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Purpose: To evaluate the effect of interleukin-6 (IL-6) inhibitor (tocilizumab) on bacterial infection-associated bone resorption around implants during osseointegration in rabbits. Materials and Methods: At total of 24 male, 9-monthold New Zealand white rabbits were included, and their two mandibular anterior teeth were extracted. Three months after extraction, 24 one-piece Dentium implants (Ø 2.5 mm, intraosseous length of 12 mm) were inserted in the anterior mandible, and the rabbits were divided into four groups (n = 6 per group). Different treatment methods were used in each group: blank control group (BC); only silk ligation (negative control [NC]); silk ligation and injection with minocycline hydrochloride ointment (positive control [PC]); and silk ligation and injection with tocilizumab at 8 mg/kg via the auricle vein (experimental [EP]). Eight weeks later, the animals were sacrificed, and samples were collected and then analyzed using microcomputed tomography (microCT) scanning, immunohistochemical analysis, and histologic analysis. Results: From the microCT measurement, the ratio of the bone volume to the total volume (BV/TV) in the EP group was 67.00% ± 2.72%, which was higher than that in the other three groups (58.85% ± 2.43% in the BC group, 55.72% ± 2.48% in the PC group, and 36.52% ± 3.02% in the NC group). From immunohistochemical analysis, the expression of IL-6 was found to be higher in the NC group than in the BC, PC, and EP groups, but there was no statistical difference between these three groups. Furthermore, the RANKL (receptor activator of nuclear factor-κB ligand) expression was the lowest in the EP group, followed by the BC group, the PC group, and the NC group, which had the highest expression; there was no difference between the NC and PC groups. Upon histologic analysis, significant new bone was found on the implant surfaces in the EP group, sparse and less new bone could be seen in the BC and PC groups, and the most serious bone resorption occurred in the NC group. Conclusions: Tocilizumab, an inhibitor of IL-6, has a certain effect in preventing bone loss around implants caused by bacterial infection during the osseointegration period. [ABSTRACT FROM AUTHOR]

The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.

Minocycline (Min), as an antibiotic, possesses various beneficial properties such as anti-inflammatory, antioxidant, and anti-apoptotic effects. Despite these known qualities, the precise cardioprotective effect and mechanism of Min in protecting against sepsis-induced cardiotoxicity (SIC) remain unspecified. To address this, our study sought to assess the protective effects of Min on the heart. Lipopolysaccharide (LPS) was utilized to establish a cardiotoxicity model both in vivo and in vitro. Min was pretreated in the models. In the in vivo setting, evaluation of heart tissue histopathological injury was performed using hematoxylin and eosin (H&E) staining and TUNEL. Immunohistochemistry (IHC) was employed to evaluate the expression levels of NLRP3 and Caspase-1 in the heart tissue of mice. During in vitro experiments, the viability of H9c2 cells was gauged utilizing the CCK8 assay kit. Intracellular ROS levels in H9c2 cells were quantified using a ROS assay kit. Both in vitro and in vivo settings were subjected to measurement of oxidative stress indexes, encompassing glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Additionglly, myocardial injury markers like lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) activity were quantified using appropriate assay kits. Western blotting (WB) analysis was conducted to detect the expression levels of NOD-like receptor protein-3 (NLRP3), caspase-1, IL-18, and IL-1β, alongside apoptosis-related proteins such as Bcl-2 and Bax, and antioxidant proteins including superoxide dismutase-1 (SOD-1) and antioxidant proteins including superoxide dismutase-1 (SOD-2), both in H9c2 cells and mouse heart tissues. In vivo, Min was effective in reducing LPS-induced inflammation in cardiac tissue, preventing cell damage and apoptosis in cardiomyocytes. The levels of LDH and CK-MB were significantly reduced with Min treatment. In vitro studies showed that Min improved the viability of H9C2 cells, reduced apoptosis, and decreased ROS levels in these cells. Further analysis indicated that Min decreased the protein levels of NLRP3, Caspase-1, IL-18, and IL-1β, while increasing the levels of SOD-1 and SOD-2 both in vivo and in vitro. Min alleviates LPS-induced SIC by suppressing the NLRP3/Caspase-1 signalling pathway in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Adolescence is a critical period for brain development in humans and stress exposure during this time can have lasting eects on behavior and brain development. Social isolation and loneliness are particularly salient stressors that lead to detrimental mental health outcomes particularly in females, although most of the preclinical work on social isolation has been done in male animals. Our lab has developed a model of post-weaning adolescent social isolation that leads to increased drug reward sensitivity and altered neuronal structure in limbic brain regions. The current study utilized this model to determine the impact of adolescent social isolation on a three-chamber social interaction task both during adolescence and adulthood. We found that while post-weaning isolation does not alter social interaction during adolescence (PND45), it has sexspecific eects on social interaction in young adulthood (PND60), potentiating social interaction in male mice and decreasing it in female mice. As early life stress can activate microglia leading to alterations in neuronal pruning, we next examined the impact of inhibiting microglial activation with daily minocycline administration during the first 3 weeks of social isolation on these changes in social interaction. During adolescence, minocycline dampened social interaction in male mice, while having no eect in females. In contrast, during young adulthood, minocycline did not alter the impact of adolescent social isolation in males, with socially isolated males exhibiting higher levels of social interaction compared to their group housed counterparts. In females, adolescent minocycline treatment reversed the eect of social isolation leading to increased social interaction in the social isolation group, mimicking what is seen in naïve males. Taken together, adolescent social isolation leads to sex-specific eects on social interaction in young adulthood and adolescent minocycline treatment alters the eects of social isolation in females, but not [ABSTRACT FROM AUTHOR]

