Honey in Alleviating Severe Oral Mucositis Among Head and Neck Cancer Patients Undergoing Radiation Therapy.

BACKGROUND/AIM: Aiming to resolve debates on honey's efficacy for radiotherapy-induced severe oral mucositis in head and neck cancer, we conducted a meta-analysis focused on randomized trials, primarily assessing severe mucositis incidence. Secondary outcomes included weight loss, pain management, and honey types. MATERIALS AND METHODS: A comprehensive literature search was conducted in PubMed, Embase, WOS, and the Cochrane Library up to December 2023. The analysis concentrated on randomized controlled trials that assessed the efficacy of honey, targeting the incidence of mucositis as the main outcome. Additional outcomes explored were weight loss, intolerable pain, and the specific types of honey used in interventions. Data analysis was performed using CMA software, and a funnel plot was employed to identify publication bias. RESULTS: The analysis of 176 records resulted in the inclusion of 10 studies with 599 patients receiving radiotherapy. The research showed that honey significantly reduced the occurrence of grade 3-4 mucositis (severe mucositis), provided significant pain relief, and had a positive effect on reducing weight loss. Regarding the type of honey used, no significant differences were found in their effectiveness in alleviating severe mucositis. CONCLUSION: Honey serves as an effective intervention for individuals with oral mucositis. It can be considered as an adjuvant in the management of clinical radiotherapy-associated oral mucositis, particularly for patients requiring prolonged use of anti-analgesic or antifungal medications.

Risk of Keratitis and Keratopathy in Hidradenitis Suppurativa Patients: A Global Federated Health Network Analysis.

BACKGROUND/AIM: Hidradenitis suppurativa (HS) is linked to immune dysregulation and systemic inflammation. While previous studies indicate a higher prevalence of ocular manifestations in HS, the specific risk of keratopathy and keratitis remains unclear. The primary aim of this study was to assess the risk of keratitis and keratopathy in individuals with HS. PATIENTS AND METHODS: In this retrospective cohort study conducted with data from the TriNetX database, 53,716 patients with HS were matched to an equivalent number of non-HS controls using propensity score matching. The study covered the period from January 1st, 2005, to December 31st, 2017. Hazard ratios and their respective 95% confidence intervals (CIs), were computed to evaluate the occurrences of keratitis and keratopathy over a 5-year duration in patients with HS, compared to non-HS controls. RESULTS: HS was associated with a 1.52 times higher risk of keratitis over a 5-year period (95%CI=1.24-1.86) and a 1.47 times higher risk of keratopathy (95%CI=1.18-1.84). These risks remained consistent in sensitivity analyses. The elevated risk of keratitis was observed across both sexes. However, the risk of keratopathy was significantly higher in women with HS (HR=1.61, 95%CI=1.24-2.10) and individuals aged 18-64 years (HR=1.32, 95%CI=1.04-1.68). CONCLUSION: HS was linked to an elevated risk of both keratitis and keratopathy over a 5-year period. Ophthalmologic manifestations are recommended to be considered in HS standard care.

Hidradenitis suppurativa as a potential risk factor of periodontitis: a multi-center, propensity-score-matched cohort study.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with systemic symptoms. Periodontitis, a prevalent dental disease, shares immune-mediated inflammatory characteristics with HS. This cohort study aims to evaluate the association between HS and periodontitis. Methods: Using the TriNetX research network, a global-federated database of electronic health records, we conducted a retrospective cohort study. People being diagnosed of HS were identified and propensity score matching was performed to identify proper control group, via balancing critical covariates Within the follow-up time of 1 year, 3 year and 5 years, hazard ratios were calculated to assess the risk of periodontitis in HS patients compared to controls. Results: Within the 53,968 HS patients and the same number of matched controls, the HS patients exhibited a significantly increased risk of developing periodontitis compared to controls after 3 years of follow-up (HR: 1.64, 95% CI: 1.11, 2.44) and 5 years of follow-up (HR: 1.64, 95% CI: 1.21, 2.24) of follow-up. Sensitivity analyses supported these findings under various matching models and washout periods. While comparing with patients with psoriasis, the association between HS and periodontitis remained significant (HR: 1.73, 95% CI: 1.23, 2.44). Conclusion: The observed increased risk suggests the need for heightened awareness and potential interdisciplinary care for individuals with HS to address periodontal health.

