Non-Hispanic Black (NHB) adults demonstrate impaired microvascular endothelial function, characterized as reduced nitric oxide (NO)-mediated vasodilation, compared to non-Hispanic White adults. A sexual dimorphism exists, where microvascular dysfunction is mediated through elevated superoxide generation in NHB men but not NHB women. Inflammatory mechanisms in NHB women may contribute, but these mechanisms have not been explored in vivo. We hypothesized that micro- and macrovascular function would improve after oral salsalate [nuclear factor kappa B (NF-κB) activation inhibitor] in NHB women. After placebo or salsalate (1,500 mg twice a day, 5 days), two intradermal microdialysis fibers were placed in 13 NHB women [28 (7) yr]. Local heating units (33°C) and laser-Doppler flowmetry (flux) probes were placed over each fiber. Increasing concentrations of acetylcholine were perfused alone (ACh; dissolved in lactated Ringer's) or with N[G]-nitro-l-arginine methyl ester (ACh+l-NAME). Cutaneous vascular conductance was calculated (CVC = flux × mmHg[-1]) and normalized to site-specific maximum (28 mM sodium nitroprusside + 43°C). Macrovascular endothelial function was assessed by brachial artery flow-mediated dilation (FMD) and handgrip-augmented FMD (FMD+HG). Salsalate treatment did not impact ACh-induced vasodilation overall (main effect, P = 0.24), but a treatment × site interaction effect emerged (P < 0.0001). ACh increased and ACh+l-NAME decreased after salsalate (both P ≤ 0.03), but this effect was small (Cohen's f = 0.19). Five-day salsalate treatment did not alter %FMD (P = 0.28) or %FMD+HG (P = 0.17). Cutaneous microvascular, but not macrovascular, function marginally improved after salsalate, indicating that inflammation via NF-κB pathways contributes to impaired cutaneous microvascular function in NHB women.NEW & NOTEWORTHY Our results show that cutaneous microvascular, but not macrovascular, function is improved after oral salsalate treatment in healthy non-Hispanic Black women. These data reveal that systemic inflammation via NF-κB pathways attenuates cutaneous microvascular function in this population.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease and is characterized by the formation and growth of fluid-filled renal cysts. With the current treatment tolvaptan not suited for the majority of patients, an urgent need remains for novel therapeutics. We have shown before that activation of adenosine monophosphate activated protein kinase (AMPK) with salsalate ameliorates disease progression in vivo to a similar extent as tolvaptan. Salsalate achieves this by affecting multiple disease mechanisms known to be involved in ADPKD pathogenesis, such as metabolic reprogramming, cell proliferation and inflammation. However, it is unclear to which extent these effects are dependent on AMPK activation or result from secondary target activation. Therefore, we investigated whether salsalate's active compound, salicylate, modulates these processes in Pkd1[-/-] renal epithelial cell lines, and whether salicylate effects are regulated by AMPK. Our findings indicate that for a large part, the effects of salicylate on targets related to cellular metabolism, cell proliferation and inflammation are dependent on its activation of AMPK. However, we also observed that salicylate induces mitochondrial uncoupling and inhibition of heme synthesis, while other AMPK activators do not, revealing AMPK-independent effects of salicylate in cystic disease. These results provide us with further insights into the working mechanisms of salsalate/salicylate and offer a solid basis for the future development of salsalate as a potential therapeutic for ADPKD.