Antibiotics with significant environmental toxicity, e.g., tetracyclines (TCs), are often used in large quantities worldwide, with 50–80% of the applied dose ending up in the environment. This study aimed to investigate the effects of exposure to tetracycline hydrochloride (TC) and minocycline hydrochloride (MIN) on L. minor. Our research evaluated the phytotoxicity of the TCs by analyzing plant growth and biomass and evaluating assimilation pigment levels and fluorescence. The research was extended with the ability potential of duckweed as a tool for removing TCs from water/wastewater. The results demonstrated that both TCs influenced Ir, Iy, biomass, and photosynthetic efficiency. The uptake of TC and MIN by duckweed was proportional to the concentration in the growth medium. The TC was absorbed more readily, reaching up to 8.09 mg × g−1 of dry weight (DW) at the highest concentration (19.2 mg × L−1), while MIN reached 6.01 mg × g−1 of DW. As indicated, the consequences of the influence of TC on plants were slightly smaller, in comparison to MIN, while the plants could biosorb this drug, even at the lowest tested concentration. This study has shown that using plants for drug biosorption can be an effective standalone or complementary method for water and wastewater treatment. [ABSTRACT FROM AUTHOR]

Inflammatory responses and neuronal ferroptosis, which are associated with abnormal accumulation of reactive oxygen species (ROS), exert crucial damaging effects on the brain after intracerebral hemorrhage (ICH). In this study, minocycline (MC)‐loaded cerium oxide nanoparticles (CeO2‐MC) are constructed for combined ICH treatment. Ultra‐small CeO2 (≈5 nm) synthesized via a high‐temperature approach exhibits powerful free‐radical scavenging and iron‐chelating abilities. In vitro experiments demonstrated that CeO2‐MC effectively attenuated the ROS levels in mouse microglial cells and neurons following oxyhemoglobin stimulation. In addition, CeO2‐MC exhibits iron chelation properties and stabilizes the mitochondrial membrane potential, thereby promoting anti‐inflammatory responses and preventing neuronal ferroptosis. In an intracerebral hemorrhage (ICH) mouse model, CeO2‐MC exhibited robust free radical scavenging capabilities and demonstrated the ability to preserve mitochondrial morphology and function, mitigate brain edema, and maintain blood–brain barrier integrity by inhibiting neuroinflammation and ferroptosis. Neurobehavioral tests demonstrated that CeO2‐MC significantly ameliorated spatial learning ability and sensorimotor function after ICH. Consequently, a general strategy using CeO2 nanoparticles to augment the therapeutic efficacy of MC highlights a new perspective for the in‐depth treatment of ICH. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) poses a global threat worldwide causing pandemics, epidemics, and seasonal outbreaks. Annual modification of vaccines is costly due to continual shifts in circulating genotypes, leading to inadequate coverage in low- and middle-income countries like India. Additionally, IAVs are evolving resistance to approved antivirals, necessitating a search for alternative treatments. In this study, the antiviral role of the FDA-approved antibiotic minocycline against IAV strains was evaluated in vitro and in vivo by quantifying viral gene expression by qRT-PCR, viral protein levels by Western blotting, and viral titers. Our findings demonstrate that minocycline at a non-toxic dose effectively inhibits IAV replication, regardless of viral strain or cell line. Its antiviral mechanism operates independently of interferon signaling by targeting the MEK/ERK signaling pathway, which is crucial for the export of viral ribonucleoproteins (vRNPs). Minocycline prevents the assembly and release of infectious viral particles by causing the accumulation of vRNPs within the nucleus. Moreover, minocycline also inhibits IAV-induced late-stage apoptosis, further suppressing viral propagation. The antiviral activity of minocycline against IAVs could offer a promising solution amidst the challenges posed by influenza and the limitations of current treatments. [ABSTRACT FROM AUTHOR]

