Advances in stimuli-responsive gold nanorods for drug-delivery and targeted therapy systems.

In recent years, the use of gold nanorods (AuNRs) has garnered considerable attention in biomedical applications due to their unique optical and physicochemical properties. They have been considered as potential tools for the advanced treatment of diseases by various stimuli such as magnetic fields, pH, temperature and light in the fields of targeted therapy, imaging and drug delivery. Their biocompatibility and tunable plasmonic properties make them a versatile platform for a range of biomedical applications. While endogenous stimuli have limited cargo delivery control at specific sites, exogenous stimuli are a more favored approach despite their circumscribed penetration depth for releasing the cargo at the specific target. Dual/multi-stimuli responsive AuNTs can be triggered by multiple stimuli for enhanced control and specificity in biomedical applications. This review provides to provide a summary of the biomedical applications of stimuli-responsive AuNRs, including their endogenous and exogenous properties, as well as their dual/multi-functionality and potential for clinical delivery. This review provides a comprehensive review on the improvement of therapeutic efficacy and the effective control of drug release with AuNRs, highlights AuNRs design strategies in recent years, discusses the advantages or challenges so far in the field of AuNRs. Finally, we have addressed the clinical translation bio-integrated nanoassemblies (CTBNs) in this field.

Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial.

OBJECTIVE: Neurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role in the paracrine effects of mesenchymal stem cells (MSCs) and have emerged as a promising therapeutic approach for SCI. Thus, this study aimed to evaluate the safety and potential effects of intrathecal administration of allogeneic exosomes derived from human umbilical cord MSCs (HUC-MSCs) in patients with complete subacute SCI. METHODS: This study was a single-arm, open-label, phase I clinical trial with a 12-month follow-up period. HUC-MSCs were extracted from human umbilical cord tissue, and exosomes were isolated via ultracentrifugation. After intrathecal injection, each participant a underwent complete evaluation, including neurological assessment using the American Spinal Injury Association (ASIA) scale, functional assessment using the Spinal Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) assessment using the NBD score, modified Ashworth scale (MAS), and lower urinary tract function questionnaire. RESULTS: Nine patients with complete subacute SCI were recruited. The intrathecal injection of allogeneic HUC-MSCs-exosomes was safe and well tolerated. No early or late adverse event (AE) attributable to the study intervention was observed. Significant improvements in ASIA pinprick (P-value = 0.039) and light touch (P-value = 0.038) scores, SCIM III total score (P-value = 0.027), and NBD score (P-value = 0.042) were also observed at 12-month after the injection compared with baseline. CONCLUSIONS: This study demonstrated that intrathecal administration of allogeneic HUC-MSCs-exosomes is safe in patients with subacute SCI. Moreover, it seems that this therapy might be associated with potential clinical and functional improvements in these patients. In this regard, future larger phase II/III clinical trials with adequate power are highly required. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765 .

Infectious Diarrhea Risks as a Public Health Emergency in Floods; a Systematic Review and Meta-Analysis.

Introduction: Infectious diarrhea, a significant global health challenge, is exacerbated by flooding, a consequence of climate change and environmental disruption. This comprehensive study aims to quantify the association between flooding events and the incidence of infectious diarrhea, considering diverse demographic, environmental, and pathogen-specific factors. Methods: In this systematic review and meta-analysis, adhering to PROSPERO protocol (CRD42024498899), we evaluated observational studies from January 2000 to December 2023. The analysis incorporated global data from PubMed, Scopus, Embase, Web of Science, and ProQuest, focusing on the relative risk (RR) of diarrhea post-flooding. The study encompassed diverse variables like age, sex, pathogen type, environmental context, and statistical modeling approaches. Results: The meta-analysis, involving 42 high-quality studies, revealed a substantial increase (RR = 1.40, 95% CI [1.29-1.52]) in the incidence of diarrhea following floods. Notably, bacterial and parasitic diarrheas demonstrated higher RRs (1.82 and 1.35, respectively) compared to viral etiologies (RR = 1.15). A significant sex disparity was observed, with women exhibiting a higher susceptibility (RR = 1.55) than men (RR = 1.35). Adults (over 15 years) faced a greater risk than younger individuals, highlighting age-dependent vulnerability. Conclusion: This extensive analysis confirms a significant correlation between flood events and increased infectious diarrhea risk, varying across pathogens and demographic groups. The findings highlight an urgent need for tailored public health interventions in flood-prone areas, focusing on enhanced sanitation, disease surveillance, and targeted education to mitigate this elevated risk. Our study underscores the critical importance of integrating flood-related health risks into global public health planning and climate change adaptation strategies.

