Drug-induced Effects Research Articles

Drug Self-Aggregation into Nano-Entities Has the Potential to Induce Immune Responses.

The free-state solution behaviors of small molecules profoundly affect their respective properties. It is becoming more obvious that compounds can adopt a three-phase equilibrium when placed in an aqueous solution, among soluble-lone molecule form, self-assembled aggregate form (nano-entities), and solid precipitate form. Recently, correlations have emerged between the existence of self-assemblies into drug nano-entities and unintended side effects. This report describes our pilot study involving a selection of drugs and dyes to explore if there may be a correlation between the existence of drug nano-entities and immune responses. We first implement practical strategies for detecting the drug self-assemblies using a combination of nuclear magnetic resonance (NMR), dynamic light scattering (DLS), transmission electron microscopy (TEM), and confocal microscopy. We then used enzyme-linked immunosorbent assays (ELISA) to monitor the modulation of immune responses on two cellular models, murine macrophage and human neutrophils, upon exposure to the drugs and dyes. The results suggest that exposure to some aggregates correlated with an increase in IL-8 and TNF-α in these model systems. Given this pilot study, further correlations merit pursuing on a larger scale given the importance and potential impact of drug-induced immune-related side effects.

Reproducibility of drug-induced effects on the contractility of an engineered heart tissue derived from human pluripotent stem cells.

Introduction: Engineered heart tissues (EHTs) are three-dimensional culture platforms with cardiomyocytes differentiated from human pluripotent stem cells (hPSCs) and were designed for assaying cardiac contractility. For drug development applications, EHTs must have a stable function and provide reproducible results. We investigated these properties with EHTs made with different tissue casting batches and lines of differentiated hPSC-cardiomyocytes and analyzed them at different times after being fabricated. Methods: A video-optical assay was used for measuring EHT contractile outputs, and these results were compared with results from motion traction analysis of beating hPSC-cardiomyocytes cultured as monolayers in two-dimensional cultures. The reproducibility of induced contractile variations was tested using compounds with known mechanistic cardiac effects (isoproterenol, EMD-57033, omecamtiv mecarbil, verapamil, ranolazine, and mavacamten), or known to be clinically cardiotoxic (doxorubicin, sunitinib). These drug-induced variations were characterized at different electrical pacing rates and variations in intracellular calcium transients were also assessed in EHTs. Results: To ensure reproducibility in experiments, we established EHT quality control criteria based on excitation-contraction coupling and contractile sensitivity to extracellular calcium concentration. In summary, a baseline contractile force of 0.2mN and excitation-contraction coupling of EHTs were used as quality control criteria to select suitable EHTs for analysis. Overall, drug-induced contractile responses were similar between monolayers and EHTs, where a close relationship was observed between contractile output and calcium kinetics. Contractile variations at multiple time points after adding cardiotoxic compounds were also detectable in EHTs. Discussion: Reproducibility of drug-induced effects in EHTs between experiments and relative to published work on these cellular models was generally observed. Future applications for EHTs may require additional mechanistic criteria related to drug effects and cardiac functional outputs to be measured in regard to specific contexts of use.

Systemic complications of intravitreal bevacizumab: a case report and literature review

Background: Systemic complications of intravitreal bevacizumab (IVB) injections have been previously reported. We aimed to summarize the systemic complications reported in online primary studies. Moreover, we describe a patient experiencing simultaneous renal and cutaneous drug-induced adverse effects, with exacerbation of chronic renal insufficiency and granulomatous skin lesions, after receiving several IVB injections to manage bilateral ischemic branch retinal vein occlusion (BRVO). Case Presentation: A 69-year-old Hispanic diabetic man with chronic renal insufficiency due to polyclonal gammopathy received several IVB injections to treat bilateral ischemic BRVO. One week after the sixth injection, the patient developed acute-on-chronic renal failure and multiple rounded maculopapular, erythematous, and ulcerated skin lesions. Renal and skin biopsy specimens revealed granulomatous drug-induced responses in both organs, and granulomatous diseases of infectious and oncological sources were ruled out. We performed an electronic search of the PubMed/MEDLINE database with no language or time restrictions using the keywords “intravitreal bevacizumab” or “intravitreal Avastin” combined with “systemic side effects,” “systemic complications,” or “systemic adverse,” or “systemic adverse event.” The search yielded 147 articles published over almost two decades. After screening and assessment, we selected and summarized 40 primary studies that mentioned IVB-related systemic complications. Conclusions: IVB-induced systemic complications, such as arteriothrombotic events, venous thrombotic events, and hypertension, are rare but potentially serious. Care should be taken when administering multiple doses of intravitreal IVB to patients with pre-existing kidney dysfunction. Bevacizumab-related toxicity must be considered in cases of sudden deterioration of renal function and / or unexpected granulomatous skin lesions in oncologic or chronically polymedicated patients.

Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations.

Chronic drug abuse is thought to induce synaptic changes in nucleus accumbens medium spiny neurons (MSNs) that promote subsequent craving and drug-seeking behavior. Accumulating data suggest acid-sensing ion channels (ASICs) may play a critical role. In drug naïve mice, disrupting the ASIC1A subunit produced a variety of synaptic changes reminiscent of wild-type mice following cocaine withdrawal, including increased AMPAR/NMDAR ratio, increased AMPAR rectification, and increased dendrite spine density. Importantly, these changes in Asic1a -/- mice were normalized by a single dose of cocaine. Here we sought to understand the temporal effects of cocaine exposure in Asic1a -/- mice and the cellular site of ASIC1A action. Six hours after cocaine exposure, there was no effect. However, 15h, 24h and 4days after cocaine exposure there was a significant reduction in AMPAR/NMDAR ratio in Asic1a -/- mice. Within 7days the AMPAR/NMDAR ratio had returned to baseline levels. Cocaine-evoked changes in AMPAR rectification and dendritic spine density followed a similar time course with significant reductions in rectification and dendritic spines 24h after cocaine exposure in Asic1a -/- mice. To test the cellular site of ASIC1A action on these responses, we disrupted ASIC1A specifically in a subpopulation of MSNs. We found that effects of ASIC1A disruption were cell autonomous and restricted to neurons in which the channels are disrupted. We further tested whether ASIC1A disruption differentially affects MSNs subtypes and found AMPAR/NMDAR ratio was elevated in dopamine receptor 1-expressing MSNs, suggesting a preferential effect for these cells. Finally, we tested if protein synthesis was involved in synaptic adaptations that occurred after ASIC1A disruption, and found the protein synthesis inhibitor anisomycin normalized AMPAR-rectification and AMPAR/NMDAR ratio in drug-naïve Asic1a -/- mice to control levels, observed in wild-type mice. Together, these results provide valuable mechanistic insight into the effects of ASICs on synaptic plasticity and drug-induced effects and raise the possibility that ASIC1A might be therapeutically manipulated to oppose drug-induced synaptic changes and behavior.

Longitudinal Gut Microbiota Dysbiosis Underlies Olanzapine-Induced Weight Gain.

Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them, Enterorhabdus (r = 0.38), Parasutterella (r = 0.43), and Prevotellaceae UCG-001 (r = 0.52) positively correlated with body weight gain. In addition, two MetaCyc metabolic pathways were identified as associated with olanzapine-induced body weight gain, including the superpathway of glucose and xylose degradation and the superpathway of l-threonine biosynthesis. In conclusion, we demonstrate that olanzapine can directly alter the gut microbiota and rapidly induce dysbiosis, which is significantly associated with body weight gain. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by olanzapine. IMPORTANCE Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain. This study provides insight to the gut microbiota target in olanzapine-induced obesity. Specifically, we explored the longitudinal gut microbiota trajectories of female Sprague-Dawley rats undergoing olanzapine treatment. We showed that olanzapine treatment causes a dynamic alteration of gut microbiota diversity. Additionally, we identified three genera, Parasutterella, Enterorhabdus, and Prevotellaceae UCG-001, that may play an important role in olanzapine-induced obesity. In this case, the supply or removal of specific elements of the gut microbiota may represent a promising avenue for treatment of olanzapine-related metabolic side effects.

