, it prevented the in vitro emergence of reduced susceptibility but did not provide additional in vivo survival benefit.

Abalone-Inspired Adhesive and Photo-Responsive Microparticle Delivery Systems for Periodontal Drug Therapy.

Antibiotics provide promising strategies for treating periodontitis, while their delivery and controllable release with desired oral retention remain challenging. Here, inspired by the unique suction-cup structures of abalones, a novel adhesive and photo-responsive microparticle (MP) delivery system is developed to treat periodontitis through microfluidic electrospray technology. Such MPs are generated by quickly ionic cross-linking of sodium alginate together with photo-curing of poly(ethylene glycol) diacrylate of the distorted microfluidic droplets during their high-speed dropping into calcium chloride solution. Attributing to their unique concave structures, the abalone-inspired MPs exhibit desired underwater adhesion ability and stability under running water. In addition, due to the loading of antibiotics minocycline hydrochloride and near-infrared (NIR)-responsive black phosphorus during their fabrication, the resultant MPs can not only eradicate bacteria directly, but also realize a controllable and effective drug release upon NIR irradiation. Based on these features, it is demonstrated from in vivo periodontitis that the abalone-inspired MPs are firmly adhesive and can controlled-release drugs on the tooth, and thus have outstanding antibacterial efficacy against Porphyromonas gingivalis. These results indicate the particular values of the abalone-inspired MPs for oral-related disease treatment.

The clinical efficacy of minocycline mouth rinse on recurrent aphthous stomatitis-A randomized controlled trial.

Introduction: Recurrent aphthous stomatitis (RAS) is one of the most common ulcerative diseases affecting the general population. The present study aimed to evaluate the clinical efficiency of 0.5% minocycline mouth rinse prescribed along with the topical anesthetic gel and vitamin supplement over the topical anesthetic gel and vitamin supplement prescribed alone for treating RAS. Materials and Methods: A total of 60 participants were randomly divided into two groups-experimental group: 0.5% minocycline mouth rinse prescribed along with vitamin supplement and topical anesthetic gel; and control group: vitamin supplement and topical anesthetic gel alone. The pain symptoms were evaluated using the VAS scores at baseline and first follow-up visits. The data were analyzed using Student's t test. Results: A significant reduction in the pain scores was observed in participants using the 0.5% minocycline mouth rinse prescribed along with vitamin supplement and topical anesthetic gel on the first follow-up visit (P = < 0.001). Conclusion: The 0.5% minocycline mouth rinse prescribed along with vitamin supplement and topical anesthetic gel had shown more reduction in the pain symptoms when compared to topical anesthetic gel and vitamin supplement prescribed alone for the treatment of RAS.

Calcinosis in dermatomyositis: Origins and possible therapeutic avenues.

Calcinosis, insoluble calcium compounds deposited in skin and other tissues, is a crippling sequela of dermatomyositis. Prolonged disease associated with ongoing inflammation, ischemia, repetitive trauma, and certain autoantibodies are associated with calcinosis. Herein, we describe potential pathogenic mechanisms including the role of mitochondrial calcification. There are no widely effective treatments for calcinosis. We review available pharmacologic therapies for calcinosis including those targeting calcium and phosphorus metabolism; immunosuppressive/anti-inflammatory therapies; and vasodilators. Mounting evidence supports the use of various formulations of sodium thiosulfate in the treatment of calcinosis. Although the early institution of aggressive immunosuppression may prevent calcinosis in juvenile dermatomyositis, only limited data support improvement once it has developed. Minocycline can be useful particularly for lesions associated with surrounding inflammation. Powerful vasodilators, such as prostacyclin analogs, may have promise in the treatment of calcinosis, but further studies are necessary. Surgical removal of lesions when amenable is our treatment of choice.

Increased Prevalence of Minocycline-Resistant Staphylococcus epidermidis with tet(M) by Tetracycline Use for Acne Treatment.