Micro-extraction, pre-concentration, and microfluidic-based separation of organophosphate insecticides followed by the miniaturized electrochemical detection system.

Introduction: A new analytical method based on the coupling of microextraction and microfluidics was developed and investigated for the pre-concentration, separation, and electrochemical detection of fenitrothion (FT) and parathion (PA) at the sub-ppm concentrations. Methods: In the first step, the microchip capillary electrophoresis technique was used to serve as a separation and detection system. Analytes were injected in the 40 mm long microchannel with 10 mm sidearms. Then, they were separated by applying a direct electrical field (+1800 V) between the buffer and detection reservoirs. 2-(n-morpholino)ethanesulfonic acid (MES) buffer (20 mM, pH 5) was used as a running buffer. The electrochemical detection was performed using three Pt microelectrodes with the width of working, counter, and reference electrodes (50, 250, and 250 µm, respectively) in the out-channel approach. Results: The system was devised to have the optimum detection potential equal to -1.2 V vs. pseudo-reference electrode. The dimensions of the SU-8 channel have 20 µm depth and 50 µm width. In the second step, an air-assisted liquid-liquid microextraction technique was used to extract and preconcentration of analytes from human blood plasma. Then, 1, 2 di-bromoethan was used as extractant solvent, the analytes were preconcentrated, and the sedimented solvent (50 µL) was evaporated in a 60 ˚C water bath followed by substitution of running buffer containing 10% ethanol. The optimal extraction cycles were found to be 8 with adding 1% NaCl to the aqueous phase. Analyzing time of the mentioned analytes was less than 100s, the precision range was 3.3 - 8.2 with a linear range of 0.8-100 ppm and 1.2-100 ppm for FT and PA, respectively. The extraction recoveries were about 91% and 87% for FT and PA, respectively. The detection limits for FT and PA were 240 and 360 ppb, respectively. Finally, the reliability of the method was investigated by GC-FID. Conclusion: The proposed method and device were validated and can be used as in situ and portable detection systems for detecting fenitrothion and parathion insecticides.

Evaluation of the protective effect of coenzyme Q10 on hepatotoxicity caused by acute phosphine poisoning.

Background: Aluminum phosphide (AlP) poisoning is prevalent in numerous countries, resulting in high mortality rates. Phosphine gas, the primary agent responsible for AlP poisoning, exerts detrimental effects on various organs, notably the heart, liver and kidneys. Numerous studies have documented the advantageous impact of Coenzyme Q10 (CoQ10) in mitigating hepatic injuries. The objective of this investigation is to explore the potential protective efficacy of CoQ10 against hepatic toxicity arising from AlP poisoning. Method: The study encompassed distinct groups receiving almond oil, normal saline, exclusive CoQ10 (at a dosage of 100 mg/kg), AlP at 12 mg/kg; LD50 (lethal dose for 50%), and four groups subjected to AlP along with CoQ10 administration (post-AlP gavage). CoQ10 was administered at 10, 50, and 100 mg/kg doses via Intraparietal (ip) injections. After 24 h, liver tissue specimens were scrutinized for mitochondrial complex activities, oxidative stress parameters, and apoptosis as well as biomarkers such as aspartate transaminase (AST) and alanine transaminase (ALT). Results: AlP induced a significant decrease in the activity of mitochondrial complexes I and IV, as well as a reduction in catalase activity, Ferric Reducing Antioxidant Power (FRAP), and Thiol levels. Additionally, AlP significantly elevated oxidative stress levels, indicated by elevated reactive oxygen species (ROS) production, and resulted in the increment of hepatic biomarkers such as AST and ALT. Administration of CoQ10 led to a substantial improvement in the aforementioned biochemical markers. Furthermore, phosphine exposure resulted in a significant reduction in viable hepatocytes and an increase in apoptosis. Co-treatment with CoQ10 exhibited a dose-dependent reversal of these observed alterations. Conclusion: CoQ10 preserved mitochondrial function, consequently mitigating oxidative damage. This preventive action impeded the progression of heart cells toward apoptosis.