Background: Acne is the most common skin disorder which is known as a chronic inflammatory disease with psychological burden and reduced quality of life. Objective: The objective of this study is to determine, in a real-world effectiveness and clinical experience in treating acne scars which includes evaluating reduction in depth, diameter, erythema and pigmentation, with an acne scar gel, and to evaluate the effect of the product on quality of life. Methods: Overall, 435 patients were assessed for 90 days. The acne scars were counted and classified as mild, moderate or severe and the type of acne scar was registered. The study participants had gone through both oral and topical treatment for a time range of 1 week to over a month depending on the severity of the scars. They had also gone through medical procedures as per the requirement. The results were assessed at an interval of 30 days to 90 days and were graded between 1-5. Results: Overall facial appearance of atrophic acne scars improved after treatment with acne scar gel. Clinical experience with acne scar gel (in terms of reduction of scar depth, diameter, erythema, and pigmentation), and subject satisfaction (happiness and confidence) score along with the sensation and perception of the skin improved in most subjects. Conclusions: Acne scar gel was effective and safe for treatment of moderate-to-severe acne scars. The acne scar gel can be used as topical treatment for acne scars, thereby reducing the need of procedural treatment for acne scars. [ABSTRACT FROM AUTHOR]

Our study explores the development of collagen membranes with integrated minocycline or irinotecan, targeting applications in tissue engineering and drug delivery systems. Type I collagen, extracted from bovine skin using advanced fibril-forming technology, was crosslinked with glutaraldehyde to create membranes. These membranes incorporated minocycline, an antibiotic, or irinotecan, a chemotherapeutic agent, in various concentrations. The membranes, varying in drug concentration, were studied by water absorption and enzymatic degradation tests, demonstrating a degree of permeability. We emphasize the advantages of local drug delivery for treating high-grade gliomas, highlighting the targeted approach's efficacy in reducing systemic adverse effects and enhancing drug bioavailability at the tumor site. The utilization of collagen membranes is proposed as a viable method for local drug delivery. Irinotecan's mechanism, a topoisomerase I inhibitor, and minocycline's broad antibacterial spectrum and inhibition of glial cell-induced membrane degradation are discussed. We critically examine the challenges posed by the systemic administration of chemotherapeutic agents, mainly due to the blood–brain barrier's restrictive nature, advocating for local delivery methods as a more effective alternative for glioblastoma treatment. These local delivery strategies, including collagen membranes, are posited as significant advancements in enhancing therapeutic outcomes for glioblastoma patients. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) profoundly impacts the central nervous system and significantly affects the lives and health of patients. SCI is characterized by a primary injury and subsequent secondary injury, which includes oxidative stress, inflammation, and apoptosis. Effectively addressing inflammation and apoptosis is crucial for SCI treatment. Minocycline (MnCy), while a widely used anti-inflammatory drug, suffers from limited efficacy in SCI treatments due to its poor targeting capabilities. Our research has identified that folic acid (FA) can improve the targeting of anti-inflammatory agents to macrophages through the activation of folate receptors 1 and 2. Additionally, exosomes derived from bone marrow mesenchymal stem cells (BMSCs) leverage the regenerative properties of stem cells and address the challenge of their low local survival rates. In this study, we engineered FA-modified BMSC-derived exosomes loaded with MnCy (FA-Exo-MnCy). Our in vivo imaging demonstrated that FA-Exo-MnCy specifically accumulates at the injury site, where it exerts a significant anti-inflammatory effect. Pharmacodynamic studies further confirmed that FA-Exo-MnCy effectively reduces both inflammation and apoptosis, showcasing its potential as a promising treatment option for SCI. [ABSTRACT FROM AUTHOR]

