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Abstract To develop a strategy for visualizing palladium species in the biological system, several turn-on bioluminescent probes were designed and synthesized by using a Pd-induced reductive reaction herein. Such probes exhibited high sensitivity (detection limit: 0.5 μM) and excellent selectivity toward Pd2+ in vitro. In particular, probe 2 was identified as a viable molecule with the capability of visualizing the fluctuations of level and distribution of Pd2+ in living cells and animals, which provides a valuable tool for tracing Pd2+ in biological system. Graphical abstract fx1 Highlights • A novel bioluminescent probe for palladium (II) has been developed by using reactivity-based strategy. • This probe exhibited good response and high selectivity toward Pd2+. • This probe was successfully applied for Pd2+ imaging in living cells and animals. [ABSTRACT FROM AUTHOR]

BACKGROUND: Local anesthetics (e.g., lidocaine) have been found to inhibit hyperpolarization-activated cyclic nucleotide-gated (HCN) channels besides sodium channels. However, the exact role of HCN channels in regional anesthesia in vivo is still elusive. METHODS: Sciatic nerve block and intrathecal anesthesia were performed using lidocaine in wild-type and HCN1 channel knockout (HCN1) mice. EC50 of lidocaine and durations of 1% lidocaine were determined. In electrophysiologic recordings, effects of lidocaine on HCN channel currents, voltage-gated sodium channel currents, and neural membrane properties were recorded on dorsal root ganglia neurons. RESULTS: In both sciatic nerve block and intrathecal anesthesia, EC50 of lidocaine for tactile sensory blockade (2 g von Frey fiber) was significantly increased in HCN1 mice, whereas EC50 of lidocaine for pinprick blockade was unaffected. Durations of 1% lidocaine were significantly shorter in HCN1 mice for both sciatic nerve block and intrathecal anesthesia (n = 10). ZD7288 (HCN blocker) could significantly prolong durations of 1% lidocaine including pinprick blockade in sciatic nerve block (n = 10). Forskolin (raising cyclic adenosine monophosphate to enhance HCN2) could significantly shorten duration of pinprick blockade of 1% lidocaine in sciatic nerve block (n = 10). In electrophysiologic recordings, lidocaine could nonselectively inhibit HCN channel and sodium channel currents both in large and in small dorsal root ganglia neurons (n = 5 to 6). Meanwhile, lidocaine caused neural membrane hyperpolarization and increased input resistance of dorsal root ganglia neurons but not in large dorsal root ganglia neurons from HCN1 mice (n = 5-7). CONCLUSIONS: These data indicate that HCN channels may contribute to regional anesthetic effects of lidocaine. By inhibiting HCN channels, lidocaine could alter membrane properties of neurons. [ABSTRACT FROM AUTHOR]

Amberlyst was found to be an effective catalyst for the condensation reactions of indoles 2 with aldehydes 3 to afford bisindolylalkanes 1 in good to excellent yields. [ABSTRACT FROM AUTHOR]

[Display omitted] • Endogenous gasotransmitters nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H 2 S), and potential candidates sulfur dioxide (SO 2), methane (CH 4), hydrogen gas (H 2), ammonia (NH 3) and carbon dioxide (CO 2), are generated within the human body. • Endogenous and potential gasotransmitters regulate inflammation, vasodilation, and oxidation in inflammatory dermatological disorders. • Endogenous and potential gasotransmitters play potential roles in psoriasis, atopic dermatitis, acne, and chronic skin ulcers. • Further research should explore the function of these gases and gas donors and inhibitors in inflammatory dermatological disorders. Endogenous gasotransmitters are small gaseous mediators that can be generated endogenously by mammalian organisms. The dysregulation of the gasotransmitter system is associated with numerous disorders ranging from inflammatory diseases to cancers. However, the relevance of these endogenous gasotransmitters, prodrug donors and inhibitors in inflammatory dermatological disorders has not yet been thoroughly reviewed and discussed. This review discusses the recent progress and will provide perspectives on endogenous gasotransmitters in the context of inflammatory dermatological disorders. Endogenous gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H 2 S) are signaling molecules that regulate several physiological and pathological processes. In addition, sulfur dioxide (SO₂), methane (CH 4), hydrogen gas (H 2), ammonia (NH 3), and carbon dioxide (CO 2) can also be generated endogenously and may take part in physiological and pathological processes. These signaling molecules regulate inflammation, vasodilation, and oxidative stress, offering therapeutic potential and attracting interest in the field of inflammatory dermatological disorders including psoriasis, atopic dermatitis, acne, rosacea, and chronic skin ulcers. The development of effective gas donors and inhibitors is a promising alternative to treat inflammatory dermatological disorders with controllable and precise delivery in the future. [ABSTRACT FROM AUTHOR]

A stable and highly selective fluorescent probe has been designed and synthesized for the rapid detection of fluoride ions (F−) in aqueous solution and living cells. The design was based on the high reactivity of F− toward a silyl group. [ABSTRACT FROM AUTHOR]

