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Dicyandiamide (DCD) reacted with amino acids 1a–f to produce biguanides 2 and 4 and guanidine pyrazolones 3, 5, 6, 7, and 8, according to the reaction. DCD exhibited the following reactions: imidodicarbonimidicdiamide 9, diazocan-2-ylguanidine 10, methyl biguanidylthion 11, N-carbamothioylimidodicarbonimidicdiamide 12, 2-guanidinebenzoimidazole 13a, 2-guanidinylbenzoxazole 13b, and 2-guanidinylbenzothiazol 13c. These reactions were triggered by 6-amino caproic acid, thioacetamide, thiourea, o-aminophenol, o-aminothiophenol, and anthranilic acid, respectively. Compound 2 had the least antimicrobial activity, while compound 13c demonstrated the most antibacterial impact against all bacterial strains. Furthermore, in terms of antiglycation efficacy (AGEs), 12, 11, and 7 were the most effective AGE cross-linking inhibitors. Eight and ten, which showed a considerable inhibition on cross-linking AGEs, come next. Compounds 4 and 6 on the other hand have shown the least suppression of AGE production. The most promising antiglycation scaffolds 8, 11, and 12 in the Human serum albumin (HAS) active site were shown to be able to adopt crucial binding interactions with important amino acids based on the results of in silico molecular docking. The most promising antiglycation compounds 8, 11, and 12 were also shown to have better hydrophilicity, acceptable lipophilicity, gastrointestinal tract absorption (GIT), and blood–brain barrier penetration qualities when their physicochemical properties were examined using the egg-boiled method.

Background Sepsis is the leading cause of death in critically ill patients, with an in-hospital mortality rate of approximately 25% to 40%. Coagulation activation serves as an initial factor to the progression of sepsis into multiple organ dysfunction syndrome (MODS). Therefore, anticoagulant therapy may be beneficial. Both preclinical experiments and clinical studies have evaluated the protective effect of nafamostat mesilate (NM) in sepsis. However, there is still a lack of randomized controlled trials (RCTs) to further confirm the therapeutic effect and safety of NM in sepsis patients. Methods This multicenter, double-blind, RCT was designed to recruit 778 subjects who met Sepsis 3.0 criteria. Participants will be randomly assigned (1:1) to receive either intravenous administration of NM or glucose along with standard treatment. The primary outcome is the all-cause mortality rate in the intensive care unit (ICU), and the secondary outcomes include the improvement in SOFA scores, changes in Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH) scores, 28-day all-cause mortality rate, and the incidence of adverse events. The allocation will remain concealed from investigators, participants, and statisticians to maintain blinding. Discussion The EASNMS trial aims to assess the efficacy and safety of NM for treating sepsis across various regions in China. As an additional treatment option, NM may potentially enhance the prognosis of sepsis patients. Ethics and dissemination Ethical approval has been obtained from all ethics committees of the involved centers. The findings of this study will be shared in peer-reviewed journals and will be presented at conferences. Trial registration ClinicalTrials.gov NCT06078839. Registered on September 20, 2023.

Background In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). Methods This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. Results One-hundred fifty-five patients were randomized to receive camostat mesilate ( n  = 78) or placebo ( n  = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0–12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0–13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. Conclusions Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. Trial registration ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in d-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by d-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study