A Pilot Study of Radiculopathy Following Osteoporotic Vertebral Fracture in Elderly Patients: An Algorithmic Approach to Surgical Management.

Background: Osteoporotic vertebral compression fractures (OVCF) due to severe and refractory back pain or neurological complications require surgical treatment. In this study, patients with radiculopathy due to foraminal stenosis following OVCF were surgically managed by performing transforaminal full-endoscopic lumbar foraminoplasty and/or discectomy (FELFD). Methods: From May 2015 to November 2019, fifteen patients underwent transforaminal FELFD. Patient data, Charlson comorbidity index (CCI), and American Society of Anesthesiologists (ASA) score were collected. Clinical outcomes, including pre- and postoperative Visual Analog Scale (VAS) scores for back and leg pain, Oswestry Disability Index (ODI), and MacNab criteria of response to surgical treatment, were evaluated. Results: Mean of age, bone mineral density (T-score), CCI, ASA, and follow-up duration were 69.5 ± 6.6 years, -2.6 ± 0.8, 5.2 ± 2.3, 2.4 ± 0.5, and 24.5 ± 8.8 months, respectively. Mean VAS for leg pain significantly decreased from 6.9 ± 0.8 preoperatively to 2.9 ± 1.1 (P < .05). Mean ODI decreased from 39.9 ± 3.2 preoperatively to 19.3 ± 4.6 postoperatively (P < .05). The satisfaction rate is 86.7% (based on Macnab criteria), showed six patients had excellent outcomes and seven had good outcomes. Conclusions: Transforaminal FELFD is an effective treatment option for patients with radiculopathy due to lumbar OVCF, including those with severe osteoporosis and elderly patients.

Effect of ethanol extracts of Hericium erinaceus mycelium on morphine­induced microglial migration.

Microglia serve important roles in chronic pain signal transduction pathways. Glia cells, especially microglia, seem to share mechanisms that lead to chronic pain and morphine­induced tolerance. Evidence has suggested that downregulating cytoskeleton activity in microglia provides pain relief in chronic pain and morphine tolerance. The purpose of the present study was to evaluate the effect of ethanol extracts of Hericium erinaceus (EHE) mycelium on morphine­induced BV2 microglial cell activation. BV2 cells were starved for 4 h in DMEM before being incubated with 100 ng/ml EHE for 30 min, followed by 1 µM morphine for 2 h. Subsequently, the cells were harvested and used for migration experiments and western blotting. The results showed that 1 µM morphine enhanced BV2 cell activation and chemotactic reaction, and it increased histone deacetylase 6 (HDAC6) expression and heat shock protein 90 (HSP90) deacetylation as well as HSP90 cleavage. Pretreatment with 100 ng/ml EHE significantly inhibited the morphine­stimulated effects on BV2 cells. The present study demonstrated that EHE inhibited morphine­induced BV2 activations by regulating the HDAC6/HSP90 deacetylation signal transduction pathway.

Melatonin regulation of transcription in the reversal of morphine tolerance: Microarray analysis of differential gene expression.

Tolerance and associated hyperalgesia induced by long­term morphine administration substantially restrict the clinical use of morphine in pain treatment. Melatonin, a neurohormone released by the pineal gland, has been demonstrated to attenuate anti­nociceptive morphine tolerance. The present study investigates differentially expressed genes in the process of morphine tolerance and altered gene expression subsequent to melatonin treatment in chronic morphine­infused ratspinal cords. Morphine tolerance was induced in male Wistar rats by intrathecal morphine infusion (the MO group). Melatonin (the MOMa group) was administered to overcome the effects derived by morphine. The mRNA collected from L5­S3 of the spinal cord was extracted and analysed by rat expression microarray. Principal component analysis and clustering analysis revealed that the overall gene profiles were different in morphine and melatonin treatments. Subsequent to Gene Ontology analysis, the biological processes of differentially expressed genes of MO and MOMa compared with the control group were constructed. Furthermore, a panel of genes exclusively expressed following melatonin treatment and another panel of genes with inverse expression between the MO and MOMa group were also established. Subsequent to PANTHER pathway analysis, a group of genes with inverse expression following melatonin administrated compared with morphine alone were identified. The expression levels of genes of interest were also confirmed using a reverse transcription­quantitative polymerase chain reaction. The gene panel that was constructed suggests a potential signaling pathway in morphine tolerance development and is valuable for investigating the mechanism of morphine tolerance and the regulatory gene profiles of melatonin treatment. These results may contribute to the discovery of potential drug targets in morphine tolerance treatments in the future.