BACKGROUND: Riluzole (RLZ), a benzothiazole, maintains glutamatergic homeostasis, salsalate (SLS) a NSAIDs suppresses NF-κB, and Nimodipine (NMD) blocks of calcium channels, addressing Alzheimer’s Diseases (AD) related excitotoxic, inflammatory, metabolic, and neurological disorders etc. has mapped drug-target-disease interactions and examined mechanism of RLZ, SLS, and NMD on AD. AIM: This study aims to employ network pharmacology approach to investigate the possible therapeutic mechanism of RLZ, SLS, and NMD in AD. MATERIALS AND METHODS: Developed a PPI network to find the main therapeutic targets of RLZ, SLS, and NMD against AD. Got canonical SMILES (Simplified Molecular Input Line Entry System) from PubChem and used several databases (SwissTargetPrediction, DisGeNET, STRING, DAVID, ShinyGO, ADMETlab 3.0, MolSoft, ProTox 3.0) to find AD-associated genes, pharmacokinetic/toxicity features, and to do functional enrichment. DrugBank, Lexicomp, DailyMed, and Medscape to analyse DDIs. RESULTS: RLZ, SLS, and NMD share 25 targets with AD and share KEGG pathways like “Alzheimer’s disease”, “neurodegeneration multiple diseases”, “insulin-resistance”, etc. with hub genes like CASP3, STAT3, APP, GSK3B, ACE, NOS3, MAPT, IGF1R, ACHE, and PPARA. RLZ primarily targeted nuclear and membrane receptors with high blood-brain barrier penetration, SLS targeted oxidoreductases and inflammatory/tau targets with a broad safety margin, and NMD targeted G-protein coupled receptors and calcium/vascular nodes despite a complex transporter-CYP interactome. DDI analysis showed moderate interactions between the NMD and SLS according to DrugBank and other 3 data base shown no significant interaction. CONCLUSIONS: RLZ, SLS, and NMD target multiple pathogenic pathways to regulate AD. Combining RLZ, SLS, and NMD may reduce excitotoxicity, neuroinflammation, metabolic dysfunction, and vascular injury in AD, suggesting promise for additional in-vivo and clinical trials.

Hyperuricemia (HU), a condition marked by an increase in serum uric acid (UA) levels, is a leading cause for the development of gout along with UA nephrolithiasis. Despite the accessibility of conventional urate-lowering therapies, many patients experience adverse effects or inadequate responses, prompting the exploration of alternative treatments. Herbal interventions have gained attention for their potential to manage HU due to their multi-targeted mechanisms, including inhibition of xanthine oxidase, enhancement of renal urate excretion, and modulation of inflammatory and oxidative stress pathways. This review emphasizes the bioactive compounds from various medicinal plants with urate-lowering properties, their molecular mechanisms, and synergistic effects when combined with synthetic drugs. Classical natural agents like salicylic acid and salsalate have also been reappraised for their mild uricosuric activity and anti-inflammatory action, offering a pharmacological bridge between traditional herbals and modern therapeutics. Certain plant-based formulations with their clinical data have also been highlighted. AI-driven screening and combinatorial chemistry are emerging tools to optimize herbal formulations while nanotechnology-based drug delivery systems offer enhanced bioavailability. Challenges of herbal therapy, such as extract standardization, dose optimization, and variability in experimental models, are also discussed. The article further explores the future scope of herbal treatments, emphasizing the need for large-scale clinical trials, regulatory approvals, and the development of standardized formulations to ensure consistency and efficacy. By integrating herbal interventions with conventional therapies, there is potential for improving patient outcomes for the management of HU, with few side effects.

Salsalate has not been studied during breastfeeding, but salsalate results in salicylic acid in the blood. Salicylic acid and aspirin have been studied during breastfeeding. The excretion of salicylate into breastmilk increases disproportionately as the maternal dosage increases. Long-term, high-dose maternal aspirin ingestion probably caused metabolic acidosis in one breastfed infant. Reye's syndrome is associated with aspirin administration to infants with viral infections, but the risk of Reye's syndrome from salicylate in breastmilk is unknown. An alternate drug is preferred over salsalate.

The Zaire Ebola virus is a highly virulent RNA virus that causes severe hemorrhagic fever in humans and nonhuman primates, with no effective treatments currently available. This study evaluates the inhibitory potential of six salicylic acid derivatives including aspirin, diflunisal, fendosal, fosfosal, salicylic acid, and salsalate; against three key Ebola virus receptor proteins through in-silico analysis. Molecular docking techniques have employed to model the interactions between these derivatives and the viral proteins VP24, VP35, and VP40. The results revealed that the salicylic acid derivatives demonstrated significantly stronger binding affinities to the VP35 receptor compared to other receptor proteins studied. Among the derivatives screened, those targeting the VP35 protein exhibited superior binding energy, glide energy, glide Emodel, glide Evdw, and glide ligand efficiency, alongside the lowest RMSD values. These findings suggest that salicylic acid derivatives hold promise as potential anti-Ebola therapies and warrant further investigation in clinical trials.