Prominent genetic variants and epigenetic changes in post-traumatic stress disorder among combat veterans.

Post-traumatic stress disorder (PTSD) is one of the most widespread and disabling psychiatric disorders among combat veterans. Substantial interindividual variability in susceptibility to PTSD suggests the presence of different risk factors for this disorder. Twin and family studies confirm genetic factors as important risk factors for PTSD. In addition to genetic factors, epigenetic factors, especially DNA methylation, can be considered as a potential mechanism in changing the risk of PTSD. So far, many genetic and epigenetic association studies have been conducted in relation to PTSD. In genetic studies, many single nucleotide polymorphisms have been identified as PTSD risk factors. Meanwhile, the variations in catecholamines-related genes, serotonin transporter and receptors, brain-derived neurotrophic factor, inflammatory factors, and apolipoprotein E are the most prominent candidates. CpG methylation in the upstream regions of many genes is also considered a PTSD risk factor. Accurate identification of genetic and epigenetic changes associated with PTSD can lead to the presentation of suitable biomarkers for susceptible individuals to this disorder. This study aimed to delineate prominent genetic variations and epigenetic changes associated with post-traumatic stress disorder in military veterans who have experienced combat, focusing on genetic and epigenetic association studies.

Chronic Cinacalcet improves skin flap survival in rats: the suggested role of the nitric oxide pathway.

Cinacalcet is a calcimimetic medicine that has been used to treat secondary hyperparathyroidism and parathyroid cancer. Various studies have proposed the positive role of calcium and its receptor in skin wound healing. Furthermore, Cinacalcet interacts with other skin repair-related mechanisms, including inflammation and nitric oxide pathways. The present study evaluated the effect of Cinacalcet on the random-pattern skin flap survival. Eighty-four Wistar male rats were used. Multiple doses of Cinacalcet (30, 3, 1, 0.3, and 0.05 mg/kg) were used in 3 different routes of administration before the surgery. Histopathological evaluations, quantitative assessment of IL-6, TNF-α, and nitric oxide (NO), and the expression of calcium-sensing receptor (CaSR) and E-cadherin were evaluated in the skin tissue. To assess the role of NO, a NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME), was used, and histopathological effects were investigated. Cinacalcet pretreatment at the IP chronic 1 mg/kg dose significantly increased the skin flap survival rate and enhanced the NO tissue level compared to the control. However, the administration of L-NAME abolished its protective effects. IP Chronic 1 mg/kg of Cinacalcet could also decline the levels of IL-6 and TNF-α and also increase the expression of CaSR and E-cadherin in the flap tissue compared with the control group. Chronic Cinacalcet at 1 mg/kg could improve skin flap survival, probably mediated by the CaSR, NO, and inflammation-related pathways.

Cilostazol pretreatment prevents PTSD-related anxiety behavior through reduction of hippocampal neuroinflammation.

Current pharmacological treatments against post-traumatic stress disorder (PTSD) lack adequate efficacy. As a result, intense research has focused on identifying other molecular pathways mediating the pathogenesis of this condition. One such pathway is neuroinflammation, which has demonstrated a role in PTSD pathogenesis by causing synaptic dysfunction, neuronal death, and functional impairment in the hippocampus. Phosphodiesterase (PDE) inhibitors (PDEIs) have emerged as promising therapeutic agents against neuroinflammation in other neurological conditions. Furthermore, PDEIs have shown some promise in animal models of PTSD. However, the current model of PTSD pathogenesis, which is based on dysregulated fear learning, implies that PDE inhibition in neurons should enhance the acquisition of fear memory from the traumatic event. As a result, we hypothesized that PDEIs may improve PTSD symptoms through inhibiting neuroinflammation rather than long-term potentiation-related mechanisms. To this end, we tested the therapeutic efficacy of cilostazol, a selective inhibitor of PDE3, on PTSD-related anxiety symptoms in the underwater trauma model of PTSD. PDE3 is expressed much more richly in microglia and astrocytes compared to neurons in the murine brain. Furthermore, we used hippocampal indolamine 2,3-dioxygenase 1 (IDO) expression and interleukin 1 beta (IL-1ß) concentration as indicators of neuroinflammation. We observed that cilostazol pretreatment prevented the development of anxiety symptoms and the increase in hippocampal IDO and IL-1ß following PTSD induction. As a result, PDE3 inhibition ameliorated the neuroinflammatory processes involved in the development of PTSD symptoms. Therefore, cilostazol and other PDEIs may be promising candidates for further investigation as pharmacological therapies against PTSD.