Assessment of sarcomere shortening and calcium transient in primary human and dog ventricular myocytes

Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to cardiac safety is profiling drug effects on cardiomyocyte (CM) sarcomere shortening and intracellular Ca2+ dynamics. Although CM from different animal species have been used to assess such effects, primary human CM isolated from human organ donor heart represent an ideal non-animal alternative approach. We performed a study to evaluate primary human CM and have them compared to freshly isolated dog cardiomyocytes for their basic function and responses to positive inotropes with well-known mechanisms. Our data showed that simultaneous assessment of sarcomere shortening and Ca2+-transient can be performed with both myocytes using the IonOptix system. Amplitude of sarcomere shortening and Ca2+-transient (CaT) were significantly higher in dog compared to human CM in the basic condition (absence of treatment), while longer duration of sarcomere shortening and CaT were observed in human cells. We observed that human and dog CMs have similar pharmacological responses to five inotropes with different mechanisms, including dobutamine and isoproterenol (β-adrenergic stimulation), milrinone (PDE3 inhibition), pimobendan and levosimendan (increase of Ca2+sensitization as well as PDE3 inhibition). In conclusion, our study suggests that myocytes obtained from both human donor hearts and dog hearts can be used to simultaneously assess drug-induced effects on sarcomere shortening and CaT using the IonOptix platform.

Longing to act: Bayesian inference as a framework for craving in behavioral addiction

Traditionally, craving is considered a defining feature of drug addiction. Accumulating evidence suggests that craving can also exist in behavioral addictions (e.g., gambling disorder) without drug-induced effects. However, the degree to which mechanisms of craving overlap between classic substance use disorders and behavioral addictions remains unclear. There is, therefore, an urgent need to develop an overarching theory of craving that conceptually integrates findings across behavioral and drug addictions. In this review, we will first synthesize existing theories and empirical findings related to craving in both drug-dependent and -independent addictive disorders. Building on the Bayesian brain hypothesis and previous work on interoceptive inference, we will then propose a computational theory for craving in behavioral addiction, where the target of craving is execution of an action (e.g., gambling) rather than a drug. Specifically, we conceptualize craving in behavioral addiction as a subjective belief about physiological states of the body associated with action completion and is updated based on both a prior belief (“I need to act to feel good”) and sensory evidence (“I cannot act”). We conclude by briefly discussing the therapeutic implications of this framework. In summary, this unified Bayesian computational framework for craving generalizes across addictive disorders, provides explanatory power for ostensibly conflicting empirical findings, and generates strong hypotheses for future empirical studies. The disambiguation of the computational components underlying domain-general craving using this framework will lead to a deeper understanding of, and effective treatment targets for, behavioral and drug addictions.

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.

Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.

Molecular mechanisms of MrgprA3-independent activation of the transient receptor potential ion channels TRPA1 and TRPV1 by chloroquine.

Itch associates several pathologies and is a common drug-induced side effect. Chloroquine (CQ) was reported to induce itch by activating the Mas-related G protein-coupled receptor MrgprA3 and subsequently TRPA1. In this study we demonstrate that CQ employs at least two MrgprA3-independent mechanisms to activate or sensitize TRPA1 and TRPV1. Patch Clamp and calcium-imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK-293T cells. In calcium-imaging, CQ induces a concentration-dependent but MrgprA3-independent activation of TRPA1 and TRPV1. While CQ itself inhibits TRPA1 and TRPV1 in patch clamp recordings, co-application of CQ and UVA-light evokes membrane currents through both channels. This effect is inhibited by the reducing agent dithiothreitol (DTT) and reduced on mutants lacking cysteine residues accounting for reactive oxygen species (ROS)-sensitivity. The combination of CQ and UVA-light triggers an accumulation of intracellular ROS, removes fast inactivation of voltage-gated sodium currents and activates TRPV2. On the other hand, CQ is a weak base and induces intracellular alkalosis. Intracellular alkalosis can activate TRPA1 and TRPV1, and CQ applied at alkaline pH-values indeed activates both channels. Our data reveal novel pharmacological properties of CQ allowing activation of TRPA1 and TRPV1 via photosensitization as well as intracellular alkalosis. These findings add complexity to the commonly accepted dogma that CQ-induced itch is specifically mediated by MrgprA3 coupling to TRPA1.