Women with endometriosis, an inflammatory disease, are at increased risk of cardiovascular disease and demonstrate impaired microvascular endothelial function, characterized by reduced nitric oxide (NO)-mediated vasodilation. In some clinical cohorts, nuclear factor-kappa B (NFκB) inhibition with salsalate improves endothelial function. We hypothesized that salsalate would improve cutaneous microvascular endothelial function in women with endometriosis. Following placebo or salsalate (3,000 mg·day[-1] for 5 days), four intradermal microdialysis probes were placed in 11 women (33 ± 7 yr) with endometriosis. Local heating units (set to 33°C) and laser-Doppler flowmetry (red blood cell flux) probes were placed over the probes. Increasing doses of acetylcholine (ACh; dissolved in lactated Ringer's solution) were perfused, alone (control) or coperfused with: N[G]-nitro-l-arginine methyl ester (l-NAME), atorvastatin (statin), or l-NAME + statin (combo). Maximal vasodilation was then induced (local heat at 43°C + sodium nitroprusside perfusion). Data were normalized as percentage of maximal cutaneous vascular conductance (CVC%max red blood cell flux/mean arterial pressure). To measure macrovascular endothelial function, flow-mediated dilation (FMD) was additionally performed. During placebo, coperfusion with statin did not impact the CVC%max ACh dose-response (P = 0.93). Oral salsalate attenuated the CVC%max response to ACh perfusion alone (P < 0.01) but did not impact the l-NAME site (P = 0.09). Salsalate significantly augmented the CVC%max response of the statin site (P < 0.01) but did not affect the combo site response (P = 1.00). FMD was not different between treatments (P = 0.79). Salsalate treatment impairs vasodilation in the cutaneous microcirculation in women with endometriosis through non-NO-dependent mechanisms.NEW & NOTEWORTHY Our results show that oral salsalate treatment negatively impacts microvascular function but does not alter macrovascular function. In contrast to the majority of other clinical populations with endothelial dysfunction, salsalate treatment reduces microcirculatory function through non-NO-dependent mechanisms in women with endometriosis.

The prevalence of obesity is rapidly increasing worldwide. Brown adipose tissue activates uncoupling protein 1 (UCP1) to generate heat through bypassing ATP synthesis, offering a potential target for obesity treatment. Targeting UCP1 activation to induce thermogenesis through small molecules presents a promising approach for obesity management. In this study, molecular docking of UCP1 activators, using 2,4-dinitrophenol (DNP) as a reference ligand (PDB ID: 8J1N, docking score: -5.343 kcal/mol), identified seven top-scoring compounds: naringin (-7.284 kcal/mol), quercetin (-6.661 kcal/mol), salsalate (-6.017 kcal/mol), rhein (-5.798 kcal/mol), mirabegron (-5.535 kcal/mol), curcumin (-5.479 kcal/mol), and formoterol (-5.451 kcal/mol). Prime MM-GBSA calculation of the top-scored molecule (i.e., naringin) in the docking study showed ΔGBind of -70.48 kcal/mol. Key interactions of these top 7 activators with UCP1 binding pocket residues Trp280, Arg276, Glu190, Arg83, and Arg91 were observed. Molecular dynamics simulations performed for 100 ns confirmed complex stability, with RMSD values below 6 Å. Additionally, most activators showed favorable intestinal absorption (>90 %) and lipophilicity (LogP 2-4), with pKa values supporting their pharmacological potential as UCP1-targeting therapeutics for obesity. These findings provide a foundation for designing potent UCP1 activators by integrating docking scores, interaction profiles, statistical profiles from MD simulations, and physicochemical assessments to develop effective anti-obesity therapies.

The transcriptional regulator nuclear factor-κB (NF-κB) is a mediator of endothelial dysfunction. Inhibiting NF-κB with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-κB can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-κB in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10[-10] to 10[-1] M, 33°C) alone and in combination with 15 mM N[G]-nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC%max; 28 mM sodium nitroprusside + 43°C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different (P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-κB improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms.NEW & NOTEWORTHY The transcription factor nuclear factor-κB (NF-κB) regulates multiple aspects of innate and adaptive immunity by encoding for genes that participate in inflammation and impact endothelial function following NF-κB inhibition with salsalate treatment. Our results show that cutaneous microvascular function is increased through non-nitric oxide (NO)-dependent mechanisms following salsalate treatment in reproductive-aged healthy women.

Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC20) on renal proximal tubule cells derived from Pkd1flox/-:TSLargeT mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their in vitro therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections in vivo, RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre) with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.