Some relevant mitigating agents of chronic aflatoxin exposure: a treatise.

Aflatoxins, a group of toxic secondary metabolites produced by Aspergillus species, pose significant threats to human health due to their potent carcinogenic, mutagenic, and immunosuppressive properties. Chronic exposure to these contaminants, commonly found in staple foods such as maize and groundnuts, has been linked to an increased risk of liver cancer, growth impairment, and immune dysfunction. Several agents, such as calcium montmorillonite clay and Lactobacillus rhamnosus GG, have shown promise in reducing aflatoxin bioavailability and alleviating its toxic effects. Additionally, dietary supplements such as chlorophyllin, selenium, and N-acetylcysteine have demonstrated potential as adjuvants to counteract aflatoxin-induced oxidative stress and support liver function. In this treatise, some of the most discussed approaches to mitigating aflatoxin effects are explored in terms of their efficacy, safety, and potential mechanisms of action, which include direct aflatoxin binding, detoxification, cellular antioxidative, and hepatocellular protection properties. However, the effectiveness of these strategies can be influenced by various factors, such as dose, duration of exposure, and individual susceptibility. Therefore, further research is needed to optimize these interventions and develop new, targeted therapies for the prevention and treatment of aflatoxin-related diseases. This review aims to provide a comprehensive analysis of 18 pharmaceutical, nutraceutical, supplement, and probiotic strategies currently available for mitigating the deleterious effects of chronic aflatoxin exposure in humans and animal models.

Dexmedetomidine versus sufentanil as adjuvants to bupivacaine for brachial plexus block during upper extremity surgery: a randomized clinical trial

Abstract Background: Brachial plexus block (BPB) has been accepted as a reliable alternative for general anesthesia in upper limb surgeries. Adding adjuvant drugs like dexmedetomidine and sufentanil has been shown to have clinical and pharmacologic advantages. In this randomized parallel clinical trial, we aim to compare the effects of these two adjuvants for bupivacaine in BPB. Methods: In this double-blinded study, by using computer-assisted block randomization, 40 patients ranged from 20 to 65 years old and scheduled for elective upper limb surgeries were assigned to two equal study groups (n = 20), receiving 1 mL of 5 μg.mL-1 sufentanil (group S) or 1 mL of 100 μg.mL-1 dexmedetomidine (group D) in adjunction to 30 mL of 0.5% bupivacaine for supraclavicular BPB under the guidance of ultrasonography. Characteristics of local anesthesia and postoperative analgesia were evaluated (n = 40). Results: The duration of blocks significantly improved in group S (sensory: estimated median difference (EMD) [95%CI] = 100.0 [70.0~130.0], p < 0.001; motor: EMD [95%CI] = 120.0 [100.0~130.0], p < 0.001). Group S also had significantly longer postoperative analgesia and lower opioid consumption within 24 hours after the surgery (EMD [95%CI] = 4.0 [3.0~7.0], p < 0.001; EMD [95%CI] = -5.0 [-5.0~-5.0], p < 0.001; respectively). None of the patients showed adverse effects concerning vital signs, nausea, or vomiting. Conclusion: Our study showed that during ultrasound-guided supraclavicular BPB, sufentanil is a fairly better choice than dexmedetomidine as an adjuvant for bupivacaine and can provide preferable sensory and motor blocks. No significant side effects were seen in either of the study groups.

Inhibition of bacterial adhesion and anti-biofilm effects of Bacillus cereus and Serratia nematodiphila biosurfactants against Staphylococcus aureus and Pseudomonas aeruginosa.

Background and Objectives: Biosurfactants are amphiphilic surface-active agents that mainly produced by various microorganisms. In this study, the anti-biofilm and inhibition of bacterial adhesion activities of two bacterial biosurfactants were investigated. Materials and Methods: After extraction and evaluation of Bacillus cereus and Serratia nematodiphila biosurfctants, inhibition of bacterial adhesion and anti-biofilm effects of them on Staphylococcus aureus and Pseudomonas aeruginosa were determined. Results: On average, the synergistic effect of two bacterial biosurfactants, caused about 60% decrease in adhesion and about 80% decrease in biofilm formation of S. aureus and P. aeruginosa. Conclusion: The results of this study showed that combination of B. cereus and S. nematodiphila biosurfactants would increase the potential of attachment inhibition and biofilm eradication with very low toxicity.