Abstract: Novel 3′-N-tert-butylsulfonyl analogues 10a–c of docetaxel were synthesized and their biological evaluation in cytotoxicity in vitro against several human tumor cell lines were presented. The biologically tested results showed that N-oxide pyridyl substituted10b–c had potent cytotoxicities against human tumor cell lines Eca-109, SKOV3, SMMC-7721, HCT-8, PC3, MCF-7, HeLa and KB. [Copyright &y& Elsevier]

Abstract: A series of bisindolylalkanes were synthesized by nucleophilic addition reactions of indole with N-tert-butanesulfinyl aldimines in good to excellent yields catalyzed by either iodine, potassium hydrogen sulfate and amberlyst. [Copyright &y& Elsevier]

Computer-aided drug design (CADD) has emerged as a highly effective and indispensable tool for streamlining the drug discovery process, leading to significant reductions in cost and time. The integration of CADD with machine learning (ML) and deep learning (DL) technologies further enhances its potential and promises novel advancements in the field. In this article, we provide a review of the computational methods employed in the development of novel anesthetics, outlining their respective advantages and limitations. These techniques have demonstrated their utility across various stages of drug discovery, encompassing the exploration of target-ligand interactions, identification and validation of new binding sites, de novo drug design, evaluation and optimization of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties in lead compounds, as well as prediction of adverse effects. Through an in-depth exploration of computational approaches and their applications, this article aims to help relevant researchers develop safer and more effective anesthetic drugs. [ABSTRACT FROM AUTHOR]

Carboxylesterase (CES), a main hydrolysis enzyme family in the human body, plays a crucial role in drug metabolism. Among them, CES1 and CES2 are the primary subtypes, and each exhibits distinct distribution and functions. However, convenient and non-invasive methods for distinguishing them and the real-time monitoring of CES2 are relatively rare, hindering the further understanding of physiological functions and underlying mechanisms. In this study, we have designed, synthesized, and evaluated the first selective bioluminescent probe (CBP 1) for CES2 with high sensitivity, high specificity and rapid reactivity. This probe offers a promising approach for the real-time detection of CES2 and its dynamic fluctuations both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

N-methyl bromide of lidocaine (QX-314) is a potential local anaesthetic with compromised penetration through cell membranes due to its obligated positive charge. Liposomes have been widely used for drug delivery with promising efficacy and safety. Therefore we investigated the local anaesthetic effects and tissue reactions of QX-314 in combination with anionic, cationic or neutral liposomes in rat sciatic nerve block model, and explored the effects of these liposomes on cellular entry of QX-314 in human embryonic kidney 293 cells. The results demonstrated that anionic liposomes substantially prolonged the duration of sensory (25.7 ± 8.3 h) and motor (41.4 ± 6.1 h) blocks of QX-314, while cationic and neutral ones had little effects. Tissue reactions from QX-314 with anionic liposomes were similar to those with commonly used local anaesthetic bupivacaine. Consistent with in vivo results, the anionic liposomes produced the greatest promotion of cellular entry of QX-314 in a time-dependent manner. In conclusion, ultra-long lasting nerve blocks were achieved by a mixture of QX-314 and anionic liposomes with a satisfactory safety profile, indicating a potential approach to improve postoperative pain management. The liposome-induced enhancement in cellular uptake of QX-314 may underlie the in vivo effects. [ABSTRACT FROM AUTHOR]

The method can be applied to a broad spectrum of phenols bearing alkyne chains in ortho-position to produce highly functionalized benzofuran structures. [ABSTRACT FROM AUTHOR]

[Display omitted] • Conventional methods and sensors for microbial detection are summarized. • Typical sensing mechanisms for rapid detection are discussed. • Rapid sensors for monitoring food, water and environment were critically reviewed. • Insights for the future development on rapid sensors are provided. Conventional techniques (e.g., culture-based method) for bacterial detection typically require a central laboratory and well-trained technicians, which may take several hours or days. However, recent developments within various disciplines of science and engineering have led to a major paradigm shift in how microorganisms can be detected. The analytical sensors which are widely used for medical applications in the literature are being extended for rapid and on-site monitoring of the bacterial pathogens in food, water and the environment. Especially, within the low-resource settings such as low and middle-income countries, due to the advantages of low cost, rapidness and potential for field-testing, their use is indispensable for sustainable development of the regions. Within this context, this paper discusses analytical methods and biosensors which can be used to ensure food safety, water quality and environmental monitoring. In brief, most of our discussion is focused on various rapid sensors including biosensors and microfluidic chips. The analytical performances such as the sensitivity, specificity and usability of these sensors, as well as a brief comparison with the conventional techniques for bacteria detection, form the core part of the discussion. Furthermore, we provide a holistic viewpoint on how future research should focus on exploring the synergy of different sensing technologies by developing an integrated multiplexed, sensitive and accurate sensors that will enable rapid detection for food safety, water and environmental monitoring. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) has emerged as a phytocannabinoid with various beneficial effects for the skin, including anti-photoaging effects, but its mechanisms of action are not fully elucidated. The study assessed CBD's photoprotective effects against acute ultraviolet B (UVB)-induced damage in HaCaT human keratinocyte cells and murine skin tissue. CBD (8 μM) alleviated UVB-induced cytotoxicity, apoptosis, and G2/M cell cycle arrest in HaCaT cells. The contents of γH2AX and cyclobutane pyrimidine dimers were decreased after CBD treatment. CBD reduced the production of reactive oxygen species and modulated the expression of antioxidant-related proteins such as nuclear factor erythroid 2-related factor 2 in UVB-stimulated HaCaT cells. Furthermore, CBD mitigated the UVB-induced cytotoxicity by activating autophagy. In addition, a cream containing 5% CBD showed effectiveness against UVB-induced photodamage in a murine model. The CBD cream improved the skin's condition by lowering the photodamage scores, reducing abnormal skin proliferation, and decreasing expression of the inflammation-related protein cyclooxygenase-2 in UVB-irradiated skin tissue. These findings indicate that CBD might be beneficial in alleviating UVB-induced skin damage in humans. The photoprotective effects of CBD might be attributed to its modulatory effects on redox homeostasis and autophagy. [ABSTRACT FROM AUTHOR]