Elemental doping is a promising way for enhancing the electrocatalytic activity of metal oxides. Herein, we fabricate Ti/ Ti4O7-CB-Ce anode materials by the modification means of carbon black and cerium co-doped Ti4O7, and this shift effectively improves the interfacial charge transfer rate of Ti4O7 and •OH yield in the electrocatalytic process. Remarkably, the Ti4O7-CB-Ce anode exhibits excellent efficiency of minocycline (MNC) wastewater treatment (100% removal within 20 min), and the removal rate reduces from 100 to 98.5% after five cycles, which is comparable to BDD electrode. •OH and 1O2 are identified as the active species in the reaction. Meanwhile, it is discovered that Ti/ Ti4O7-CB-Ce anodes can effectively improve the biochemical properties of the non-biodegradable pharmaceutical wastewater (B/C values from 0.25 to 0.44) and significantly reduce the toxicity of the wastewater (luminescent bacteria inhibition rate from 100 to 26.6%). This work paves an effective strategy for designing superior metal oxides electrocatalysts. [ABSTRACT FROM AUTHOR]

Tick-borne Encephalitis (TBE) is a zoonotic disease caused by the Tick-borne Encephalitis virus (TBEV), which affects the central nervous system of both humans and animals. Currently, there is no specific therapy for patients with TBE, with symptomatic treatment being the primary approach. In this study, the effects of minocycline (MIN), which is a kind of tetracycline antibiotic, on TBEV propagation and cellular protection in TBEV-infected cell lines were evaluated. Indirect immunofluorescence, virus titers, and RT-qPCR results showed that 48 h post-treatment with MIN, TBEV replication was significantly inhibited in a dose-dependent manner. In addition, the inhibitory effect of MIN on different TBEV multiplicities of infection (MOIs) in Vero cells was studied. Furthermore, the transcriptomic analysis and RT-qPCR results indicate that after incubation with MIN, the levels of TBEV and CALML4 were decreased, whereas the levels of calcium channel receptors, such as RYR2 and SNAP25, were significantly increased. MIN also regulated MAPK-ERK-related factors, including FGF2, PDGFRA, PLCB2, and p-ERK, and inhibited inflammatory responses. These data indicate that administering MIN to TBEV-infected cells can reduce the TBEV level, regulate calcium signaling pathway-associated proteins, and inhibit the MAPK-ERK signaling pathway and inflammatory responses. This research offers innovative strategies for the advancement of anti-TBEV therapy. [ABSTRACT FROM AUTHOR]