Bipolar Androgen Therapy: When Excess Fuel Extinguishes the Fire.

Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through "Darwinian" treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment.

Oleanolic acid increases the anticancer potency of doxorubicin in pancreatic cancer cells.

Combination therapy is a novel cancer therapy approach that combines two or more chemotherapy drugs. This treatment modality enhances the efficacy of chemotherapy by targeting key pathways in an additive or synergistic manner. Therefore, we investigated the efficacy of combination therapy by widely used chemotherapy drug doxorubicin (DOX) and oleanolic acid (OA) to induction of apoptosis for pancreatic cancer (PC) therapy. The effects of DOX, OA, and their combination (DOX-OA) were investigated on proliferation and viability of PC cell line (PANC-1) by MTT assay. Moreover, migration and invasion of the cancer cells were evaluated by trans-well migration assay and wound healing assay. Flow cytometry and DAPI (4',6-diamidino-2-phenylindole) staining were employed to investigate apoptosis quantification and qualification of the treated cancer cells. Finally, mRNA expression of apoptosis-related genes was assessed by quantitative real-time polymerase chain reaction. Our results demonstrated that the proliferation and metastasis potential of PC cells significantly decreased after treatment by DOX, OA, and DOX-OA. Moreover, we observed an increase in apoptosis percentage in the treated cancer cells. The apoptosis-related gene expression was modified to increase the apoptosis rate in all of the treatment groups. However, the anticancer potency of DOX-OA combination was significantly more than that of DOX and OA treatments alone. Our study suggested that DOX-OA combination exerts more profound anticancer effects against PC cell lines than DOX or OA monotherapy. This approach may increase the efficiency of chemotherapy and reduce unintended side effects by lowering the prescribed dose of DOX.

Phosphodiesterase inhibitors in psychiatric disorders.

RATIONALE: Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. OBJECTIVES: In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. RESULTS: PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. CONCLUSIONS: Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies.

Beneficial Effects of Statins on Seizures Independent of Their Lipid-Lowering Effect: A Narrative Review.

Among the many types of central nervous system (CNS) disorders, seizures and epilepsy severely affect the quality of life and routine daily activity of the sufferers. We aimed to review research studies that investigated the effect of statins on the prevention and treatment of seizures and epilepsy. Both animal models and human studies were included in this review. This article starts with a brief introduction about seizure, its prevalence, treatment, and various animal models of seizures and epilepsy. Next, we discuss statin's mechanism of action, side effects, and effects on neurological disorders with a specific focus on seizures. Finally, the effects of different types of statins on seizures are compared. The present review gives a better understanding of the therapeutic effects of statins on neurological disorders in animal models and human studies. This permits researchers to set up study designs to resolve current ambiguities and contradictions on the beneficial effects of statins on neurological disorders.

Dexmedetomidine versus sufentanil as adjuvants to bupivacaine for brachial plexus block during upper extremity surgery: a randomized clinical trial.

BACKGROUND: Brachial plexus block (BPB) has been accepted as a reliable alternative for general anesthesia in upper limb surgeries. Adding adjuvant drugs like dexmedetomidine and sufentanil has been shown to have clinical and pharmacologic advantages. In this randomized parallel clinical trial, we aim to compare the effects of these two adjuvants for bupivacaine in BPB. METHODS: In this double-blinded study, by using computer-assisted block randomization, 40 patients ranged from 20 to 65 years old and scheduled for elective upper limb surgeries were assigned to two equal study groups (n = 20), receiving 1 mL of 5 ..g.mL-1 sufentanil (group S) or 1 mL of 100 ..g.mL-1 dexmedetomidine (group D) in adjunction to 30 mL of 0.5% bupivacaine for supraclavicular BPB under the guidance of ultrasonography. Characteristics of local anesthesia and postoperative analgesia were evaluated (n = 40). RESULTS: The duration of blocks significantly improved in group S (sensory: estimated median difference (EMD) [95%CI] = 100.0 [70.0...130.0], p < 0.001; motor: EMD [95%CI] = 120.0 [100.0...130.0], p < 0.001). Group S also had significantly longer postoperative analgesia and lower opioid consumption within 24 hours after the surgery (EMD [95%CI] = 4.0 [3.0...7.0], p < 0.001; EMD [95%CI] = -5.0 [-5.0...-5.0], p < 0.001; respectively). None of the patients showed adverse effects concerning vital signs, nausea, or vomiting. CONCLUSION: Our study showed that during ultrasound-guided supraclavicular BPB, sufentanil is a fairly better choice than dexmedetomidine as an adjuvant for bupivacaine and can provide preferable sensory and motor blocks. No significant side effects were seen in either of the study groups.