Sulfide and persulfide are chemically different and one might expect persulfide to be more effective in mediating sulfur signaling because persulfide can directly modify protein cysteine residue. However, rapid scrambling, and interconversions occur among sulfur species. Then there is the question of whether the chemical reactivity differences between sulfide and persulfide would translate into pharmacological differences. Utilizing a delivery system to generate pure hydrogen sulfide (H2S), hydrogen persulfide (H2S2), and N‐acetyl‐l‐cysteine persulfide (N‐CysSSH), we examined the activities of sulfide and persulfide in vitro and in vivo. Persulfide prodrugs exhibited increased activities compared to the H2S prodrug. In particular, the H2S2 prodrug offers much‐elevated analgesic effects compared to the H2S prodrug in vivo. Persulfide prodrugs also possess a reduced level of toxicity compared to the H2S prodrug in vivo, indicating persulfide might represent a better therapeutic paradigm than H2S. [ABSTRACT FROM AUTHOR]

Sulfide and persulfide are chemically different and one might expect persulfide to be more effective in mediating sulfur signaling because persulfide can directly modify protein cysteine residue. However, rapid scrambling, and interconversions occur among sulfur species. Then there is the question of whether the chemical reactivity differences between sulfide and persulfide would translate into pharmacological differences. Utilizing a delivery system to generate pure hydrogen sulfide (H2S), hydrogen persulfide (H2S2), and N‐acetyl‐l‐cysteine persulfide (N‐CysSSH), we examined the activities of sulfide and persulfide in vitro and in vivo. Persulfide prodrugs exhibited increased activities compared to the H2S prodrug. In particular, the H2S2 prodrug offers much‐elevated analgesic effects compared to the H2S prodrug in vivo. Persulfide prodrugs also possess a reduced level of toxicity compared to the H2S prodrug in vivo, indicating persulfide might represent a better therapeutic paradigm than H2S. [ABSTRACT FROM AUTHOR]

[Display omitted] Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c , 18d , and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b , 15c , 15e , and 15h having a shorter duration at 272.7 nmol/kg. The structure–activity and configuration-activity relationships of these derivatives and 29a 's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA. [ABSTRACT FROM AUTHOR]

[Display omitted] The Na V 1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and Na V 1.8, we developed two series with a total of 19 molecules and examined their binding affinity to Na V 1.8 in vitro and analgesic effect in vivo. One compound, named 2j , stood out with notable activity against the Na V 1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] Chronic pain is a serious problem that affects billions of people worldwide, but current analgesic drugs limit their use in chronic pain management due to their respective side effects. As a first-line clinical drug for chronic pain, COX-2 selective inhibitors can relieve mild to moderate pain, but they also have some problems. The most prominent one is that their analgesic intensity is not enough, and they cannot well meet the treatment needs of chronic pain. Therefore, there is an urgent need to develop COX-2 inhibitors with stronger analgesic intensity. In this article, we used virtual screening method to screen out the structurally novel COX-2 inhibitor for chronic pain management, and conducted a preliminary study on its mechanism of action using molecular dynamics simulation. [ABSTRACT FROM AUTHOR]

A practical and efficient asymmetric synthesis of the key precursor furanose 3 for the synthesis of K252a and CEP-701 has been achieved in nine steps with an overall yield of 12.8% from (R)-methyl β-hydroxytetradecanoate 5, an industrial intermediate for production of orlistat. [image omitted] [ABSTRACT FROM AUTHOR]