Neonicotinoid seed coating is associated with reduced density of wild bees, as well as reduced nesting of solitary bees and reduced colony growth and reproduction of bumblebees, but appears not to affect honeybees. Bees' responses to neonicotinoids examined Reports that neonicotinoid insecticides have adverse effects on bee populations remain controversial. Some studies have been criticized as using unrealistically high insecticide dosages or conditions far removed from those in the field, and it has been suggested that bees might be able to detect the insecticides and avoid treated crops. Two papers in this issue of Nature present results that fill some of the gaps in our knowledge. In laboratory experiments Sébastien Kessler et al . use field-level doses of three commonly used neonicotinoids — clothianidin, imidacloprid and thiamethoxam — to show that both honeybees and bumblebees are able to detect their presence. However, the bees do not avoid neonicotinoid-treated food and may even prefer it. Maj Rundlöf et al . sowed oilseed rape with and without a clothianidin seed coating in matched and replicated agricultural landscapes. They found the seed coating to be associated with reduced density of wild bees, as well as reduced nesting of solitary bees and reduced colony growth of bumblebees, but they did not detect an effect on honeybees. Understanding the effects of neonicotinoid insecticides on bees is vital because of reported declines in bee diversity and distribution 1 , 2 , 3 and the crucial role bees have as pollinators in ecosystems and agriculture 4 . Neonicotinoids are suspected to pose an unacceptable risk to bees, partly because of their systemic uptake in plants 5 , and the European Union has therefore introduced a moratorium on three neonicotinoids as seed coatings in flowering crops that attract bees 6 . The moratorium has been criticized for being based on weak evidence 7 , particularly because effects have mostly been measured on bees that have been artificially fed neonicotinoids 8 , 9 , 10 , 11 . Thus, the key question is how neonicotinoids influence bees, and wild bees in particular, in real-world agricultural landscapes 11 , 12 , 13 . Here we show that a commonly used insecticide seed coating in a flowering crop can have serious consequences for wild bees. In a study with replicated and matched landscapes, we found that seed coating with Elado, an insecticide containing a combination of the neonicotinoid clothianidin and the non-systemic pyrethroid β-cyfluthrin, applied to oilseed rape seeds, reduced wild bee density, solitary bee nesting, and bumblebee colony growth and reproduction under field conditions. Hence, such insecticidal use can pose a substantial risk to wild bees in agricultural landscapes, and the contribution of pesticides to the global decline of wild bees 1 , 2 , 3 may have been underestimated. The lack of a significant response in honeybee colonies suggests that reported pesticide effects on honeybees cannot always be extrapolated to wild bees.

BackgroundContinuous regional arterial infusion (CRAI) of protease inhibitor nafamostat mesilate (NM) is used in the context of predicted severe acute pancreatitis (SAP) to prevent the development of pancreatic necrosis. Although this therapy is well known in Japan, its efficacy and safety remain unclear.MethodsThis investigator-initiated and -driven, multicenter, open-label, randomized, controlled trial (UMIN000020868) enrolled 39 patients with predicted SAP and low enhancement of the pancreatic parenchyma on computed tomography (CT). Twenty patients were assigned to the CRAI group, while 19 served as controls and were administered NM at the same dose intravenously (IV group). The primary endpoint was the development of pancreatic necrosis as determined by CT on Day 14, judged by blinded central review.ResultsThere was no difference between the CRAI and IV groups regarding the percentages of participants who developed pancreatic necrosis (more than 1/3 of the pancreas: 25.0%, range 8.7–49.1% vs. 15.8%, range 3.4–39.6%, respectively, P = 0.694; more than 2/3 of the pancreas: 20%, range 5.7–43.7% vs. 5.3%, range 0.1–26.0%, respectively, P = 0.341). The early analgesic effect was evaluated based on 24-h cumulative fentanyl consumption and additional administration by intravenous patient-controlled analgesia. The results showed that the CRAI group used significantly less analgesic. There were two adverse events related to CRAI, namely bleeding and splenic infarction.ConclusionsCRAI with NM did not inhibit the development of pancreatic necrosis although early analgesic effect of CRAI was superior to that of IV. Less-invasive IV therapy can be considered a viable alternative to CRAI therapy.

Marine sponges contain a variety of low-molecular-weight compounds including guanidine alkaloids possessing different biological activities. Monanchomycalin B and urupocidin A were isolated from the marine sponge Monanchora pulchra. We found that they act as inhibitors of the TRPV1, TRPV2, and TRPV3 channels, but are inactive against the TRPA1 receptor. Monanchomycalin B is the most active among all published marine alkaloids (EC50 6.02, 2.84, and 3.25 μM for TRPV1, TRPV2, and TRPV3, correspondingly). Moreover, monanchomycalin B and urupocidin A are the first samples of marine alkaloids affecting the TRPV2 receptor. Two semi-synthetic urupocidin A derivatives were also obtained and tested against TRP (Transient Receptor Potential) receptors that allowed us to collect some data concerning the structure-activity relationship in this series of compounds. We showed that the removal of one of three side chains or double bonds in the other side chains in urupocidin A led to a decrease of the inhibitory activities. New ligands specific to the TRPV subfamily may be useful for the design of medicines as in the study of TRP channels biology.