E019 A case of RS3PE triggered by immune check point inhibitor

Abstract Background/Aims Immune checkpoint inhibitors (ICIs) are increasingly being used in oncology and there is growing evidence of rheumatological problems arising in these group of patients. ICIs have been approved for the treatment of several cancers including non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma and other malignancies. Pembrolizumab, an anti-PD1, is known to cause inflammatory arthritis in some patients, and we report a case of relapsing-remitting synovitis with pedal oedema (RS3PE) in a patient with lung cancer. Methods A 67-year-old lady was diagnosed with adenocarcinoma in her left lung with pleural and pulmonary metastasis. She was commenced on carboplatin, pemetrexed and pembrolizumab initially for 4 cycles followed by pembrolizumab maintenance therapy for another 2 years. However, while on pembrolizumab therapy, she started to develop intermittent pain and swelling in her small joints of the hands and feet. There was marked pitting pedal oedema extending up to the knee along with swelling of the dorsum of the hand. She had intermittent swelling in the knee joints as well. Results The blood tests were negative for rheumatoid factor, anti-CCP and ANA. The CRP was markedly raised (120) from her previous values since she started developing joint symptoms. The kidney and liver function tests were within normal limits. A CT chest, abdomen pelvis was done which did not reveal any metastasis or progression of lung cancer. At the time of the review she was started on prednisolone 20mg once daily. Following this, the joint pain and swelling started to resolve, and the patient was advised to taper the steroids gradually. The pembrolizumab therapy was stopped few months later. The pedal oedema resolved within a few weeks of starting steroids and the joint inflammation settled after stopping the treatment. Conclusion ICI therapy has been known to trigger inflammatory arthropathy like RA. Psoriatic arthritis, undifferentiated monoarthritis and oligoarthritis, RS3PE and tenosynovitis have also been reported. Most published cases are mild to moderate in severity often responding to corticosteroids. Several patients have been treated with traditional DMARDs and biologics. RS3PE syndrome could be part of the paraneoplastic process but the onset of symptoms after starting pembrolizumab and rapid resolution after stopping the treatment indicates that this is likely a drug-induced adverse effect. Disclosure D. Ramachandran: None. W. Mushtaq: None. D. Makkuni: None.

Does Enhanced Structural Maturity of hiPSC-Cardiomyocytes Better for the Detection of Drug-Induced Cardiotoxicity?

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are currently used following the Comprehensive in vitro Proarrhythmic Assay (CiPA) initiative and subsequent recommendations in the International Council for Harmonization (ICH) guidelines S7B and E14 Q&A, to detect drug-induced cardiotoxicity. Monocultures of hiPSC-CMs are immature compared to adult ventricular cardiomyocytes and might lack the native heterogeneous nature. We investigated whether hiPSC-CMs, treated to enhance structural maturity, are superior in detecting drug-induced changes in electrophysiology and contraction. This was achieved by comparing hiPSC-CMs cultured in 2D monolayers on the current standard (fibronectin matrix, FM), to monolayers on a coating known to promote structural maturity (CELLvo™ Matrix Plus, MM). Functional assessment of electrophysiology and contractility was made using a high-throughput screening approach involving the use of both voltage-sensitive fluorescent dyes for electrophysiology and video technology for contractility. Using 11 reference drugs, the response of the monolayer of hiPSC-CMs was comparable in the two experimental settings (FM and MM). The data showed no functionally relevant differences in electrophysiology between hiPSC-CMs in standard FM and MM, while contractility read-outs indicated an altered amplitude of contraction but not changes in time course. RNA profiling for cardiac proteins shows similarity of the RNA expression across the two forms of 2D culture, suggesting that cell-to-matrix adhesion differences may explain account for differences in contraction amplitude. The results support the view that hiPSC-CMs in both 2D monolayer FM and MM that promote structural maturity are equally effective in detecting drug-induced electrophysiological effects in functional safety studies.

Innovative Strategies for Hair Regrowth and Skin Visualization.