Background: Activated microglia release harmful substances to retinal ganglion cells (RGCs), but may also benefit by removing cellular debris and secreting neurotrophic factors. These paradoxical roles remain controversial because the nature and time-course of the injury that defines their role is unknown. The aim of this study was to determine if pharmacological manipulation of microglia to acquire a pro-inflammatory or pro-survival phenotype will exacerbate or enhance neuronal survival after injury.Material and methods: Treated HAP I (highly aggressively proliferating immortalized) microglia were injected into the vitreous or tail vein (T V) of female Sprague-Dawley rats. Retinas were examined at 4-14 days following optic nerve crush (ONC) and the number of surviving RGCs was determined.Results: Injection of untreated HAP I cells resulted in the greater loss of RGCs early after ONC when injected into the vitreous and later after ONC when injected into the T V. LP S activated HAP I cells injected into the vitreous resulted in greater RGC loss with and without injury. When injected into the T V with ONC there was no loss of RGCs 4 days after ONC but greater loss afterwards. Minocycline treated HAP I cells injected into the vitreous resulted in greater RGC survival than untreated HAP I cells. However, when injected into the T V with ONC there was greater loss of RGCs. These results suggest that optic nerve signals attract extrinsic microglia to the retina, resulting in a proinflammatory response.Conclusion: Neuroprotection or cytotoxicity of microglia depends on the type of activation, time course of the injury, and if they act on the axon or cell body. HAPI microglia migrate to the retina or optic nerve following optic nerve injury when injected into the vitreous or tail vein, respectively. Pretreatment with LPS or minocycline differentially effects retinal ganglion cell survival. In most cases, the result late in the injury process is greater retinal ganglion cell loss. We show here that neuroprotection is not solely determined by the microglial activation state but factors such as the environment and time-course of the injury. Culture microglia can be treated in vitro and then injected in vivo. The cells migrate to the site of injury, cell body of retinal ganglion cells if in the vitreous or to the optic nerve if injected in the tail vein. Retinal ganglion cell death is dependent on the location the microglia act, time-course of injury, and activation state. Proinflammatory microglia can be neuroprotective early in the injury when the primary site of action is on the axons whereas hypoactivated microglia are neuroprotective early in injury when they act on the soma. Later in the injury, both become detrimental. [ABSTRACT FROM AUTHOR]

• Major microglia clusters in the female HAB brain show higher expression of genes related to phagocytosis. • Hippocampal microglia from female HAB brain engulf more synaptic material compared to themale HAB. • Minocycline alleviates the higher synaptic engulfment and shows anxiolytic effect on female HAB behavior. • Cell surface phagocytosis markers (TREM2, CX3CR1, C3) are altered in high vs. normal anxiety in both sexes. Microglia modulate synaptic refinement in the central nervous system (CNS). We have previously shown that a mouse model with innate high anxiety-related behavior (HAB) displays higher CD68+ microglia density in the key regions of anxiety circuits compared to mice with normal anxiety-related behavior (NAB) in males, and that minocycline treatment attenuated the enhanced anxiety of HAB male. Given that a higher prevalence of anxiety is widely reported in females compared to males, little is known concerning sex differences at the cellular level. Herein, we address this by analyzing microglia heterogeneity and function in the HAB and NAB brains of both sexes. Single-cell RNA sequencing revealed ten distinct microglia clusters varied by their frequency and gene expression profile. We report striking sex differences, especially in the major microglia clusters of HABs, indicating a higher expression of genes associated with phagocytosis and synaptic engulfment in the female compared to the male. On a functional level, we show that female HAB microglia engulfed a greater amount of hippocampal vGLUT1+ excitatory synapses compared to the male. We moreover show that female HAB microglia engulfed more synaptosomes compared to the male HAB in vitro. Due to previously reported effects of minocycline on microglia, we finally administered oral minocycline to HABs of both sexes and showed a significant reduction in the engulfment of synapses by female HAB microglia. In parallel to our microglia-specific findings, we further showed an anxiolytic effect of minocycline on female HABs, which is complementary to our previous findings in the male HABs. Our study, therefore, identifies the altered function of synaptic engulfment by microglia as a potential avenue to target and resolve microglia heterogeneity in mice with innate high anxiety. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate‐to‐severe acne vulgaris (AV).To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate‐to‐severe facial AV.This was a multi‐centre, randomized, double‐blind, vehicle‐controlled phase 3 study in Chinese subjects with moderate‐to‐severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12.In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (−21.0 [0.08] vs. −12.3 [1.14]; LSM [SE] difference, −8.7 [1.34]; 95% CI [−11.3, −6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (−19.4 [1.03] vs. −14.9 [1.47]; LSM [SE] difference, −4.5 [1.74]; 95% CI [−8.0, −1.1]; p = 0.009). Most treatment‐emergent adverse events (TEAEs) were mild‐to‐moderate in severity, and no treatment‐related treatment‐emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well‐tolerated product during the 12‐week treatment period.FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate‐to‐severe facial AV. It also showed a well acceptable safe and tolerability profile. [ABSTRACT FROM AUTHOR]