Staphylococcus epidermidis, a major skin bacterium, can cause opportunistic infections. Use of antimicrobial agents against Cutibacterium acnes for acne treatment becomes a risk factor for emergence of antimicrobial-resistant skin bacteria. In this study, the impact of antimicrobial treatment of acne vulgaris on S. epidermidis antimicrobial resistance was assessed. A total of 344 S. epidermidis strains isolated from patients with acne vulgaris who visited hospital (165 strains) and dermatological clinics (179 strains), respectively, were analyzed. Except for doxycycline, the resistance rates were higher in strains isolated from patients who had used antimicrobials for acne treatment than in those isolated from patients who had not used antimicrobials. The prevalence rates of strains with erm(C) from patients who used macrolides and clindamycin (hospital, 78.0%; clinics, 61.3%) and those of strains with tet(M) from patients who used tetracyclines (hospital, 27.5%; clinics, 42.4%) were significantly higher than those of strains from patients who did not use antimicrobials (p < 0.05). All strains with erm(A) (8/8) and 91.7% strains with erm(C) (156/170) showed high-level resistance to macrolides and clindamycin (MIC ≥256 µg/mL). Furthermore, almost all strains with tet(M) showed resistance to minocycline. Our results showed that the use of antimicrobials for acne treatment may lead to an increased prevalence of antimicrobial-resistant S. epidermidis. In particular, the emergence of minocycline-resistant strains with tet(M) owing to the use of tetracyclines (doxycycline and minocycline) is a critical issue. Appropriate antimicrobial use for acne treatment may be an important strategy to prevent the emergence of antimicrobial-resistant skin bacteria.

Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is a major cause of CRC recurrence and mortality. Several antibiotic drugs have been reported to exert potential anticancer activities, however, whether and how the tetracycline antibiotic minocycline exhibit tumor suppressive effect on CRC remains unknown. Here, we found that minocycline markedly inhibits the epithelial-mesenchymal transition (EMT) process and metastasis of CRC cells both in vitro and in vivo. Using chemical proteomics screening combined with docking analysis and site-directed mutagenesis, we identified LYN as a direct bind target of minocycline, and Ala255 of LYN is required for minocycline binding. Mechanistically, minocycline binding inactivates LYN, leading to STAT3 inactivation and EMT suppression, thereby inhibits CRC metastasis. Tissue microarray analysis further confirmed the clinical relevance of LYN-STAT3 axis in the EMT and progression of CRC. In addition to CRC, minocycline also significantly prevents EMT process and inhibits the metastasis of several other cancer types. Our findings elucidate the mechanism of action of minocycline for the inhibition of CRC metastasis by LYN binding, and suggest that repurposing minocycline may represent a promising strategy for the treatment of advanced CRC and other cancer types.

In vitro and in vivo comparison of eravacycline- and tigecycline-based combination therapies for tigecycline-resistant Acinetobacter baumannii.

Several antimicrobial combination therapies are used to treat multiple drug resistant (MDR) and extensively drug resistant (XDR) Acinetobacter baumannii infections. A novel antibiotic, eravacycline, shows a higher potency than tigecycline. The efficacies of eravacycline-based therapies have not yet been evaluated. We demonstrated the effectiveness of eravacycline- and tigecycline-based combination therapies in XDR and especially tigecycline resistant A. baumannii. Thirteen eligible isolates were selected from 642 non-duplicate Acinetobacter blood isolates from four medical centres in 2010-2014. Tigecycline/imipenem and eravacycline/imipenem combinations were simultaneously effective against some isolates in vitro with fractional inhibitory concentration index of 0.5. In contrast, eravacycline- and tigecycline-based combination therapies provided no additional benefits in mouse survival compared to those for monotherapy. In summary, colistin is still the final resort for XDR-A. baumannii treatment according to the sensitivities. Owning to rapid development of resistance in A. baumannii, novel antibiotics are urgently needed.

Treatment of rosacea during pregnancy.