It has been suggested that the negative effects on bees of neonicotinoid pesticides could be averted in field conditions if they chose not to forage on treated nectar; here field-level neonicotinoid doses are used in laboratory experiments to show that honeybees and bumblebees do not avoid neonicotinoid-treated food and instead actually prefer it. Bees' responses to neonicotinoids examined Reports that neonicotinoid insecticides have adverse effects on bee populations remain controversial. Some studies have been criticized as using unrealistically high insecticide dosages or conditions far removed from those in the field, and it has been suggested that bees might be able to detect the insecticides and avoid treated crops. Two papers in this issue of Nature present results that fill some of the gaps in our knowledge. In laboratory experiments Sébastien Kessler et al . use field-level doses of three commonly used neonicotinoids — clothianidin, imidacloprid and thiamethoxam — to show that both honeybees and bumblebees are able to detect their presence. However, the bees do not avoid neonicotinoid-treated food and may even prefer it. Maj Rundlöf et al . sowed oilseed rape with and without a clothianidin seed coating in matched and replicated agricultural landscapes. They found the seed coating to be associated with reduced density of wild bees, as well as reduced nesting of solitary bees and reduced colony growth of bumblebees, but they did not detect an effect on honeybees. The impact of neonicotinoid insecticides on insect pollinators is highly controversial. Sublethal concentrations alter the behaviour of social bees and reduce survival of entire colonies 1 , 2 , 3 . However, critics argue that the reported negative effects only arise from neonicotinoid concentrations that are greater than those found in the nectar and pollen of pesticide-treated plants 4 . Furthermore, it has been suggested that bees could choose to forage on other available flowers and hence avoid or dilute exposure 4 , 5 . Here, using a two-choice feeding assay, we show that the honeybee, Apis mellifera , and the buff-tailed bumblebee, Bombus terrestris , do not avoid nectar-relevant concentrations of three of the most commonly used neonicotinoids, imidacloprid (IMD), thiamethoxam (TMX), and clothianidin (CLO), in food. Moreover, bees of both species prefer to eat more of sucrose solutions laced with IMD or TMX than sucrose alone. Stimulation with IMD, TMX and CLO neither elicited spiking responses from gustatory neurons in the bees’ mouthparts, nor inhibited the responses of sucrose-sensitive neurons. Our data indicate that bees cannot taste neonicotinoids and are not repelled by them. Instead, bees preferred solutions containing IMD or TMX, even though the consumption of these pesticides caused them to eat less food overall. This work shows that bees cannot control their exposure to neonicotinoids in food and implies that treating flowering crops with IMD and TMX presents a sizeable hazard to foraging bees.

Leishmaniasis remains an important neglected tropical disease, and current treatments are limited by toxicity, resistance, and low bioavailability. In this study, novel guanidine derivatives were evaluated through an integrated approach, combining in silico physicochemical profiling with in vitro biological assays using Leishmania (Viannia) braziliensis, the etiological agent of American Tegumentary Leishmaniasis (ATL). Most compounds exhibited favorable drug-like properties, though variations in lipophilicity and solubility influenced biological performance. Among the tested molecules, FURL-G5 emerged as the most promising candidate, showing potent activity against promastigote forms and low cytotoxicity in murine macrophages, resulting in high selectivity indices (SI > 10), comparable to those of LQOF-G1, a compound with previously established leishmanicidal effects. These compounds were also tested on intracellular amastigotes, drastically reducing the infection rate of macrophages. The integration of an in silico approach and biological validation enabled rational compound prioritization and supports the early-stage development of these scaffolds. Overall, this study reinforces the potential of guanidine-based compounds as leads for innovative ATL drug discovery and demonstrates the value of multidisciplinary strategies for identifying selective and safe therapeutic candidates.

Streptococcus suis, an encapsulated zoonotic pathogen, has been reported to cause a variety of infectious diseases, such as meningitis and streptococcal-toxic-shock-like syndrome. Increasing antimicrobial resistance has triggered the need for new treatments. In the present study, we found that isopropoxy benzene guanidine (IBG) significantly attenuated the effects caused by S. suis infection, in vivo and in vitro, by killing S. suis and reducing S. suis pathogenicity. Further studies showed that IBG disrupted the integrity of S. suis cell membranes and increased the permeability of S. suis cell membranes, leading to an imbalance in proton motive force and the accumulation of intracellular ATP. Meanwhile, IBG antagonized the hemolysis activity of suilysin and decreased the expression of Sly gene. In vivo, IBG improved the viability of S. suis SS3-infected mice by reducing tissue bacterial load. In conclusion, IBG is a promising compound for the treatment of S. suis infections, given its antibacterial and anti-hemolysis activity.