-
Sexual Medicine Reviews Jun 2024Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection... (Review)
Review
INTRODUCTION
Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982.
OBJECTIVES
To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine's History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy.
METHODS
Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed.
RESULTS
The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine.
CONCLUSIONS
After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.
Topics: Humans; Male; Erectile Dysfunction; History, 20th Century; History, 21st Century; Injections; Vasodilator Agents; Papaverine; Alprostadil; Phentolamine
PubMed: 38644056
DOI: 10.1093/sxmrev/qeae020 -
Journal of Ethnopharmacology Sep 2024Long-term chronic inflammation often leads to chronic diseases. Although Sophora flavescens has been shown to have anti-inflammatory properties, its detailed molecular...
ETHNOPHARMACOLOGICAL RELEVANCE
Long-term chronic inflammation often leads to chronic diseases. Although Sophora flavescens has been shown to have anti-inflammatory properties, its detailed molecular mechanism is still unknown.
AIM OF STUDY
This study investigated the effect of Radix Sophorae Flavescentis on the LPS-induced inflammatory response in macrophages.
MATERIALS AND METHODS
LPS was used to induce the peritoneal macrophages to simulate the inflammatory environment in vitro. Different concentrations of Radix Sophorae Flavescentis-containing (medicated) serum were used for intervention. The peritoneal macrophages were identified by using hematoxylin-eosin and immunofluorescence staining. ELISA was used to measure the TNF-α and IL-6 expression to determine the concentration of LPS. ELISA and Western blot (WB) were used to detect the PGE2 and CFHR2 expression in each group, respectively. The lentiviral vector for interference and overexpression of the CFHR2 gene was constructed, packaged, and transfected into LPS-induced macrophages. The transfection efficiency was verified by WB. Then, ELISA was used to detect the TNF-α, PGE2, and IL-6 expression. WB was used to detect the CFHR2, iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression.
RESULTS
The primary isolated cells were identified as macrophages. The LPS-treated macrophages exhibited significantly higher expression of PGE2 and CFHR2, and the inflammatory factors TNF-α and IL-6, as well as iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression compared with the control group (P < 0.05). The TNF-α, PGE2, and IL-6 levels, as well as CFHR2, iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression were considerably lower in the LPS-induced+10% medicated-serum group, LPS-induced+20% medicated-serum group, and shCFHR interference group compared with the LPS group (P < 0.05).
CONCLUSION
Radix Sophorae Flavescentis might mediate CFHR2 expression and play an important role in inhibiting the LPS-induced pro-inflammatory response of macrophages. Radix Sophorae Flavescentis could be a potential treatment for LPS-induced related inflammatory diseases.
Topics: Animals; Lipopolysaccharides; Sophora; Anti-Inflammatory Agents; Mice; Macrophages, Peritoneal; Interleukin-6; Tumor Necrosis Factor-alpha; Dinoprostone; Plant Extracts; Inflammation; Toll-Like Receptor 2; Male; STAT1 Transcription Factor; Plant Roots; Cells, Cultured; Macrophages; Toll-Like Receptor 4; Sophora flavescens
PubMed: 38641074
DOI: 10.1016/j.jep.2024.118210 -
Journal of Molecular Endocrinology Jul 2024The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour and cancer....
The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding the spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE), which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs-biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane-initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This, in turn, could highlight important considerations for future selective targeting of EP2 signalling pathways.
Topics: Humans; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction; Female; Pregnancy; Cyclic AMP; GTP-Binding Proteins; Endosomes; Protein Transport; Myometrium; Alprostadil; HEK293 Cells; Animals
PubMed: 38639976
DOI: 10.1530/JME-23-0153 -
Archives of Toxicology Jul 20243-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in...