BACKGROUND: Exacerbation of rosacea may occur during pregnancy and there are multiple associated cases of rosacea fulminans (RF). Treatment during pregnancy poses a significant challenge as many rosacea treatments are contraindicated or have limited evidence regarding potential adverse fetal effects. OBJECTIVE: Review the pregnancy categories of various treatments and develop algorithms for treating pregnant patients with rosacea and RF. METHODS: Rosacea treatments showing efficacy in randomized controlled trials were searched through DailyMed to review pregnancy labelling. Searching the PubMed/MEDLINE database for English articles using keywords "rosacea fulminans AND pregnancy" without publishing-time restrictions yielded 8 articles. We summarized treatments used in cases of RF during pregnancy. RESULTS: Topical ivermectin was more effective than metronidazole, but has a more concerning pregnancy category. Three pregnant women with RF were treated successfully with topical metronidazole in combination with other therapies. Azithromycin is the only oral rosacea therapy that is considered safe for pregnant patients and it has been used to treat RF. CONCLUSIONS: This review highlights the challenging aspects of treating pregnant patients with rosacea, as there is limited pregnancy-related treatment efficacy and safety data. The pregnancy categories of therapeutic options are summarized. Further studies are needed to learn which therapies are effective and safe for use during pregnancy.

Vitiligo: an update on systemic treatments.

Vitiligo is an autoimmune skin condition characterized by depigmented macules and patches, and has a huge psychosocial impact on patients. Treatment of vitiligo aims to prevent the spread of disease and facilitate repigmentation of affected lesions. The mainstay of treatment for unstable vitiligo has been topical agents (corticosteroids, calcineurin inhibitors) and phototherapy. However, systemic treatments are increasingly being shown to have a significant impact on the course of the disease as monotherapy or adjunctive therapy. Of note, oral mini-pulsed corticosteroid therapy, methotrexate, minocycline, ciclosporin, Janus kinase inhibitors and certain supplements have been used in the systemic treatment of vitiligo. We review the underlying evidence supporting the use of each of these systemic treatments.

[Content of prostate small extracorporeal protein in the urine as an index in evaluating the therapeutic effect on chronic prostatitis].

OBJECTIVE: To investigate the clinical value of the prostate small extracorporeal protein (PSEP) level in the urine in evaluating the therapeutic effect on chronic prostatitis (CP). METHODS: Totally 188 CP patients were treated with minocycline and Ningmitai Capsules in our hospital and regularly returned for follow-up examination from November 2017 to November 2018. Based on the results of treatment after 4 and 8 weeks of medication, we divided the patients into a cured, an effective and an ineffective group and compared the contents of PSEP in the urine samples of the three groups of patients before and after treatment. RESULTS: Compared with the baseline, the PSEP content in the urine after 4 weeks of medication was decreased in the cured group (n = 20) (ï¼»3.63 ± 3.81ï¼½ vs ï¼»1.16 ± 0.41ï¼½ ng/ml, P < 0.05), effective group (n = 85) (ï¼»4.13 ± 4.05ï¼½ vs ï¼»2.97 ± 2.89ï¼½ ng/ml, P > 0.05) and ineffective group (n = 83) (ï¼»4.72 ± 2.98ï¼½ vs ï¼»3.74 ± 1.31ï¼½ ng/ml, P > 0.05), and so was that after 8 weeks of treatment in the cured group (n = 48) (ï¼»3.72 ± 3.51ï¼½ vs ï¼»0.89 ± 0.37ï¼½ ng/ml, P < 0.05), effective group (n = 106) (ï¼»4.37 ± 3.93ï¼½ vs ï¼»1.83 ± 0.71ï¼½ ng/ml, P < 0.05) and ineffective group (n = 34) (ï¼»4.61 ± 3.59ï¼½ vs ï¼»3.58 ± 1.15ï¼½ ng/ml, P > 0.05). CONCLUSIONS: The PSEP level in the urine can be used as an index for clinical evaluation of the therapeutic effect on chronic prostatitis.