Lung metastasis of breast cancer is a leading cause of cancer-related death in women. Herein, we attempted to simultaneously inhibit the growth and lung metastasis of breast cancer by delivering quercetin (QU) using LyP-1-functionalized regenerated silk fibroin-based nanoparticles (NPs). The generated LyP-1-QU-NPs had a desirable diameter (203.2 nm) and a negatively charged surface (−12.7 mV). Interestingly, these NPs exhibited intrinsic responsibilities when triggered by various stimulating factors in the tumor microenvironment (acidic pH, reactive oxygen species, and glutathione). In vitro experiments revealed that the introduction of LyP-1 to the NP surface could significantly increase their cellular uptake efficiencies by 4 T1 cells, and facilitate their accumulation in mitochondria. Moreover, LyP-1-QU-NPs showed the strongest mitochondrial damage effect among all the treatment groups. We also found that LyP-1-QU-NPs not only exhibited excellent pro-apoptotic activities but also presented strong inhibitory effects on cell mobility (migration and invasion) through anti-glycolysis and pro-autophagy. Mice experiments confirmed that LyP-1-QU-NPs could efficiently inhibit the in situ growth of breast tumors and further restrict their lung metastasis. Collectively, our results demonstrate that LyP-1-QU-NPs, which integrates the functions of tumor cell targeting, mitochondria targeting, bioresponsive drug release, pro-apoptosis, and anti-mobility, can be developed as a promising nanotherapeutic for the effective treatment of breast cancer and its lung metastasis. Triple-bioresponsive nanotherapeutics for targeted treatment of breast cancer and its lung metastasis. Unlabelled Image • LyP-1-functionalized nanoparticles (NPs) were fabricated for breast tumor-targeted delivery of quercetin (QU). • LyP-1-QU-NPs had a particle size around 203.2 nm, narrow size distribution, and negative surface charge (−12.7 mV). • LyP-1-QU-NPs exhibited intrinsic pH/H 2 O 2 /GSH-responsibilities. • LyP-1-QU-NPs showed obviously inhibitory effects on the proliferation, migration, and invasion of 4 T1 cells. • LyP-1-QU-NPs could be accumulated in tumor tissues and inhibit the growth and lung metastasis of breast cancer. [ABSTRACT FROM AUTHOR]

The integration of multimodal functions into one nanoplatform holds great promise for enhancing anticancer drug action and mitigating adverse effects. Herein, we prepared hyaluronic acid-functionalized regenerated silk fibroin-based nanoparticles (NPs) loading with photosensitizer (NIR770) and doxorubicin (DOX). The resultant HNDNPs had a desirable diameter of 161.0 nm and a negative zeta-potential of −30.5 mV. Interestingly, they showed excellent responses when triggered with various stimuli (acidity, reactive oxygen species, glutathione, hyaluronidase, or hyperthermia). Cell experiments revealed that HNDNPs could be specifically internalized by A549 cells, and efficiently released the payloads into the cytoplasm. Moreover, NIR770 was preferentially retained in mitochondria due to its lipophilic and cationic properties, which exhibited highly efficient photothermal therapy and photodynamic therapy upon near infrared (NIR) irradiation. Meanwhile, DOX molecules were mainly accumulated in the nucleus. Intravenous injection of HNDNPs into mice followed by NIR irradiation provided excellent multimodal imaging (NIR, photothermal, and photoacoustic imaging), almost eliminated the entire tumor, and greatly prolonged mice survival time with no side effects. Our study demonstrates that this HNDNP, which integrates the functions of tumor targeting, on-demand drug release, multimodal imaging, mitochondrial phototherapy, and chemotherapy, can be exploited as a promising nanococktail for imaging-guided synergistic treatment of cancer. Unlabelled Image • Hyaluronic acid-functionalized nanoparticles (NPs) loading with photosensitizer and doxorubicin were produced. • The resultant HNDNPs showed obvious responses to various stimuli (acidity, reactive oxygen species, glutathione, hyaluronidase, and hyperthermia). • The released NIR770 molecules from HNDNPs preferentially accumulated in mitochondria, resulting in the enhanced phototherapeutic effects. • HNDNPs showed excellent triple-modal imaging (NIRI, PTI, and PAI) for imaging-guided cancer treatment. • The synergistic therapeutic effects of HNDNPs were achieved by the combined application of triple-modal therapeutic strategies (PTT, PDT, and chemotherapy). [ABSTRACT FROM AUTHOR]

A novel platform rationally integrating indocyanine green analogues and an arginine-rich dendritic peptide with both nitroreductase (NTR) and glutathione (GSH) reduction responsive linkers was developed. This multifunctional platform can enable selective and efficient gene delivery and specific turn-on fluorescence imaging in tumors. [ABSTRACT FROM AUTHOR]

Iron plays an essential role in biological system. An approach for in vivo imaging of this metal ion is needed to investigate its complex contributions to physiological and pathological processes. Herein, we present a bioluminescent probe FP-1 as a powerful tool for targeting Fe2+ detection in vitro and in vivo. The turn-on sensing scheme is based on the caged strategy of luciferin-luciferase system. FP-1 not only can detect accumulations of exogenous Fe2+ in living animal, but also has the capability of monitoring labile endogenous Fe2+ levels in animal model of sepsis. Implementation of this technique provides a valuable opportunity for understanding underlying mechanisms of Fe2+ in biological processes and disease states. Image 1 • A novel bioluminescent probe for visualizing Iron (II) has been developed with high sensitivity and selectivity. • This probe was successfully appied to detect exogenous Fe2+ in living animal and monitor labile endogenous Fe2+ levels in animal disease model. [ABSTRACT FROM AUTHOR]