Ganoderma microsporum immunomodulatory protein induces apoptosis and potentiates mitomycin C-induced apoptosis in urinary bladder urothelial carcinoma cells.

Current chemotherapy and immunotherapy treatments followed by transurethral resection for urinary bladder urothelial carcinoma (UC) usually suffer from poor prognosis and high recurrence rate. Design and modification of current formulation with the novel adjuvants are needed. A recombinant protein derived from Ganoderma microsporum named as Ganoderma microsporum immunomodulatory protein (GMIP) was used to treat UC cells. We found GMIP elicits a dose-dependent and time-dependent anti-UC cell proliferation effect, with a half-maximal inhibition concentration (IC50 ) comparable to mitomycin C (MMC), a commonly used chemotherapy agent. After GMIP treatment, UC cells showed apoptotic phenomenon including cell cycle arrest in the G1 phase, elevated sub-G1 population, mitochondrial membrane potential loss, up-regulated p21 expression, p21 nuclear translocation, caspase activation, and PARP cleavage in a p53-independent but p21-mediated pathways. Unlike lung cancer cells, GMIP treated UC cells showed no autophagic scheme including Beclin-1, an autophagy to apoptosis switch marker, was not cleaved by caspase 3 and slight LC3B-II accumulation. Also, the classic autophagic inhibitor, chloroquine had no effect in GMIP-mediated cell death made us conclude that GMIP induced apoptosis through caspase activation but not autophagy in UC cells. Additionally, GMIP showed synergistic effects with MMC in killing UC cells and thus decreased the concentration of MMC usage to reach the comparable apoptotic effects. Our results delineate novel strategies for treatment of UC by GMIP alone or in combination with MMC application and provide a promising therapeutic cocktail for better treatment of urinary bladder urothelial carcinoma.

Association of anterior cruciate ligament injury with knee osteoarthritis and total knee replacement: A retrospective cohort study from the Taiwan National Health Insurance Database.

OBJECTIVE: This study aimed to support the potential protective role of anterior cruciate ligament (ACL) reconstruction against the development of osteoarthritis (OA). METHODS: In this retrospective cohort study, the long-term results of ACL reconstruction in Taiwan were evaluated based on data from the National Health Insurance Research Database (NHIRD). In total, 8,769 eligible cases were included from 11,921 ACL-injured patients. The cumulative incidence rates of OA and total knee replacement (TKR) were analyzed using the Kaplan-Meier estimator. Cox proportional hazards models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of OA. RESULTS: There was a lower cumulative incidence of OA among ACL-reconstructed patients (271, 33.1%) than among non-reconstructed patients (1,874, 40.3%; p < 0.001). Patients who underwent ACL reconstruction had a lower cumulative incidence of TKR during the follow-up period (0.6%) than the non-reconstructed patients (4.6%, p < 0.001). After adjusting for covariates, ACL-injured patients who underwent reconstruction within one month after ACL injury showed a significantly lower risk of OA than those who never underwent reconstruction (adjusted HR = 0.83, 95% CI = 0.69-0.99). CONCLUSIONS: These results indicate that ACL reconstruction might not provide complete protection from OA development after traumatic knee injury but does yield a lower cumulative incidence of OA development and TKR. Moreover, based on the present study, ACL-injured patients should undergo reconstruction as early as possible (within one month) to lower the risk of OA.

Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression.