Neuronal nitric oxide synthase inhibition accelerated the removal of fluoxetine's anxiogenic activity in an animal model of PTSD.

While SSRIs are the current first-line pharmacotherapies against post-traumatic stress disorder (PTSD), they suffer from delayed onset of efficacy and low remission rates. One solution is to combine SSRIs with other treatments. Neuronal nitric oxide synthase (nNOS) has been shown to play a role in serotonergic signaling, and there is evidence of synergism between nNOS modulation and SSRIs in models of other psychiatric conditions. Therefore, in this study, we combined subchronic fluoxetine (Flx) with 7-nitroindazole (NI), a selective nNOS inhibitor, and evaluated their efficacy against anxiety-related behavior in an animal model of PTSD. We used the underwater trauma model to induce PTSD in rats. Animals underwent the open field (OFT) and elevated plus maze tests on days 14 (baseline) and 21 (post-treatment) after PTSD induction to assess anxiety-related behaviors. Between the two tests, the rats received daily intraperitoneal injections of 10 mg/kg Flx or saline, and were injected intraperitoneally before the second test with either 15 mg/kg NI or saline. The change in behaviors between the two tests was compared between treatment groups. Individual treatment with both Flx and NI had anxiogenic effects in the OFT. These effects were associated with modest increases in cFOS expression in the hippocampus. Combination therapy with Flx + NI did not show any anxiogenic effects, while causing even higher expression levels of cFOS. In conclusion, addition of NI treatment to subchronic Flx therapy accelerated the abrogation of Flx's anxiogenic properties. Furthermore, hippocampal activity, as evidenced by cFOS expression, was biphasically related to anxiety-related behavior.

Evaluating the effects of zeolitic imidazolate framework and Eremostachys binalodensis extract on Candida albicans and Streptococcus mutans biofilms.

Biofilms represent longstanding challenges to oral health care. Candida albicans and Streptococcus mutans are the common pathogens forming biofilms. The growing resistance to and the adverse effects of antibiotics limit their usage and raise the need for novel approaches. Herbal extracts have emerged as efficient choices with lower costs and fewer adverse effects. Metal frameworks have captivated interest due to their high surface area, special biocompatibility, and non-toxicity. The effects of zeolitic imidazolate frameworks/layered double hydroxide (ZIF/LDH) on fungal infections and the potential effects of Eremostachys binalodensis on bacteria encouraged the researchers to evaluate the effect of ZIF/LDH, E. binalodensis, and their combination on C. albicans and S. mutans biofilms. ZIF/LDH nanocomposite was synthesized and characterized using scanning electron microscopy, Fourier transform infrared spectra, and X-ray diffraction to assess morphology and chemical structure. Methanol extracts of the areal parts of E. binalodensis were obtained by Soxhlet extraction. The microdilution tests and biofilm crystal violet staining were applied. Concentrations of 2.048 and 4.096 mg/ml E. binalodensis prevented C. albicans and S. mutans biofilm formation. The combination of ZIF/LDH + E. binalodensis prevented C. albicans and S. mutans biofilm formation. This research suggests the use of E. binalodensis-loaded ZIF/LDH nanocomposites for removing biofilms.

High-Intensity Interval Training-Induced Hippocampal Molecular Changes Associated with Improvement in Anxiety-like Behavior but Not Cognitive Function in Rats with Type 2 Diabetes.

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80-100% of VMax, 4-10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.

Targeting neuronal nitric oxide synthase and the nitrergic system in post-traumatic stress disorder.

RATIONALE: Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR. OBJECTIVE: In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted. RESULTS: Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade. CONCLUSIONS: Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.