One-lung ventilation (OLV)–induced inflammation is a risk factor for acute lung injury that is responsible for 20% of postoperative pulmonary complications after lung resection. Inflammation is an important trigger for acute lung injury. Fatty acid amide hydrolase (FAAH) is the major enzyme that degrades the endocannabinoid arachidonoylethanolamine (AEA), an important regulator of inflammation, and its downstream metabolites such as arachidonic acid (AA) are also involved in inflammation. Importantly, AEA is also found in lung parenchyma. However, it remains unclear whether pharmacological inhibition of FAAH inhibitor using compounds such as URB937 can attenuate OLV-induced lung injury. New Zealand white rabbits were anesthetized to establish a modified OLV-induced lung injury model. Twenty-four male rabbits were randomly divided into four groups (n = 6): TLV-S (2.5-h two-lung ventilation [TLV] + 1.5 mL/kg saline + 1-h TLV), OLV-S (2.5-h OLV + 1.5 mL/kg saline + 0.5-h OLV + 0.5-h TLV), U-OLV (1.5 mL/kg URB937 + 3.0-h OLV + 0.5-h TLV), and OLV-U (2.5-h OLV + 1.5 mL/kg URB937 + 0.5-h OLV + 0.5-h TLV). Arterial blood gases, lung wet/dry ratio, and lung injury score of the nonventilated lungs were measured. The levels of AEA, AA, prostaglandin I2 (PGI2), thromboxane A2 (TXA2), and leukotriene B4 (LTB4) in the nonventilated lung were also quantified. The arterial oxygenation index (PaO 2 /FiO 2) decreased after 0.5-h OLV in the three OLV groups. The PaO 2 /FiO 2 in the OLV-U group was better than that in the OLV-S and U-OLV groups and was accompanied with reductions in the wet/dry ratio and lung injury scores of the nonventilated lungs. The FAAH inhibitor URB937 administered not before but 2.5 h after OLV attenuated OLV-induced lung injury by increasing AEA levels and reducing the levels of downstream metabolites including AA, PGI2, TXA2, and LTB4. Posttreatment with the FAAH inhibitor URB937 attenuated OLV-induced lung injury in rabbits and was associated with increased AEA levels and decreased levels of AA and its downstream metabolites. [ABSTRACT FROM AUTHOR]

Prodrug approaches represent an excellent solution to certain pharmaceutical issues commonly encountered in the drug discovery and development process. Along this line, the chemistry needed for the bio-reversible derivatization of drug functional groups for on-demand release is critical. In recent years, “click and release” approaches have shown great promise in the design of prodrugs because of their bioorthogonality and controlled bond-cleavage, which help ensure prodrug stability during circulation and ready cleavage at the desired site of action. This review highlights recent developments of this research field and discusses issues yet to be addressed. [ABSTRACT FROM AUTHOR]

Objectives: Monoacylglycerol lipase participates in organ protection by regulating the hydrolysis of the endocannabinoid 2-arachidonoylglycerol. This study investigated whether blocking monoacylglycerol lipase protects against postresuscitation myocardial injury and improves survival in a rat model of cardiac arrest and cardiopulmonary resuscitation.Design: Prospective randomized laboratory study.Setting: University research laboratory.Subjects: Male Sprague-Dawley rat (n = 96).Interventions: Rats underwent 8-minute asphyxia-based cardiac arrest and resuscitation. Surviving rats were randomly divided into cardiopulmonary resuscitation + URB602 group, cardiopulmonary resuscitation group, and sham group. One minute after successful resuscitation, rats in the cardiopulmonary resuscitation + URB602 group received a single dose of URB602 (5 mg/kg), a small-molecule monoacylglycerol lipase inhibitor, whereas rats in the cardiopulmonary resuscitation group received an equivalent volume of vehicle solution. The sham rats underwent all of the procedures performed on rats in the cardiopulmonary resuscitation and cardiopulmonary resuscitation + URB602 groups minus cardiac arrest and asphyxia.Measurements and Main Results: Survival was recorded 168 hours after the return of spontaneous circulation (n = 22 in each group). Compared with vehicle treatment (31.8%), URB602 treatment markedly improved survival (63.6%) 168 hours after cardiopulmonary resuscitation. Next, we used additional surviving rats to evaluate myocardial and mitochondrial injury 6 hours after return of spontaneous circulation, and we found that URB602 significantly reduced myocardial injury and prevented myocardial mitochondrial damage. In addition, URB602 attenuated the dysregulation of endocannabinoid and eicosanoid metabolism 6 hours after return of spontaneous circulation and prevented the acceleration of mitochondrial permeability transition 15 minutes after return of spontaneous circulation.Conclusions: Monoacylglycerol lipase blockade may reduce myocardial and mitochondrial injury and significantly improve the resuscitation effect after cardiac arrest and cardiopulmonary resuscitation. [ABSTRACT FROM AUTHOR]

Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy 'handle' for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs. [ABSTRACT FROM AUTHOR]

Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy 'handle' for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs. [ABSTRACT FROM AUTHOR]

Intratumoral environment as a hypoxic, non-inflamed "cold" state is difficult for many agents to accumulate and activate the immune system. Intrinsically, facultative anaerobic Salmonella VNP20009 target the tumor hypoxic areas, invade into tumor cells and exhibit an immune effect. Here we engineer the bacteria by decorating their surface with newly synthesized heptamethine cyanine dyes NHS–N782 and JQ-1 derivatives to obtain the biohybrid agent N –V-J, leading to the deep tumor targeted photothermal therapy and magnified immunotherapy. Due to the mitochondrial targeting capacity of NHS–N782, N –V-J becomes susceptive to the temperature rise when reaching tumors. This synergistic strategy promotes the systemic immunity by creating an inflamed "hot" tumor state from three different dimensions, which include the inherent immunogenicity of bacteria, the near-infrared laser triggered tumor antigens and the downregulation of PD-L1 expression. All these approaches result in effective and long-lasting T cell immune responses to prevent local and distant tumors for extended time. Leveraging the attenuated bacteria to transport dual drugs to the tumor tissues for self-synthetic vaccines provides a novel paradigm to enhance the bacteria-mediated cancer immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Hydrogen Persulfide Prodrug, Hydrogen Sulfide Prodrug, Sulfur Chemistry, Sulfur Species Keywords: Hydrogen Persulfide Prodrug; Hydrogen Sulfide Prodrug; Sulfur Chemistry; Sulfur Species EN Hydrogen Persulfide Prodrug Hydrogen Sulfide Prodrug Sulfur Chemistry Sulfur Species 1 1 1 05/05/22 20220509 NES 220509 B A series of sulfur species prodrugs b (reactive sulfur species in a capsule) that can release pure hydrogen sulfide (H SB 2 sb S) and hydrogen persulfide (H SB 2 sb S SB 2 sb ) was used by Bowen Ke et al. in their Communication (e202201668) to compare the pharmacological differences between sulfide and persulfide. Cover Picture: Prodrugs of Persulfide and Sulfide: Is There a Pharmacological Difference between the Two in the Context of Rapid Exchanges among Various Sulfur Species In Vivo?. [Extracted from the article]

Eine Serie von Schwefel‐Prodrugs (verkapselte reaktive Schwefelspezies), die reinen Schwefelwasserstoff (H2S) und Persulfidwasserstoff (H2S2) freisetzen können, wurde von Bowen Ke et al. in ihrer Zuschrift (e202201668) verwendet, um die pharmakologischen Unterschiede zwischen Sulfid und Persulfid zu untersuchen. Das H2S2‐Prodrug weist im Vergleich zum H2S‐Prodrug eine höhere Aktivität und geringere Toxizität in vivo auf, was darauf hindeutet, dass Persulfid ein besseres therapeutisches Agens darstellen könnte als H2S. [ABSTRACT FROM AUTHOR]

Hydrogen Persulfide Prodrug, Hydrogen Sulfide Prodrug, Sulfur Chemistry, Sulfur Species Das H SB 2 sb S SB 2 sb -Prodrug weist im Vergleich zum H SB 2 sb S-Prodrug eine höhere Aktivität und geringere Toxizität in vivo auf, was darauf hindeutet, dass Persulfid ein besseres therapeutisches Agens darstellen könnte als H SB 2 sb S. B Photokatalyse b In ihrer Zuschrift (e202202079) verwenden Masaichi Saito, Stephan Kupfer, Benjamin Dietzek-Ivansi'c, Wolfgang Weigand et al. einen edelmetallfreien Photokatalysator bestehend aus einem Mimetikum der [FeFe]-Hydrogenase für die Wasserstoffentwicklung unter sichtbarem Licht. Keywords: Hydrogen Persulfide Prodrug; Hydrogen Sulfide Prodrug; Sulfur Chemistry; Sulfur Species EN Hydrogen Persulfide Prodrug Hydrogen Sulfide Prodrug Sulfur Chemistry Sulfur Species 1 1 1 05/05/22 20220509 NES 220509 B Eine Serie von Schwefel-Prodrugs b (verkapselte reaktive Schwefelspezies), die reinen Schwefelwasserstoff (H SB 2 sb S) und Persulfidwasserstoff (H SB 2 sb S SB 2 sb ) freisetzen können, wurde von Bowen Ke et al. in ihrer Zuschrift (e202201668) verwendet, um die pharmakologischen Unterschiede zwischen Sulfid und Persulfid zu untersuchen. [Extracted from the article]