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Ketoconazole and Minocycline based ointment for Combating Fungal and bacterial infections. As the global burden of infectious diseases continues to rise, innovative therapeutic approaches are essential. The proposed based ointment offers a promising solution, capitalizing on the synergistic antimicrobial properties of ketoconazole and minocycline.The development process involves a comprehensive exploration of various pharmaceutical parameters, including formulation strategies, physicochemical characterization, stability assessment, and biopharmaceutical considerations. By integrating these components, this review provide potential overview of ketoconazole,minocycline based ointment as a versatile therapeutic option.Formulation Strategies the article discusses the formulation techniques used to create a stable and efficacious ointment, taking into account factors such as excipient selection, particle size, and compatibility of active ingredients.Physicochemical Characterization an in-depth analysis of the physical and chemical properties of the based ointment is presented, including particle size distribution, morphology, crystallinity, and drug release profiles.Stability assessment the long-term stability of the powder is critically evaluated, examining factors like moisture sensitivity, photostability, and shelf-life considerations, ensuring its suitability for clinical use.Biopharmaceutical Considerationsthe pharmacokinetic and pharmacodynamic aspects of ketoconazole and minocycline in the ointment formulation are discussed, highlighting their bioavailability and potential drug-drug interactions.Antimicrobial Efficacy the antimicrobial activity of the powder against fungal and bacterial pathogens is assessed, shedding light on its potential as a broad-spectrum therapeutic agent.clinical relevance: The article explores the clinical implications of this novel formulation, including its applicability in treating various infectious diseases and potential to minimize drug resistance.Future perspectives a forward-looking perspective discusses the future directions and challenges in the development of ointment for infectious diseases, emphasizing the need for further research and clinical trials. [ABSTRACT FROM AUTHOR]

The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin inhibits cyclooxygenase (COX) activity, and minocycline inhibits 5-lipoxygenase (5-LOX) activity. Male Sprague Dawley rats with paclitaxel-induced mechanical allodynia were treated with indomethacin, minocycline, IPM combination, licofelone (a dual COX/LOX inhibitor), or their vehicles. AM251, a CB1 receptor antagonist, and AM630, a CB2 receptor antagonist, were administered before the IPM combination or licofelone. Mechanical allodynia was measured using a dynamic plantar aesthesiometer. Molecular docking was performed using CB-Dock2. Licofelone and IPM combination had antiallodynic effects, which were significantly higher than either indomethacin or minocycline alone. AM251 and AM630 blocked the antiallodynic effects of IPM combination and licofelone. Molecular docking showed that licofelone binds to both CB1 and CB2 receptors with a high affinity similar to the phytocannabinoid 1-trans-delta-9-tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2. Licofelone inhibits COX and LOX and/or directly interacts with CB receptors to produce antiallodynic effects in a rat model of PINP. The findings further suggest that licofelone could be a therapeutic agent for managing PINP. [ABSTRACT FROM AUTHOR]

Infections due to drug-resistant Acinetobacter baumannii strains are increasing and cause significant morbidity and mortality, especially in hospitalized and critically ill patients. A. baumannii rapidly develops resistance to numerous antibiotics, and antibiotics traditionally used against this deadly pathogen have been failing in recent years, highlighting the need to identify new treatment strategies. Treatment options that have shown promise include revisiting common antibiotics not typically used against A. baumannii, evaluating new antibiotics recently introduced to market, and identifying combinations of antibiotics that display synergistic interactions. In this study, we characterized the antibiotic susceptibility profiles of extensively (XDR) and pandrug-resistant (PDR) A. baumannii patient isolates. We examined the potency of 22 standard-of-care antibiotics and the newer antibiotics eravacycline, omadacycline, and plazomicin against these strains. Furthermore, we examined combinations of these antibiotics against our collection to identify synergistic effects. We found that this collection is highly resistant to most or all standard-of-care antibiotics, except for minocycline and rifampin. We show that eravacycline and omadacycline are effective against these strains based on minimum inhibitory concentrations. We also identified two highly effective combinations, cefepime and amikacin and cefepime and ampicillin–sulbactam, which exhibited high rates of synergy against this collection. This information is valuable in our battle against highly drug resistant and virtually untreatable A. baumannii infections. [ABSTRACT FROM AUTHOR]