Today, about 50% of men and 15-30% of women are estimated to face hair-related problems, which create a significant psychological burden. Conventional treatments, including drug therapy and transplantation, remain the main strategies for the clinical management of these problems. However, these treatments are hindered by challenges such as drug-induced adverse effects and poor drug penetration due to the skin's barrier. Therefore, various efforts have been undertaken to enhance drug permeation based on the mechanisms of hair regrowth. Notably, understanding the delivery and diffusion of topically administered drugs is essential in hair loss research. This review focuses on the advancement of transdermal strategies for hair regrowth, particularly those involving external stimulation and regeneration (topical administration) as well as microneedles (transdermal delivery). Furthermore, it also describes the natural products that have become alternative agents to prevent hair loss. In addition, given that skin visualization is necessary for hair regrowth as it provides information on drug localization within the skin's structure, this review also discusses skin visualization strategies. Finally, it details the relevant patents and clinical trials in these areas. Together, this review highlights the innovative strategies for skin visualization and hair regrowth, aiming to provide novel ideas to researchers studying hair regrowth in the future.

Vascular Redox Signaling, Endothelial Nitric Oxide Synthase Uncoupling, and Endothelial Dysfunction in the Setting of Transportation Noise Exposure or Chronic Treatment with Organic Nitrates.

Significance: Cardiovascular disease and drug-induced health side effects are frequently associated with-or even caused by-an imbalance between the concentrations of reactive oxygen and nitrogen species (RONS) and antioxidants, respectively, determining the metabolism of these harmful oxidants. Recent Advances: According to the "kindling radical" hypothesis, the initial formation of RONS may further trigger the additional activation of RONS formation under certain pathological conditions. The present review specifically focuses on a dysfunctional, uncoupled endothelial nitric oxide synthase (eNOS) caused by RONS in the setting of transportation noise exposure or chronic treatment with organic nitrates, especially nitroglycerin (GTN). We further describe the various "redox switches" that are proposed to be involved in the uncoupling process of eNOS. Critical Issues: In particular, the oxidative depletion of tetrahydrobiopterin and S-glutathionylation of the eNOS reductase domain are highlighted as major pathways for eNOS uncoupling upon noise exposure or GTN treatment. In addition, oxidative disruption of the eNOS dimer, inhibitory phosphorylation of eNOS at the threonine or tyrosine residues, redox-triggered accumulation of asymmetric dimethylarginine, and l-arginine deficiency are discussed as alternative mechanisms of eNOS uncoupling. Future Directions: The clinical consequences of eNOS dysfunction due to uncoupling on cardiovascular disease are summarized also, providing a template for future clinical studies on endothelial dysfunction caused by pharmacological or environmental risk factors.

Histone deacetylase 1 regulates haloperidol-induced motor side effects in aged mice

BackgroundAntipsychotic drugs prescribed to elderly patients with neuropsychiatric disorders often experience severe extrapyramidal side effects. Previous studies from our group suggest that changes in histone modifications during aging increase the risk for antipsychotic drug side effects, because co-administration of antipsychotics with class 1 histone deacetylase (HDAC) inhibitors could mitigate the severity of motor side effects in aged mice. However, which HDAC subtype contributes to the age-related sensitivity to antipsychotic drug side effects is unknown. MethodsIn this study, we overexpressed histone deacetylase type 1(HDAC1) in the striatum of 3-month-old mice and knocked down HDAC 1 in the striatum of 21-month-old mice by microinjection of AAV9-HDAC1-GFP or AAV9-CRISPR/Cas9-HDAC1-GFP vectors. Four weeks after the viral-vector delivery, the typical antipsychotic drug haloperidol was administered daily for 14 days, followed by motor function assessments through the open field, rotarod, and catalepsy behavioral tests. ResultsYoung mice with overexpressed HDAC1 showed increased cataleptic behavior induced by haloperidol administration, which is associated with the increased HDAC1 level in the striatum. In contrast, aged mice with HDAC1 knocked down rescued locomotor activity, motor coordination, and decreased cataleptic behavior induced by haloperidol administration, which is associated with decreased HDAC1 level in the striatum. ConclusionsOur results suggest that HDAC1 is a critical regulator in haloperidol-induced severe motor side effects in aged mice. Repression of HDAC1 expression in the striatum of aged mice could mitigate typical antipsychotic drug-induced motor side effects.

Acute effect of antiseizure drugs on background oscillations in Scn1a A1783V Dravet syndrome mouse model.