[Display omitted] A series of novel procaine derivatives for intravenous anesthesia were prepared and evaluated by physicochemical properties and pharmacodynamic experiments in vivo and in vitro. Systematic optimization of procaine led to the identification of 6f , 6g , 6h , 6o , 6p and 6q with higher TI value and moderate log D. Compared with procaine (TI = 1.65), most procaine derivatives demonstrated better security, among which compound 6h (TI = 2.68) was the most notable one and showed fewer adverse events in animals. The result of hNR2B-HEK293 assay indicated that compound 6h suppressed the NMDA receptor 2B subtype channel activity and it showed more than 80% inhibitory effect at the concentration of 500 μM. [ABSTRACT FROM AUTHOR]

Sulfide and persulfide are chemically different and one might expect persulfide to be more effective in mediating sulfur signaling because persulfide can directly modify protein cysteine residue. However, rapid scrambling, and interconversions occur among sulfur species. Then there is the question of whether the chemical reactivity differences between sulfide and persulfide would translate into pharmacological differences. Utilizing a delivery system to generate pure hydrogen sulfide (H2S), hydrogen persulfide (H2S2), and N‐acetyl‐l‐cysteine persulfide (N‐CysSSH), we examined the activities of sulfide and persulfide in vitro and in vivo. Persulfide prodrugs exhibited increased activities compared to the H2S prodrug. In particular, the H2S2 prodrug offers much‐elevated analgesic effects compared to the H2S prodrug in vivo. Persulfide prodrugs also possess a reduced level of toxicity compared to the H2S prodrug in vivo, indicating persulfide might represent a better therapeutic paradigm than H2S. [ABSTRACT FROM AUTHOR]

Post-synthesis modification of DNA is an important way of functionalizing DNA molecules. Herein, we describe a method that first enzymatically incorporates a cyanobenzothiazole (CBT)-modified thymidine. The side-chain handle CBT can undergo a rapid and site-specific cyclization reaction with 1,2-aminothiols to afford DNA functionalization in aqueous solution. Another key advantage of this method is the formation of a single stereo/regioisomer in the process, which allows for precise control of DNA modification to yield a single component for aptamer selection work and other applications. [ABSTRACT FROM AUTHOR]

Revealing the structural and functional change of microvasculature is essential to match vascular response with neuronal activities in the investigation of neurovascular coupling. The increasing use of rhesus models in fundamental and clinical studies of neurovascular coupling presents an emerging need for a new imaging modality. Here we report a structural and functional cerebral vascular study of rhesus monkeys using an ultrafast, portable, and high resolution photoacoustic microscopic system with a long working distance and a special scanning mechanism to eliminate the relative displacement between the imaging interface and samples. We derived the structural and functional response of the cerebral vasculature to the alternating normoxic and hypoxic conditions by calculating the vascular diameter and functional connectivity. Both vasodilatation and vasoconstriction were observed in hypoxia. In addition to the change of vascular diameter, the decrease of functional connectivity is also an important phenomenon induced by the reduction of oxygen ventilatory. These results suggest that photoacoustic microscopy is a promising method to study the neurovascular coupling and cerebral vascular diseases due to the advanced features of high spatiotemporal resolution, excellent sensitivity to hemoglobin, and label-free imaging capability of observing hemodynamics. [ABSTRACT FROM AUTHOR]

Abstract: Amphoteric refraction of light ray at the interface between isotropic materials and anisotropic materials is analyzed. Depending on the incident angle, the refractive light ray can either refract positively or negatively. This amphoteric refraction phenomenon can be quite prevalent when the difference of the two principal refractive indices is large. The reflectance under various incident angles has also been calculated, and an experimental demonstration with a calcite crystal in air is presented. [Copyright &y& Elsevier]

[Display omitted] Pyroglutamate aminopeptidase (PGP) specifically cleaves the peptide bond of pyroglutamic acid linked to the N-terminal end of a polypeptide or protein. Previous studies showed that PGP was associated with several physiological processes and diseases especially those involving inflammation. Utilizing a 'caging' strategy, we designed and synthesized a bioluminescence probe (PBL) with a limit-of-detection of 3.7 * 10−4 mU/mL. In vivo imaging in a mouse model of inflammatory liver disease revealed that the probe has excellent sensitivity and selectivity and provides a powerful tool for studying the physiological and pathological processes involving PGP. [ABSTRACT FROM AUTHOR]

Etomidate is a sedative-hypnotic with excellent pharmacological effects, including rapid onset and hemodynamic stability. However, etomidate causes adrenocortical toxicity via binding to 11β-hydroxylase. Therefore, developing an approach to screen new etomidate analogues without endocrine-disrupting effects is urgently warranted. In this study, we employed the adrenocortical tumour cell line, NCI-H295R, as an in vitro system for etomidate analogues screening and detected the hormone levels in these cells using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. After obtaining the concentration-response curves of hormone release, the "Adrenocortical Inhibitory Index" was used to evaluate the adrenocortical inhibitory potency of each compound. In summary, we demonstrate the benefits of our methods for screening of etomidate analogues that lack adrenocortical suppression, especially when this in vitro system is combined with in vivo testing. • H295R assay would serve as a good in vitro system for etomidate analogs screening. • AII may be used as a preliminary evaluation criterion for adrenocortical toxicity. • An in vitro system may predict adrenocortical inhibition in vivo. [ABSTRACT FROM AUTHOR]

