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Acta Biomaterialia Jul 2024Intratumor microbes have attracted great attention in cancer research due to its influence on the tumorigenesis, progression and metastasis of cancer. However, the...
Intratumor microbes have attracted great attention in cancer research due to its influence on the tumorigenesis, progression and metastasis of cancer. However, the therapeutic strategies targeting intratumoral microbes are still in their infancy. Specific microorganisms, such as Fusobacterium nucleatum (F. nucleatum), are abundant in various cancer and always result in the CRC progression and chemotherapy resistance. Here, a combined anticancer and antibacterial therapeutic strategy is proposed to deliver antitumor drug to the tumors containing intratumor microbiota by the antibacerial polymeric drug carriers. We construct oral tellurium-containing drug carriers using a complex of tellurium-containing polycarbonate with cisplatin (PTE@CDDP). The results show that the particle size of the prepared nanoparticles could be maintained at about 105 nm in the digestive system environment, which is in line with the optimal particle size of oral nanomedicine. In vitro mechanism study indicates that the tellurium-containing polymers are highly effective in killing F.nucleatum through a membrane disruption mechanism. The pharmacokinetic experiments confirmed that PTE@CDDP has the potential function of enhancing the oral bioavailability of cisplatin. Both in vitro and in vivo studies show that PTE@CDDP could inhibit intratumor F.nucleatum and lead to a reduction in cell proliferation and inflammation in the tumor site. Together, the study identifies that the CDDP-loaded tellurium-containing nanoparticles have great potential for treating the F.nucleatum-promoted colorectal cancer (CRC) by combining intratumor microbiota modulation and chemotherapy. The synergistic therapeutic strategy provide new insight into treating various cancers combined with bacterial infection. STATEMENT OF SIGNIFICANCE: The synthesized antibacterial polymer was first employed to remodel the intratumor microbes in tumor microenvironment (TME). Moreover, it was the first report of tellurium-containing polymers against F.nucleatum and employed for treatment of the CRC. A convenient oral dosage form of cisplatin (CDDP)-loaded tellurium-containing nanoparticles (PTE@CDDP) was adopted here, and the synergistic antibacterial/chemotherapy effect occurred. The PTE@CDDP could quickly and completely eliminate F.nucleatum in a safe dose. In the CRC model, PTE@CDDP effectively reversed the inflammation level and even restored the intestinal barrier damaged by F.nucleatum. The ultrasensitive ROS-responsiveness of PTE@CDDP triggered the fast oxidation and efficient drug release of CDDP and thus a highly efficient apoptosis of the tumors. Therefore, the tellurium-containing polymers are expected to serve as novel antibacterial agents in vivo and have great potential in the F.nucleatum-associated cancers. The achievements provided new insight into treating CRC and other cancers combined with bacterial infection.
PubMed: 38964527
DOI: 10.1016/j.actbio.2024.06.042 -
International Journal of Pharmaceutics Jul 2024In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active...
In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active pharmaceutical ingredients. The choice of coformers took into account their potential to increase the aqueous solubility/dissolution rate of TMP or its antibacterial activity. All the binary systems were characterized by thermal analysis, powder X-ray diffraction and infrared spectroscopy, and 3 equimolar systems with FTIR pointing to salts, and 4 eutectic mixtures were identified. The intrinsic dissolution rate of TMP in combination with nicotinic acid (a salt) and with paracetamol (eutectic mixture) were 25% and 5% higher than for pure TMP, respectively. For both Gram-positive and -negative strains, the antibacterial activity of TMP with some of the coformers was improved, since the dosage used was lower than the TMP control. A significant increase in antibacterial activity against E. coli was found for the eutectic mixture with curcumin, with the best results being obtained for the eutectic and equimolar mixtures with ciprofloxacin.. Combining trimethoprim with coformers offers an interesting alternative to using trimethoprim alone: multicomponent forms with enhanced TMP dissolution rates were identified, as well as combinations showing enhanced antibacterial activity relatively to the pure drug.
PubMed: 38964490
DOI: 10.1016/j.ijpharm.2024.124416 -
Phytomedicine : International Journal... Jun 2024With the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of...
BACKGROUND
With the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear.
PURPOSE
The objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS.
METHODS
An in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting.
RESULTS
Mice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro.
CONCLUSION
HAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.
PubMed: 38964152
DOI: 10.1016/j.phymed.2024.155849 -
Journal of Psychiatric Research Jun 2024The variation in improvement among individuals with addiction after abstinence is a critical issue. Here, we aimed to identify robust multimodal markers associated with...
