This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

UNASSIGNED: Osteoarthritis (OA) related pain has affected millions of people worldwide. However, the current pharmacological options for managing OA-related pain have not achieved a satisfactory effect.
UNASSIGNED: This narrative review provides an overview of the current and emerging drugs for OA-related pain. It covers the drugs\' mechanism of action, safety, efficacy, and limitations. The National Library of Medicine (PubMed) database was primarily searched from 2000 to 2024.
UNASSIGNED: Current treatment options are limited and suboptimal for OA pain management. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are the recognized and first-line treatment in the management of OA-related pain, and other drugs are inconsistent recommendations by guidelines. Emerging treatment options are promising for OA-related pain, including nerve growth factor (NGF) inhibitors, ion channel inhibitors, and calcitonin gene-related peptide (CGRP) antagonists. Besides, drugs repurposing from antidepressants and antiepileptic analgesics are shedding light on the management of OA-related pain. The management of OA-related pain is challenging as pain is heterogeneous and subjective. A more comprehensive strategy combined with non-pharmacological therapy needs to be considered, and tailored management options to individualized patients.

暂无摘要。

BACKGROUND: Outcomes from cardiopulmonary resuscitation (CPR) following sudden cardiac arrest are suboptimal. Postresuscitation targeted temperature management has been shown to have benefit in subjects with sudden cardiac arrest due to ventricular fibrillation, but there are few data for outcomes from sudden cardiac arrest due to pulseless electrical activity. In addition, intra-CPR cooling is more effective than postresuscitation cooling. Physical cooling is associated with increased protein kinase B activity. Therefore, our group developed a novel peptide, TAT-PHLPP9c, which regulates protein kinase B. We hypothesized that when given during CPR, TAT-PHLPP9c would improve survival and neurologic outcomes following pulseless electrical activity arrest.
RESULTS: In 24 female pigs, pulseless electrical activity was induced by inflating balloon catheters in the right coronary and left anterior descending arteries for ≈7 minutes. Advanced life support was initiated. In 12 control animals, epinephrine was given after 1 and 3 minutes. In 12 peptide-treated animals, 7.5 mg/kg TAT-PHLPP9c was also administered at 1 and 3 minutes of CPR. The balloons were removed after 2 minutes of support. Animals were recovered and neurologically scored 24 hours after return of spontaneous circulation. Return of spontaneous circulation was more common in the peptide group, but this difference was not significant (8/12 control versus 12/12 peptide; P=0.093), while fully intact neurologic survival was significantly more common in the peptide group (0/12 control versus 11/12 peptide; P<0.00001). TAT-PHLPP9c significantly increased myocardial nicotinamide adenine dinucleotide levels.
CONCLUSIONS: TAT-PHLPP9c resulted in improved survival with full neurologic function after sudden cardiac arrest in a swine model of pulseless electrical activity, and the peptide shows potential as an intra-CPR pharmacologic agent.

Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host-microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host genetics on microbial composition. In the wild, the C. elegans gut contains various microbial species, while in the laboratory it is usually a host for a single bacterial species. There is a potential host-microbe interaction between microbial metabolites, drugs, and C. elegans phenotypes. This mini-review aims to summarize the current understanding regarding the microbiome in C. elegans. Examples using C. elegans to study host-microbe-metabolite interactions are discussed.

Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.

OBJECTIVE: Cervical cancer (CxCa) stands as a significant global health challenge, ranking fourth in cancer-related mortality among the female population. While chemotherapy regimens have demonstrated incremental progress in extending overall survival, the outlook for recurrent CxCa patients remains disheartening. An imperative necessity arises to delve into innovative therapeutic avenues, with molecular targeted therapy emerging as a promising candidate. Previous investigations have shed light on the therapeutic effectiveness of five distinct herbal compounds, epicatechin, curcumin, myricetin, jatrorrhizine, and arborinine, within the context of CxCa.
METHODS: A systems biology approach was employed to discern differentially expressed genes (DEGs) in CxCa tissues relative to healthy cervical epithelial tissues. A protein-protein interaction network (PPIN) was constructed, anchored in the genes related to CxCa. The central genes were discerned within the PPIN, and Kaplan-Meier survival curves explored their prognostic significance. An assessment of the binding affinity of the selected herbal compounds to the master regulator of prognostic markers in CxCa was conducted.
RESULTS: A significant correlation between the overexpression of MYC, IL6, JUN, RRM2, and VEGFA and an adverse prognosis in CxCa was indicated. The regulation of these markers is notably influenced by the transcription factor CEBPD. Molecular docking analysis indicated that the binding affinity between myricetin and the CEBPD DNA binding site was robust.
CONCLUSIONS: The findings presented herein have unveiled pivotal genes and pathways that play a central role in the malignant transformation of CxCa. CEBPD has emerged as a potential target for harnessing the therapeutic potential of myricetin in this context.

Red fluorescent dyes are usually charged, lypophilic molecules with the relatively high molecular weight, which tend to localize in specific intracellular locations, e.g., a cyanine dye Cy5 is biased towards mitochondria. They are often used as markers of biomolecules including nucleic acids and proteins. Since molecular weight of the dyes is much smaller than that of the biomolecules, the labelling has a negligible effect on the properties of the biomolecules. In contrast, conjugation of the dyes to low molecular weight (pro)drugs can dramatically alter their properties. For example, conjugates of Cy5 with lysosome-targeting aminoferrocenes accumulate in mitochondria and exhibit no intracellular effects characteristic for the parent (pro)drugs. Herein we tested several neutral and negatively charged dyes for labelling lysosome-targeting aminoferrocenes 7 and 8 as well as a non-targeted control 3. We found that a BODIPY derivative BDP-TR exhibits the desired unbiased properties: the conjugation does not disturb the intracellular localization of the (pro)drugs, their mode of action and cancer cell specificity. We used the conjugates to clarify the mechanism of action of the aminoferrocenes. In particular, we identified new intermediates, explained why lysosome targeting aminoferrocenes are more potent than their non-targeted counterparts and evaluated their distribution in vivo.

Platinum (II) drugs, including cisplatin, carboplatin, and oxaliplatin, have achieved significant clinical success in cancer treatment. However, their clinical application has been greatly hindered by various adverse factors such as non-specific activation and drug resistance. Compared with Pt(II) drugs, the axial ligands within Pt(IV) compounds can improve the pharmacokinetic properties, selectivity, and biological activity, implementing alternative cytotoxic mechanisms beyond DNA cross-linking and partially overcoming drug resistance. The controlled conversion of Pt(IV) prodrugs into Pt(II) agents at the tumor site has been extensively explored internationally. In this review, Pt(IV) prodrug modification strategies are first summarized, next the development of the predominant external and internal photosensitizers is listed. Finally, three representative photoreduction mechanisms and strategies for developing corresponding Pt(IV) prodrugs are discussed. This work provides constructive instruction for the subsequent molecular design of Pt(IV) prodrugs.

.