Magnetic Field Exposure Modulates the Anti-Inflammatory Efficiency of Minocycline in Rats with Peripheral Acute Inflammation.

BACKGROUND AND OBJECTIVE: Microglial activation in spinal cord is key contributor and its inhibition by Minocycline (MCN) can result in anti-inflammatory actions. Effect of pulsed magnetic field (PMF) in living system is a very complex process and many biological and cellular processes can play key roles. In this study aimed to reveal the roles of PMF exposure on anti-inflammatory potentials of MCN treatment by evaluating the inflammatory profiles of either inflamed site or spinal cord. METHODS: In this study, we investigated the anti-inflammatory effects of PMF, MCN or their combination treatments in rats with carrageenan (CG)-induced peripheral inflammation by examining the cardinal signs, hyperalgesia, allodynia, edema and fever. The levels of various inflammation markers (tumor necrosis factor-α), interleukin (IL)-1ß, IL-6, IL-17, IL-4, IL-10, C-C motif chemokine ligand3 (CCL3), C-X-C motif chemokine ligand1 and myeloperoxidase were also measured in paw and spinal cord tissues. RESULTS: CG induced inflammation caused edema, fever, and hypersensitivities. MNC or PMF treatments ameliorated these responses by suppressing pro-inflammatory markers in both inflamed paw and spinal cord. Although anti-hypersensitive, anti-edematous and anti-pyretic actions of MCN or PMF, in combined treatments PMF exposure decreased the anti-hyperalgesic and anti-allodynic actions of MCN treatment. These may be associated with decreases in IL-4 and IL-10 levels and an increase in CCL3 level of spinal cord tissues. CONCLUSION: Present findings support that MCN or PMF has anti-inflammatory properties duo to the down-regulating central microglial and/or peripheral inflammatory markers. Our data showed here, for the first time, PMF exposure may suppress the anti-hypersensitive actions of MCN by modulating microglia function/phenotype and microglial markers.

Diterpenoids and triterpenoids from Triadica rotundifolia and their effects on microglial nitric oxide production.

Four new diterpenoids (1-4), three new triterpenoids (12-14), and seven known diterpenoids (5-11) were obtained from an aqueous EtOH extract of the aerial parts of Triadica rotundifolia. The structures of new compounds were determined by spectroscopic techniques. Their absolute configurations were verified via single-crystal X-ray diffraction data, Mo2(OAc)4 induced electronic circular dichroism (ECD), and ECD calculations. The antineuroinflammatory effects of the isolates were assessed by inhibiting NO production in LPS-induced BV-2 microglial cells. Compared with the positive control minocycline (IC50 = 16.1 µM), compounds 3, 8, 11 showed moderate inhibitory activities with IC50 values of 35.9, 17.0, 31.5 µM, respectively.

Longitudinal multiparametric MRI study of hydrogen-enriched water with minocycline combination therapy in experimental ischemic stroke in rats.

Free radicals are downstream mediators of several cytotoxic cascades contributing to ischemic brain injury. Molecular hydrogen (H2) is an antioxidant potentially useful in the treatment of stroke. Hydrogen is easy to deliver, biologically non-toxic and diffuses freely through all biological structures including the blood-brain barrier and cellular membranes. This study evaluated the efficacy of hydrogen treatments in a rat stroke model compared to vehicle-treated controls using multiparametric MRI and neurological tests. Additionally, comparison of H2 treatment alone was made with H2 combined with minocycline (H2M) treatment (12 rats per group). The primary findings were: i) H2 therapy reduced infarct volume in both H2 and H2M groups compared to controls at 1 and 7 days after stroke, and ii) both H2 and H2M improved neurologic functional recovery on day 7. The secondary outcomes were: iii) H2M treatment attenuated post-stroke hyperperfusion in the hyperacute phase, and iv) H2M markedly minimized white matter injury. In conclusion, this is the first study to use MRI to longitudinally study H2 and H2M treatment on ischemic stroke and the first study to compare H2 treatment combined with another potential stroke therapeutic (H2M).