Dravet syndrome (Dravet) is a rare and severe form of developmental epileptic encephalopathy. Antiseizure medications (ASMs) for Dravet patients include valproic acid (VA) or clobazam (CLB), with or without stiripentol (STP), while sodium channel blockers like carbamazepine (CBZ) or lamotrigine (LTG) are contraindicated. In addition to their effect on epileptic phenotypes, ASMs were shown to modify the properties of background neuronal activity. Nevertheless, little is known about these background properties alterations in Dravet. Here, utilizing Dravet mice (DS, Scn1a A1783V/WT), we tested the acute effect of several ASMs on background electrocorticography (ECoG) activity and frequency of interictal spikes. Compared to wild-type mice, background ECoG activity in DS mice had lower power and reduced phase coherence, which was not corrected by any of the tested ASMs. However, acute administration of Dravet-recommended drugs, VA, CLB, or a combination of CLB + STP, caused, in most mice, a reduction in the frequency of interictal spikes, alongside an increase in the relative contribution of the beta frequency band. Conversely, CBZ and LTG increased the frequency of interictal spikes, with no effect on background spectral properties. Moreover, we uncovered a correlation between the reduction in interictal spike frequency, the drug-induced effect on the power of background activity, and a spectral shift toward higher frequency bands. Together, these data provide a comprehensive analysis of the effect of selected ASMs on the properties of background neuronal oscillations, and highlight a possible correlation between their effect on epilepsy and background activity.

Acupuncture for Women with Overactive Bladder: Perspective of Traditional Chinese Medicine and Related Mechanism.

Overactive bladder (OAB) syndrome is one of the most common diseases in urology and affects quality of life. Although the current treatment for OAB is based on oral medications, there are limitations and many patients have difficulty accepting drug-induced adverse effects. This review aimed to analyze the efficacy of acupuncture and its related mechanisms and provide a preliminary therapeutic regimen. Two authors independently searched PubMed, Embase, and Cochrane Library up to April 2022. They searched related English literature and extracted the data under a standard form based on the search strategy. Clinical trials which included OAB women with the treatment of acupuncture were included. Common acupuncture alone without other pharmacotherapy, external treatments was in the treatment group. The control interventions may include any active treatments, sham placebo, or no establishment of a control group. Outcomes included 3-day or 24-hour voiding diary, overactive bladder symptom score, etc. The Cochrane risk of bias tool was also used to assess the methodological quality of the randomized controlled trials (RCTs). We analyzed five RCTs and one comparative study on acupuncture for OAB to review and discuss the acupoint location, treatment course, and retention time based on clinical evidence and treatment ideas in traditional Chinese medicine. Additionally, we used the available evidence to reveal and discuss the acupuncture mechanisms for OAB. Acupuncture may regulate bladder function by inhibiting C-fibers, modulating nerve growth factors and reducing spontaneous contractions of the detrusor muscle. Combined with the available evidence, the combination of local acupoints and distal acupoints should be necessary to consider, especially the lumbosacral acupoints, the small abdomen acupoints and the lower limb acupoints. Among them, acupuncture at SP4, CV4 and KI3 are strongly recommended. The treatment course of acupuncture should be no less than 4 weeks and maintain the frequency of acupuncture no less than once a week. The duration of each session should be no less than 20 minutes. In addition, investigations remain necessary to verify acupuncture's efficacy and precise mechanism for OAB treatment in further exploration.

Biohybrid 3D Printing of a Tissue‐Sensor Platform for Wireless, Real‐Time, and Continuous Monitoring of Drug‐Induced Cardiotoxicity (Adv. Mater. 11/2023)

Tissue–Sensor Platforms In article number 2208983, Uijung Yong, Donghwan Kim, Hojoong Kim, Woon-Hong Yeo, Jinah Jang, and co-workers report a biohybrid 3D-printing method for the fabrication of tissue–sensor platforms. The integration of electronics with living cardiac tissues makes it possible to continuously monitor their contractile force and, ultimately, of the drug-induced cardiotoxicity effects on cardiac tissues. This method can create a next-generation tissue–sensor platform for an effective drug development process.