Background: Stenotrophomonas maltophilia is an opportunistic, gram-negative bacillus with few therapeutic options due to a high level of intrinsic resistance. Trimethoprim/sulfamethoxazole (SXT) is recommended as the first-line treatment; however, minocycline (MIN) has been shown to have similar clinical outcomes in treating S. maltophilia and addresses concern for increasing resistance to SXT. Objective: The objective of this study is to evaluate the efficacy and safety outcomes of nonurinary, monomicrobial infections due to S. maltophilia in hospitalized patients treated with MIN or SXT. Methods: This was a retrospective study of hospitalized adult patients receiving MIN or SXT for nonurinary monomicrobial S. maltophilia infection from April 1, 2018 to March 31, 2020. The primary outcome was clinical disposition classified as rates of clinical failure, clinical improvement, or clinical success. Results: Eighty-two patients (88.2%) received MIN and 11 patients (11.8%) received SXT initially. Clinical failure occurred in 16 (19.5%) patients in the MIN group and in 4 (36.4%) patients in the SXT group (P = 0.242). Clinical improvement occurred in 11 (13.4%) patients in the MIN group and in 1 (9.1%) patient in the SXT group (P = 1.0). Clinical success occurred in 55 (67.1%) patients in the MIN group and in 6 (54.5%) patients in the SXT group (P = 0.503). Total duration of antimicrobial therapy (P = 0.3198), in-hospital mortality (P = 1.0), hospital length of stay (P = 0.9668), intensive care unit (ICU) length of stay (P = 0.1384), and 30-day readmission (P = 0.686) were similar between groups. Conclusions and Relevance: Rates of clinical failure, clinical improvement, or clinical success were similar between MIN and SXT for nonurinary monomicrobial S. maltophilia infections. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of minocycline (Mino) on the polarization of types M1/M2 microglia (pro- and anti-inflammatory type) in the spinal dorsal horn of rats with neuropathic pain (NP) induced by spinal nerve ligation (SNL) and its underlying mechanism. Methods A total of 36 adult male SD rats were randomly stratified into Sham-operation (Sham) group, SNL group and Mino+SNL group by stratified random sampling based on body weight. Mechanical pain threshold and cold nociceptive thresholds of rat hind paw were measured in 1 d before and 14 d after modelling. Spinal cord tissue at the lumbar 5 (L5) segment was taken at 14 d after modelling, and the total number of microglia as well as the numbers of M1 and M2 microglia in the spinal dorsal horn were measured with immunohistochemistry and stereology. With aid of bioinformatics techniques, the core target in the spinal cord, Cst7, was selected. Then, the protein levels of microglia marker Iba-1, M1 microglia marker iNOS, M2 microglia marker CD206, Cst7 encoded protein cystatin F (CF) and pathway CatS/CX3CL1/CX3CR1 were detected with Western blotting. The expression levels of TNF-α, IL-6 and IL-10 in the spinal cord tissues were measured with ELISA. Results The mechanical pain and cold nociceptive thresholds were both significantly higher in the M+SNL group than the SNL group at 7~14 d after modelling (P < 0.01). The total number of microglia and the numbers of M1/M2 microglia in the spinal dorsal horn as well as the expression levels of CatS, CX3CL1, CX3CR1, TNF-α, IL-6, and IL-10 in the spinal cord tissues were obviously increased, and the expression level of CF was notably decreased in the SNL model group than the Sham group (P < 0.01). While, Mino treatment remarkably reversed above phenomena, with decreased total number of microglia and number of M1 microglia as well as expression levels of CatS, CX3CL1, CX3CR1, TNF-α and IL-6, and increased number of M2 microglia as well as CF and IL-10 levels when compared with the SNL group (P < 0.05). Conclusion Mino alleviates SNL induced neuropathic pain, probably through up-regulating CF in the microglia, and thus inhibiting the CatS/CX3CL1/CX3CR1 signaling pathway, promoting the conversion of microglia from type M1 to M2 to balance the imbalance in the M1/M2 polarization, and thus reducing neuroinflammation.