AIMS: Melatonin has been reported to attenuate opioid tolerance. In this study, we explored the possible mechanism of melatonin in diminishing morphine tolerance. MAIN METHODS: Two intrathecal (i.t.) catheters were implanted in male Wistar rats for drug delivery. One was linked to a mini-osmotic pump for morphine or saline infusion. On the seventh day, 50µg of melatonin or vehicle was injected through the other catheter instantly after discontinuation of morphine or saline infusion; 3h later, 15µg of morphine or saline was injected. The antinociceptive response was then measured using the tail-flick test every 30min for 120min. KEY FINDINGS: The results showed that chronic morphine infusion elicited antinociceptive tolerance and upregulated heat shock protein 27 (HSP27) expression in the dorsal horn of the rat spinal cord. Melatonin pretreatment partially restored morphine's antinociceptive effect in morphine-tolerant rats and reversed morphine-induced HSP27 upregulation. In addition, chronic morphine infusion induced microglial cell activation and was reversed by melatonin treatment. SIGNIFICANCE: The present study provides evidence that melatonin, acting via inhibiting morphine-induced neuroinflammation, can be useful as a therapeutic adjuvant for patients under long-term opioid treatment for pain relief.

Resveratrol reverses morphine-induced neuroinflammation in morphine-tolerant rats by reversal HDAC1 expression.

BACKGROUND/PURPOSE: We previously showed that subsequent intrathecal (i.t.) injection of resveratrol (30 µg) significantly reverses morphine-evoked neuroinflammation in morphine-tolerant rats. The present study examined the underlying mechanism. METHODS: Male Wistar rats were implanted with two i.t. catheters, one of which was connected to a miniosmotic pump and used for morphine (15 µg/h) or saline infusion for 120 hours. To examine the effects on spinal cord expression of histone deacetylase 1 (HDAC1), the inflammatory cytokine tumor necrosis factor-α (TNF-α), and TNF receptor (TNFR) 1 and TNFR2 during tolerance induction, a tail-flick test was performed prior to infusion and after 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours of infusion. RESULTS: Resveratrol treatment prior to morphine challenge restored the antinociceptive effect of morphine in morphine-tolerant rats and reversed the morphine infusion-induced increase in HDAC1, TNF-α, and TNFR1 expression. Moreover, chronic morphine infusion increased TNFR1-specific expression in neuron in morphine-tolerant rat spinal cords, and this effect was almost completely inhibited by resveratrol treatment prior to morphine challenge. CONCLUSION: Resveratrol restores the antinociceptive effect of morphine by reversing morphine infusion-induced spinal cord neuroinflammation and increase in TNFR1 expression. The reversal of the morphine-induced increase in TNFR1 expression by resveratrol is partially due to reversal of the morphine infusion-induced increase in HDAC1 expression. Resveratrol pretreatment can be used as an adjuvant in clinical pain management for patients who need long-term morphine treatment or with neuropathic pain.

Sulfasalazine attenuates ACL transection and medial menisectomy-induced cartilage destruction by inhibition of cystine/glutamate antiporter.

We had previously demonstrated that excitatory amino acid glutamate plays a role in the progression and severity of knee osteoarthritis (OA), and early hyaluronic acid injection attenuates the OA progression by attenuation of knee joint glutamate level, which was also related to the cystine/glutamate antiporter system X (system XC-) expression. System XC- uptakes cystine into chondrocytes for glutathione (GSH) synthesis, but the role of system XC- in OA is rarely addressed. Sulfasalazine (SSZ) is a system XC- inhibitor; SSZ was applied intra-articularly to study the function of system XC- in the development of OA in rats subjected to anterior cruciate ligament transection and medial meniscectomy (ACLT + MMx). Moerover, the system XC- activator N-acetylcysteine (NAC) was also applied to verify the role of system XC-. The intra-articular injection of SSZ significantly attenuated knee swelling and cartilage destruction in the knees of ACLT + MMx rats and this effect was blocked by NAC. The results showed that inhibition of system XC- function can attenuate ACLT + MMx-induced cartilage destruction. In the present study, system XC- inhibitor SSZ was shown to reduce glutamate content in synovial fluid and GSH in chondrocytes. It was also showed SSZ could attenuate ACLT + MMx-induced cartilage destruction, and treatment of NAC reversed the protective effect of SSZ.

(+)-Naloxone inhibits morphine-induced chemotaxis via prevention of heat shock protein 90 cleavage in microglia.