3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
Topics: Animals; Reactive Oxygen Species; Zebrafish; Fluorenes; NF-kappa B; Endothelium, Vascular; Endothelial Cells; Cell Line; Cyclooxygenase 2; Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Inflammation; Dinoprostone; Dose-Response Relationship, Drug; Capillary Permeability
PubMed: 38635053
DOI: 10.1007/s00204-024-03751-0 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Feb 2024Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum...
Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1β(IL-1β) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1β, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1β-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.
Topics: Humans; Rats; Animals; NF-kappa B; Chondrocytes; Caspase 3; Ligusticum; bcl-2-Associated X Protein; Cyclooxygenase 2; Interleukin-1beta; HMGB1 Protein; Dinoprostone; Myeloid Differentiation Factor 88; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Signal Transduction; Inflammation; Osteoarthritis; Apoptosis; RNA, Messenger
PubMed: 38621908
DOI: 10.19540/j.cnki.cjcmm.20230904.401 -
International Journal of Molecular... Mar 2024Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; ) both participate in diverse pathologies including cancer progression. However, the biological...
Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; ) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.
Topics: Humans; Female; Cyclooxygenase 2; Gene Expression Regulation; Endometrial Neoplasms; NFATC Transcription Factors; Signal Transduction; Dinoprostone; Factor V; Transcription Factors
PubMed: 38612478
DOI: 10.3390/ijms25073666 -
World Neurosurgery Jun 2024Patients with Lumbar Spinal Stenosis (LSS) typically complain of back pain and leg pain. These symptoms reduce the quality of life (QoL) and also cause sleep... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
BACKGROUND
Patients with Lumbar Spinal Stenosis (LSS) typically complain of back pain and leg pain. These symptoms reduce the quality of life (QoL) and also cause sleep disturbances. This study compares pregabalin and limaprost's efficacy in LSS for pain, disability, QoL, and sleep, aiming to offer insights for medication selection.
METHODS
This study was designed as a prospective, randomized, single-center, single-blinded, clinical superiority trial targeting patients with LSS. For 6 weeks, 111 patients per group were administered medication following a standard regimen, after which patient-reported outcomes were measured. The primary outcome was the Visual Analogue Scale (VAS) for back and leg pain, and the secondary outcomes included the Oswestry Disability Index (ODI), European Quality of Life 5 Dimensions (EQ-5D), and sleep quality.
RESULTS
After 6 weeks of medication, there were significant improvements over time in the primary outcome, VAS for back pain and leg pain, in both groups, but no significant difference between the 2 groups. Similarly, for the secondary outcomes, ODI and EQ-5D, both groups showed significant improvements, yet there was no significant difference between them. In the subgroup analysis targeting poor sleepers (Pittsburgh sleep quality index, PSQI >5), both groups also exhibited significant improvements in sleep quality, but again, there was no significant difference between the groups.
CONCLUSIONS
Efficacy of pregabalin, limaprost in back and leg pain, ODI, EQ-5D, and sleep quality, but there was no significant difference between the 2 groups. Thus, it is advisable to prescribe based on individual drug responses and potential complications.
Topics: Humans; Pregabalin; Spinal Stenosis; Male; Female; Aged; Middle Aged; Prospective Studies; Lumbar Vertebrae; Treatment Outcome; Single-Blind Method; Analgesics; Quality of Life; Alprostadil; Pain Measurement
PubMed: 38608818
DOI: 10.1016/j.wneu.2024.04.033 -
European Journal of Cell Biology Jun 2024Mesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved...
Mesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved in endochondral bone development. This study aimed to identify drivers of PGE2 and its role in the inadvertent MSC misdifferentiation into hypertrophic chondrocytes. PGE2 release, which rose in the first three weeks of MSC chondrogenesis, was jointly stimulated by endogenous BMP, WNT, and hedgehog activity that supported the exogenous stimulation by TGF-β1 and insulin to overcome the PGE2 inhibition by dexamethasone. Experiments with PGE2 treatment or the inhibitor celecoxib or specific receptor antagonists demonstrated that PGE2, although driven by prohypertrophic signals, exerted broad autocrine antihypertrophic effects. This chondroprotective effect makes PGE2 not only a promising option for future combinatorial approaches to direct MSC tissue engineering approaches into chondral instead of endochondral development but could potentially have implications for the use of COX-2-selective inhibitors in osteoarthritis pain management.