The variation in improvement among individuals with addiction after abstinence is a critical issue. Here, we aimed to identify robust multimodal markers associated with high response to 8-month abstinence in the individuals with heroin use disorder (HUD) and explore whether the identified markers could be generalized to the individuals with methamphetamine use disorder (MUD). According to the median of craving changes, 53 individuals with HUD with 8-month abstinence were divided into two groups: higher craving reduction and lower craving reduction. At baseline, clinical variables, cortical thickness and subcortical volume, fractional anisotropy (FA) of fibers and resting-state functional connectivity (RSFC) were extracted. Different strategies (single metric, multimodal neuroimaging fusion and multimodal neuroimaging-clinical data fusion) were used to identify reliable features for discriminating the individuals with HUD with higher craving reduction from those with lower reduction. The generalization ability of the identified features was validated in the 21 individuals with MUD. Multimodal neuroimaging-clinical fusion features with best performance was achieved an 87.1 ± 3.89% average accuracy in individuals with HUD, with a moderate accuracy of 66.7% when generalizing to individuals with MUD. The multimodal neuroimaging features, primarily converging in frontal regions (e.g., the left superior frontal (LSF) thickness, FA of the LSF-occipital tract, and RSFC of left middle frontal-right superior temporal lobe), collectively contributed to prediction alongside dosage and attention impulsiveness. In this study, we identified the validated multimodal frontal neuroimaging markers associated with higher response to long-term abstinence and revealed insights for the neural mechanisms of addiction abstinence, contributing to clinical strategies and treatment for addiction.
PubMed: 38964089
DOI: 10.1016/j.jpsychires.2024.06.035 -
Hormones and Behavior Jul 2024Melatonin, the multi-functional neurohormone, is synthesized in the extra-pineal tissues such as the hippocampus. The key enzyme in hippocampal melatonin synthesis is...
Melatonin, the multi-functional neurohormone, is synthesized in the extra-pineal tissues such as the hippocampus. The key enzyme in hippocampal melatonin synthesis is arylalkylamine-N-acetyltransferase (AANAT). The importance of melatonin synthesis in the hippocampus has not yet been determined. We investigated hippocampal AANAT role in cognitive function using gene silencing small interference RNA (siRNA) technology. The hippocampal local melatonin synthesis was inhibited by AANAT-siRNA injection. The time-gene silencing profile of AANAT-siRNA was obtained by RT-PCR technique. The cytotoxicity of siRNA dose was determined by MTT assay on the B65 neural cells. Animals received the selected dosage of AANAT-siRNA. Then, the spatial working memory (Y maze), object recognition memory and spatial reference memory (Morris's water maze, MWM) were evaluated. The anxiety-like behaviors were evaluated by the elevated plus maze. After one week, following the probe test of MWM, the rats were sacrificed for histological analysis. The hippocampal melatonin levels were measured using the liquid chromatography-mass spectrometry technique. The hippocampal melatonin levels in the AANAT-siRNA group decreased. Animals receiving the AANAT-siRNA showed deficits in spatial learning and working memory which were verified by increased escape latency and reduced spontaneous alternations, respectively. There was an increase in anxiety-like behaviors as well as a deficit in recognition memory in the AANAT-siRNA group. The Nissl staining and immunohistochemistry of activated caspase-3 showed the neuronal loss and cell apoptosis in hippocampal tissue of the AANAT-siRNA group. The F-FDG-PET imaging displayed lower glucose metabolism following the reduction in AANAT mRNA. Data suggest that the AANAT mRNA and hippocampal melatonin synthesis might be an essential factor for learning, memory and some aspects of cognition, as well as homeostasis of hippocampal cells.
PubMed: 38964019
DOI: 10.1016/j.yhbeh.2024.105599 -
Spectrochimica Acta. Part A, Molecular... Jun 2024Nausea and vomiting are considered common series side effects induced by chemotherapy treatment in cancer patients. This annoying side effect can impair the patient's...