BACKGROUND/PURPOSE: Microglia have a crucial role in maintaining neuronal homeostasis in the central nervous system. Immune factors released from microglia have important roles in nociceptive signal transduction. Activation of microglia seems to be a shared mechanism in pathological pain and morphine tolerance because pharmacological attenuation of microglia activation provides satisfactory management in both situations. METHODS: In the present study, we investigated the effect of 1nM (+)-naloxone, which is not an opioid receptor antagonist, on morphine-induced activation of microglia EOC13.31 cells. RESULTS: Our results showed that 1µM morphine enhanced microglia activation and migration, decreased α-tubulin acetylation, and induced heat shock protein 90 (HSP90) fragmentation and histone deacetylase 6 (HDAC6) expression. Morphine-induced α-tubulin deacetylation and HSP90 fragmentation were HDAC6-dependent. Pretreatment with (+)-naloxone (1nM) inhibited morphine-evoked microglia activation and chemotaxis and prevented α-tubulin deacetylation and HSP90 fragmentation by inhibiting HDAC6 expression. CONCLUSION: Based on the findings of the present study, we suggest that (+)-naloxone inhibits morphine-induced microglia activation by regulating HDAC6-dependent α-tubulin deacetylation and HSP90 fragmentation.

Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats.

BACKGROUND/PURPOSE: In a recent study, we found that baicalin exhibited a potent analgesic effect on carrageenan-evoked thermal hyperalgesia. The underlining mechanisms may be associated with inhibition of inflammatory mediator overproduction, including proinflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). In the present study, we examined the effect of baicalin on the antinociceptive effect of morphine and histone deacetylase 1 (HDAC1) expression in the spinal cord dorsal horn in neuropathic pain rats. METHODS: Neuropathic pain was induced by tight ligation of the left L5 spinal nerve of the rats. An intrathecal catheter was implanted for drug administration. Nociception was assessed by using the plantar test with the Hargreaves radiant heat apparatus, and the von Frey test with the dynamic plantar anesthesiometer. Spinal cords were removed for histone acetyl-H3 and HDAC1 western blot analysis at the end of the nociceptive assessment. RESULTS: The results showed that hyperalgesia and allodynia were observed in the spinal nerve ligated (SNL) left hindlimb; it was companied by histone-H3 deacetylation and HDAC1 overexpression on the ipsilateral side of the spinal cord dorsal horn. Intrathecal injection of baicalin (10 µg) significantly attenuated the allodynia and hyperalgesia, and enhanced the antinociceptive effect of morphine (15 µg). Moreover, baicalin reversed the histone-H3 acetylation and suppressed HDAC1 expression on the ipsilateral side of the spinal cord dorsal horn of SNL rats. CONCLUSION: The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats.

Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats.

BACKGROUND/PURPOSE: As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine. METHODS: Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 µg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 µl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 µl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 µg in 5 µl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45-52°C, respective). RESULTS: Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine. CONCLUSION: This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management.

Early intraarticular injection of hyaluronic acid attenuates osteoarthritis progression in anterior cruciate ligament-transected rats.

SUBJECT: Hyaluronic acid (HA) is widely used to relieve the symptoms of osteoarthritis (OA). An association of reduction of glutamate content with the synovial fluid of OA rats was reported previously. DESIGN: Anterior cruciate ligament transaction (ACLT) was performed on one knee in male Wistar rats, the other knee was assigned to sham control and HA or saline was injected intraarticularly into the ACLT knee from week 3 to week 7. Knee dialysate was collected for amino acid measurement at week 20. Morphology and histopathology of the femoral medial condyles and synovium were examined and evaluated using Mankin and synovitis scores. RESULTS: HA injection provided better cartilage (3.38 ± 0.03 vs. 5.45 ± 0.0.02) and synovial condition (3 ± 0.02 vs. 6.03 ± 0.02) than saline controls. Moreover, HA injection reduced the concentration of glutamates in knee dialysates compared to saline controls (1.11 ± 0.14-folds and 2.21 ± 0.19-folds of the sham-operated knee, respectively). Cystine/glutamate antiporter system [Formula: see text] expression was significantly downregulated in the saline group, but not in the HA group (0.32 ± 0.08-folds and 0.71 ± 0.10-folds of the sham-operated knee, respectively). CONCLUSION: Early intraarticular injection of HA attenuates the progression of cartilage destruction in the ACLT knee, and the downregulation of the cystine/glutamate antiporter system [Formula: see text] was accompanied by the progression of OA.