Topics: Mesenchymal Stem Cells; Chondrogenesis; Dinoprostone; Humans; Cell Differentiation; Cells, Cultured; Chondrocytes
PubMed: 38608422
DOI: 10.1016/j.ejcb.2024.151412 -
Journal of Obstetrics and Gynaecology :... Dec 2024Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. decoction (GGD), a traditional Chinese medicine, has shown promise in treating...
BACKGROUND
Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. decoction (GGD), a traditional Chinese medicine, has shown promise in treating PD, but its exact mechanisms remain unclear. Here, we aimed to investigate the efficiency of GGD in alleviating PD using a rat model to understand its precise mechanism of action.
METHODS
We established a rat model of dysmenorrhoea induced by oestradiol and oxytocin. The PD rats were administered GGD or Ibuprofen (positive control) intragastrically once daily for seven consecutive days. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), β-endorphin (β-EP), thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α) were determined using an enzyme-linked immunosorbent assay (ELISA). The expression levels of oestrogen receptor alpha (ERα) and cyclooxygenase-2 (COX-2) in uterine tissue were measured using immunohistochemical assays, and those of phosphorylated and total extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were assessed using western blot analysis.
RESULTS
Treatment with GGD significantly reduced writhing behaviour, histopathological scores, and levels of COX-2, PGE2, and PGF2α in the serum of PD rats. Additionally, GGD increased β-EP content and inhibited ERK1/2 activation and ERα expression in uterine tissues.
CONCLUSIONS
The results of this study suggest that GGD alleviates PD in rats by suppressing the COX-2-mediated release of PGE2 and PGF2α, modulating the ERα/ERK1/2/COX-2 pathway, and increasing β-EP content. These results provide insights into the potential mechanisms of GGD in treating PD and support its further investigation as an alternative therapy for this condition.
Topics: Humans; Female; Rats; Animals; Dysmenorrhea; Cyclooxygenase 2; Estrogen Receptor alpha; Dinoprostone; Dinoprost
PubMed: 38594870
DOI: 10.1080/01443615.2024.2337691 -
The Aging Male : the Official Journal... Dec 2024To evaluate the efficacy of a novel approach to achieve the optimal penile erection during the penile doppler ultrasound (PDU) examination, which was oral sildenafil... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To evaluate the efficacy of a novel approach to achieve the optimal penile erection during the penile doppler ultrasound (PDU) examination, which was oral sildenafil combined alprostadil injection.
MATERIALS AND METHODS
A total of 60 ED patients were enrolled in our prospective study, and they were randomly assigned to two group with different PDU order. The approaches assisted the PDU included two models, mode A meaning injection of 15 μg alprostadil and model B meaning oral sildenafil 100 mg plus injection of 15 μg alprostadil. The PDU parameters were measured continuously before induced erection, and 5, 10, 15, 20, 25 min.
RESULTS
Each group included 30 ED patients with similar clinical characteristics. After pooling the results together, the PSV, EDV, and RI were all improved significantly, when adding the oral sildenafil administration to assist PDU. Also, the clinical response of oral sildenafil administration plus alprostadil injection was better than that in alprostadil injection alone ( = 0.016). The arterial ED were decreased from 31.67% to 15.00% with the P value 0.031, and the mixed ED was also decreased statistically (23.33% vs 8.33%, = 0.024).
CONCLUSION
Oral sildenafil administration plus alprostadil injection could improve the diagnostic accuracy of PDU.
Topics: Male; Humans; Sildenafil Citrate; Penile Erection; Alprostadil; Erectile Dysfunction; Prospective Studies; Penis; Ultrasonography, Doppler
PubMed: 38590113
DOI: 10.1080/13685538.2024.2339352