Nausea and vomiting are considered common series side effects induced by chemotherapy treatment in cancer patients. This annoying side effect can impair the patient's compliance to cancer treatment and affect their quality of life. Dimenhydrinate and cinnarizine in combined pharmaceutical dosage form is used to control chemotherapy induced nausea and vomiting in cancer patients. For safety, selective spectrophotometric methods based on novel dual resolution strategies were introduced to estimate dimenhydrinate and cinnarizine in presence of their harmful impurities namely benzophenone and 1- (diphenylmethyl)piperazine, respectively. These methods namely, dual ratio difference (DRD), dual ratio extraction (DRE) and dual absorbance extraction coupled with dual ratio extraction (DAE-DRE) were successfully performed to simultaneously analyze the drug of interests dimenhydrinate and cinnarizine in their pure form, synthetic mixtures and in market dosage form. Linearity ranges were 6.0-60.0 μg/mL and 3.0-30.0 μg/mL for dimenhydrinate and cinnarizine, respectively with good recovery% of Mean ± SD for all the proposed methods 99.82 ± 0.48, 99.79 ± 0.40, 100.14 ± 0.82, 100.03 ± 0.69, respectively. ICH guidelines were adhered in accordance with confirming validation of the proposed methods where fulfilling results were accomplished. Various unified greenness and whiteness assessment tools, such as the chlorTox scale, greenness index via spider chart, AGREE (The Analytical Greenness Metric), green certificate, and the RGB12 algorithm were employed in this research to assess the greenness and sustainability of the introduced UV-spectrophotometric methods in comparison to the reported HPLC method. As a result, these methods hold significant potential for utilization in the quality control department of pharmaceutical companies, contributing to enhanced pharmaceutical product analysis and overall sustainability practices.
PubMed: 38963943
DOI: 10.1016/j.saa.2024.124740 -
Skin Therapy Letter Jul 2024Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne - specifically scarring... (Review)
Review
Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne - specifically scarring and dyspigmentation - can be long-lasting, challenging to treat and have substantial psychosocial impact on affected individuals. For acne scarring, treatment modalities include topical, physical, and laser and light therapies, with combination approaches typically yielding optimal outcomes. Trifarotene is a novel fourth generation retinoid with targeted action towards retinoid acid receptor gamma (RAR-γ), the most common isotype found in the epidermis, that has previously been approved for the management of moderate-to-severe facial and truncal acne in individuals over the age of 12 years. Recently, data on trifarotene supports its application in acne scarring. Herein, we provide a succinct review on various treatments for acne scarring and explore how trifarotene and its mechanism of action present an additional topical approach to target atrophic acne scarring.
Topics: Humans; Acne Vulgaris; Cicatrix; Retinoids; Dermatologic Agents; Atrophy; Administration, Cutaneous
PubMed: 38963911
DOI: No ID Found -
Acta Chirurgiae Orthopaedicae Et... 2024Adequate postoperative pain treatment is important for quality of life, patient satisfaction, rehabilitation, function, and total opioid consumption, and might lower...
BACKGROUND
Adequate postoperative pain treatment is important for quality of life, patient satisfaction, rehabilitation, function, and total opioid consumption, and might lower both the risk of chronic postoperative pain and the costs for society. Prolonged opioid consumption is a well-known risk factor for addiction. Previous studies in upper extremity surgery have shown that total opioid consumption is a third of the amount prescribed, which can be explained by package size. The aim of this study was to examine whether implementation of prepacked takehome analgesia bags reduced the quantity of prescribed and dispensed opioids.
MATERIAL AND METHODS
We introduced prepacked take-home analgesia bags for postoperative pain treatment in outpatient surgery. The bags came in two sizes, each containing paracetamol, etoricoxib, and oxycodone. The first 147 patients who received the prepacked analgesia bags were included in the study, and received a questionnaire one month after surgery covering self-assessed pain (visual analog scale of 0-10) and satisfaction (0-5), as well as opioid consumption. Prescription data after introducing the analgesia bags were compared with data before the bags were introduced.
RESULTS
Of the 147 patients included in the study, 58 responded. Compared to standard prescription (small bag group: 14 oxycodone immediate release capsules (5 mg), large bag group: additional 28 oxycodone extended release tablets (5 mg), based on the smallest available package), the patients in the small analgesia bag group received 50% less oxycodone and 67% less for the large bag group. Patients with small bags consumed a median of 0.0 mg oxycodone and those with large bags consumed a median of 25.0 mg oxycodone. The median satisfaction was 5.0 (range: 2-5) and the median pain score was acceptable at the first postoperative day. Prescription data showed a significant reduction of 60.0% in the total amount of prescribed opioids after the introduction of prepacked analgesia bags.
CONCLUSIONS
The introduction of prepacked analgesia bags dramatically reduced the quantity of opioids prescribed after outpatient hand surgery. Patient satisfaction was high and the postoperative pain level was acceptable.
KEY WORDS
analgesia, hand surgery, opioids, outpatint surgery, wrist surgery.