Anti-proliferative effects of cabergoline nano conjugated form on lung cancer cells

Lung cancer is one of the deadliest and most drug-resistant cancers in the world. In this type of cancer, the effect of neurological factors and disruption of neurotransmitter pathways is significant. Cabergoline (CAB) is a specific dopamine receptor (DR) agonist that suppresses tumor cell proliferation and induces cell death. Since the high doses of this drug cause metabolic effects in patients, drug delivery methods have helped bring about better effects of the drug at lower doses. This study aimed to compare the effect of CAB and its nanofluid sample on the expression of DR genes on a lung cancer cell line (A549). Multi-wall carbon nanotubes conjugated with CAB were prepared using a reflux system and evaluated qualitatively. Nanofluid-containing nanodrug was delivered to lung cancer cells (A549) and normal cells (MRC-5) and evaluated by an MTT assay and flow cytometry. Then, the expression of DR genes was studied by real-time polymerase chain reaction before and after the treatment by drug and nanodrug. The findings revealed that nanodrug has a significant lethal influence on cancer cells. In addition, the findings showed the death of cancer cells located in the lung at a lower dose than the pure drug; however, it was not toxic to MRC-5 cells. The design of this nano-targeted drug delivery system showed that it could be a new strategy for the treatment of non-small-cell lung cancer, increase drug delivery efficiency, and consequently induce apoptosis in cancer cells while reducing drug-induced side effects in normal cells.

Design and synthesis of a small molecular NIR-II chemiluminescence probe for in vivo-activated H2S imaging

Chemiluminescence (CL) with the elimination of excitation light and minimal autofluorescence interference has been wieldy applied in biosensing and bioimaging. However, the traditional emission of CL probes was mainly in the range of 400 to 650 nm, leading to undesired resolution and penetration in a biological object. Therefore, it was urgent to develop CL molecules in the near-infrared window [NIR, including NIR-I (650 to 900 nm) and near-infrared-II (900 to 1,700 nm)], coupled with unique advantages of long-time imaging, sensitive response, and high resolution at depths of millimeters. However, no NIR-II CL unimolecular probe has been reported until now. Herein, we developed an H2S-activated NIR-II CL probe [chemiluminiscence donor 950, (CD-950)] by covalently connecting two Schaap's dioxetane donors with high chemical energy to a NIR-II fluorophore acceptor candidate via intramolecular CL resonance energy transfer strategy, thereby achieving high efficiency of 95%. CD-950 exhibited superior capacity including long-duration imaging (~60 min), deeper tissue penetration (~10 mm), and specific H2S response under physiological conditions. More importantly, CD-950 showed detection capability for metformin-induced hepatotoxicity with 2.5-fold higher signal-to-background ratios than that of NIR-II fluorescence mode. The unimolecular NIR-II CL probe holds great potential for the evaluation of drug-induced side effects by tracking its metabolites invivo, further facilitating the rational design of novel NIR-II CL-based detection platforms.

Quantitative male-to-female translation of cardiac electrophysiological response to drugs.

Despite evidence that women are at higher risk of drug-induced Torsade de Pointes and sudden cardiac death, female sex is vastly underrepresented in cardiovascular research studies and clinical trials, thus limiting our fundamental understanding of sex-specific arrhythmia mechanisms and our ability to predict arrhythmia propensity. Indeed, we have shown that adoption of male-biased metrics can lead to a systematic underestimation of torsadogenic risk in women. To facilitate evaluation of the impact of sex differences on cardiomyocyte function and arrhythmogenesis, we developed quantitative tools that predict the electrophysiological response to drug administration in female cardiomyocytes starting from data collected in males. Using our mathematical models of excitation-contraction coupling in male and female human ventricular myocytes, we generated populations of models by randomly varying baseline model parameters. We collected action potential (AP) and Ca2+ transient (CaT) properties in each model variants and used multivariable regression to construct a “male-to-female translator”, i.e., a set of regression coefficients mapping male features onto female electrophysiology. We validated our translator against independent simulated data sets describing the effects of a large group of drugs on the baseline male and female models. Our results show high accuracy of prediction of drug-induced effects on female AP and CaT, where the average discrepancy between predicted and actual biomarkers falls within 1-2%. Next, we will use "male-to-female" translated features as inputs into our previously developed female-specific classifier of drug-induced torsadogenic risk to test the suitability of our translator for cardiac safety assessment in women. Classifier performance obtained with simulated data as input features will be used as a benchmark. Completion of this work will facilitate the translatability of male-biased experimental observations to female physiology and advance the characterization of sex differences in cardiac electrophysiology and drug cardiotoxicity.