Sulfites are widely used as preservative and antioxidant additives in food and drug. A non-invasive method for in vivo imaging of sulfite represents a powerful tool for estimating its potential effects in living organisms. Herein, we report the design, development, and application of sulfite bioluminescent probes (SBPs) for the analyte-specific detection of sulfite through sulfite-mediated intramolecular cleavage. Among them, SBP-1 exhibited the excellent responsivity, high selectivity and sensitivity. By taking advantage of this probe, the first in vivo imaging of sulfate was successfully carried out, not only to trace exogenous sulfite level in living animal, but also to investigate endogenous sulfite in a sulfite oxidase deficiency model. Image 1 • We have developed three sulfite bioluminescent probes (SBPs) for the first time. • The recognition of SBPs towards sulfite is based on the mechanism of a sulfite-mediated intramolecular cleavage reaction. • Among three SBPs, SBP-1 exhibited the excellent responsivity, selectivity and sensitivity towards sulfite. • SBP-1 can not only trace exogenous sulfite in vivo , but also monitor sulfite oxidase deficiency in relative mice model. [ABSTRACT FROM AUTHOR]

Cysteine (Cys) is a semi-essential amino acid that exerts a vital role in numerous biological functions. A noninvasive method for in vivo imaging of cysteine could represent a valuable tool for research cysteine and its complex contributions in living organisms. Thus, we developed a turn-on bioluminescence probe (CBP) not only for detecting exogenous and endogenous cysteine in vitro and in vivo, but also for visualizing these cysteines in whole animal. The current applications may help shed light on the complex mechanisms of cysteine in miscellaneous physiological and pathological processes. [ABSTRACT FROM AUTHOR]

The severe mortality and morbidity of myocardial infarction requests appropriate and accurate detection. Considering pathological profile of the acidic myocardial infarction microenvironments, herein, the low pH-sensitive albumin nanocomposites with MnO 2 motifs (MnO 2 @BSA) have been engineered for T 1 -weighted MR imaging of myocardial infarction, while using non-pH-responsive Gd 2 O 3 @BSA nanocomposites as control. The nanocomposites were 20–30 nm in diameter with spheroid morphology. Besides, the MnO 2 @BSA have exhibited pH-triggered releasing of Mn2+, demonstrating approximately 38-fold and 55-fold increased molecular relaxivity at acute myocardial infarction-mimicking pH 6.5 (13.08 mM−1s−1) and macrophage intracellular pH 5.0 (18.76 mM−1s−1) compared to the extremely low relaxivity (0.34 mM−1s−1) at normal physiological conditions (pH 7.4). However, the Gd 2 O 3 @BSA with molecular relaxivity approximately 10 mM−1s−1 were without pH-sensitive properties. Furthermore, the MnO 2 @BSA have demonstrated high accumulation in the acute myocardial infarction regions and fast metabolism from the body after systemic injection, accounting high contrast enhancement for accurate MR imaging of acute myocardial infarction in rabbit models, demonstrating better diagnostic performance over the controls. [ABSTRACT FROM AUTHOR]

In article number 1806916, Haiyuan Zhang, Hubing Shi, and co‐workers provide a novel framework for combining targeted therapy and immune checkpoint blockade by using a mesoporous silica nanoparticle (MSNP) system. The MSNP‐carried MEK inhibitor is specifically enriched in the tumor microenvironment, and selectively internalized by tumor cells rather than T‐cells. The cellular‐specific delivery avoids T‐cell toxicity and synergizes oncogene‐targeted therapy and PD‐1 blockade. [ABSTRACT FROM AUTHOR]

The combination of BRAF/MEK‐targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK‐inhibitor‐induced T‐cell toxicity impedes effective cooperation. In this experiment, a pH‐responsive on‐demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein‐isothiocyanate‐loaded MSNP can be specifically delivered into tumor cells rather than T‐cells. MEK‐inhibitor‐loaded MSNP avoids proliferative and functional inhibitions of T‐cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK‐inhibitor‐induced suppression of activated CD8+ T‐cells, and enhances the secretion of INF‐γ and IL‐2. The combination of BRAF inhibitor plus MSNP‐loaded MEK inhibitor and anti‐PD‐1 antibody synergistically inhibits tumor growth via promoting robust immune‐related antitumor response. This work provides a novel and generalized framework for combining T‐cell‐impaired targeted therapy and immune checkpoint blockade by using a nanoparticle‐based delivery system. MEK inhibitor (MEKi)‐induced T‐cell toxicity impedes the effective cooperation of BRAF/MEK‐targeted therapy and immunotherapy. The MEKi (AZD6244) loaded MSNPs are specifically enriched in the tumor microenvironment and internalized by tumor cells but not T‐cells. However, T‐cells do not internalize MSNP‐AZD6244 and are not impaired. Thus, MAPK targeted therapy is synergized with anti‐PD‐1 therapy by MSNP encapsulation of MEKi. [ABSTRACT FROM AUTHOR]