Topics: Humans; Pain, Postoperative; Analgesics, Opioid; Ambulatory Surgical Procedures; Female; Male; Hand; Pain Measurement; Middle Aged; Patient Satisfaction; Oxycodone; Adult; Pain Management; Acetaminophen
PubMed: 38963898
DOI: 10.55095/achot2024/018 -
Acta Chirurgiae Orthopaedicae Et... 2024Our aim was to compare the effects of intraarticular and intravenous (IV) tranexemic acid (TXA) application on bleeding and complication rates in patients who underwent... (Comparative Study)
Comparative Study
PURPOSE OF THE STUDY
Our aim was to compare the effects of intraarticular and intravenous (IV) tranexemic acid (TXA) application on bleeding and complication rates in patients who underwent total knee arthroplasty (TKA).
MATERIAL AND METHODS
Between 2017 and 2021, 406 patients who underwent TKA with 2 g of IV TXA and retrograde 1.5 g of TXA applied through the drain were included in the study. Of the patients, 206 were in the IV TXA group. Preoperative and postoperative hemoglobin levels, drain output, BMI, ASA score, blood loss, and the number of transfused patients were recorded. Complications such as symptomatic venous thromboembolism were also recorded.
RESULTS
There was no significant difference between the two groups in terms of age, sex, American Society of Anesthesiologists (ASA) score, or BMI (p = 0.68, 0.54, 0.28, 0.45). Total drain output and blood loss were significantly higher in the IV TXA group than in the intraarticular TXA group (p < 0.0001, p < 0.0001). Eighteen patients in the IV TXA group and 1 patient in the intraarticular TXA group received a blood transfusion (p < 0.0001). There was no difference between the two groups in terms of preoperative hemoglobin or platelet count (p = 0.24). However, postoperative hemoglobin level was higher in the patients who received intraarticular TXA (p=0.0005). More thromboembolism events were seen in the IV TXA group (p < 0.0001).
CONCLUSIONS
Intraarticular TXA application reduces blood loss more than IV application, reduces the blood transfusion rate, and causes fewer complications.
KEY WORDS
tranexemic acid, total knee arthroplasty, intraarticular injection, blood loss, blood transfusion.
Topics: Humans; Arthroplasty, Replacement, Knee; Female; Male; Tranexamic Acid; Blood Loss, Surgical; Aged; Injections, Intra-Articular; Antifibrinolytic Agents; Middle Aged; Blood Transfusion; Administration, Intravenous; Postoperative Hemorrhage; Constriction; Retrospective Studies
PubMed: 38963893
DOI: 10.55095/achot2024/019 -
International Ophthalmology Jul 2024To understand factors affecting visual prognosis and the number of intravitreal antivascular endothelial growth factor (anti-VEGF) injections needed to stabilize wet...
PURPOSE
To understand factors affecting visual prognosis and the number of intravitreal antivascular endothelial growth factor (anti-VEGF) injections needed to stabilize wet age-related macular degeneration (AMD).
METHODS
In this retrospective cohort, 119 treatment-naïve wet AMD patients were followed for two years. In patients with bilateral disease, the eye with worse best-corrected visual acuity (BCVA) or that received more intravitreal injections was recruited as the study eye. In all visits, BCVA was recorded, ophthalmological examination was performed including macular optical coherence tomography imaging. Twenty health status/lifestyle questions were asked to the patients via phone as potential risk factors. All patients received 3 loading doses of intravitreal bevacizumab injections and received repeat injections of aflibercept or ranibizumab when the eye had a new, active neovascular lesion.
RESULTS
Patients who took regular micronutrition had similar visual outcome and injection numbers compared to the ones who did not. Patients with bilateral disease needed less intravitreal injections compared to unilateral AMD patients (p = 0.016) and women on hormone replacement therapy (HRT) required less injections compared to the women who were not (p = 0.024). Female patients had a mean gain of 2.7 letters while male patients lost 3.8 letters (p = 0.038). Wet AMD started at an earlier age in smokers (p = 0.002). Patients with a better education level presented earlier with better BCVA (p = 0.037).
CONCLUSION
HRT and anti-VEGF injections to the fellow eye improved the prognosis of wet AMD, while male patients had slightly worse prognosis. Estrogen's protective effects and potential contribution in wet AMD needs further attention. Retrospectively registered: 2020/0622.
Topics: Humans; Male; Intravitreal Injections; Retrospective Studies; Female; Wet Macular Degeneration; Angiogenesis Inhibitors; Visual Acuity; Aged; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Bevacizumab; Tomography, Optical Coherence; Prognosis; Vascular Endothelial Growth Factor A; Aged, 80 and over; Follow-Up Studies; Middle Aged; Fluorescein Angiography
PubMed: 38963653
DOI: 10.1007/s10792-024-03243-1