Pharmaceuticals

32 pages, 3368 KB

Open AccessArticle

Systems Biology and Structure-Based In Silico Evaluations of Quercetin–Psychobiotic Interactions for the Management of Depression

by Samridhi Kurl, Neeraj Mittal, Rajwinder Kaur, Balakumar Chandrasekaran and Gurpreet Kaur

Pharmaceuticals 2026, 19(9), 1366; https://doi.org/10.3390/ph19091366 - 28 Aug 2026

Abstract

Background/Objectives: Psychobiotics are live microorganisms that, when administered in appropriate amounts, can enhance mental health. Through the production of neuroactive metabolites, regulation of immune responses, and interactions along the gut–brain axis, they modulate host neurophysiology. However, significant strain-specific variability exists in their metabolic [...] Read more.

Background/Objectives: Psychobiotics are live microorganisms that, when administered in appropriate amounts, can enhance mental health. Through the production of neuroactive metabolites, regulation of immune responses, and interactions along the gut–brain axis, they modulate host neurophysiology. However, significant strain-specific variability exists in their metabolic capabilities, colonization potential, and functional interactions, necessitating a systematic approach for psychobiotic strain selection. Methods: In the present study, an integrated in silico systems biology approach combining comparative genomics, genome-scale metabolic modeling, network pharmacology, molecular docking, molecular dynamics, and ADMET analysis was employed to computationally evaluate the therapeutic potential and molecular interactions of a quercetin-psychobiotic co-delivery system for managing depression by modulating the gut–brain axis. Results: Comparative genomic analysis of candidate psychobiotic strains from the genera Bifidobacterium and Lactobacillus predicted the presence of key functional genes involved in neuroactive metabolite production, immune modulation, oxidative stress tolerance, and adhesion. The presence of acetate-producing pathways alongside the absence of classical butyrate biosynthesis genes indicated an indirect contribution to short-chain fatty acid production via microbial cross-feeding interactions. Genome-scale metabolic Modeling under the conditions of quercetin supplementation predicted a significant inter-strain variation in terms of predicted biomass flux, nutrient utilization, and metabolic adaptability. Results of molecular docking showed that the binding energies were in the range of −5.854 to −9.489 kcal/mol. Conclusion: Collectively, these in silico findings provided a computational basis for the selection of psychobiotic strains and predicted that a combination of psychobiotics and quercetin could present a promising strategy for the modulation of the gut–brain axis. Full article

(This article belongs to the Special Issue Advances in Structure-Based Drug Design and Small-Molecule Therapeutics)

26 pages, 3391 KB

Open AccessArticle

Untargeted Metabolomic and Phytochemical Profiling of Berberis crataegina DC. Plant Parts: Antidiabetic Potential and Cytoprotection in High-Glucose-Exposed SH-SY5Y Cells

by Yiğit Erkmen, Zekiye Ceren Arıtuluk Aydın, Engin Koçak, Hasya Nazlı Gök, Emirhan Nemutlu and Merve Yüzbaşıoğlu Baran

Pharmaceuticals 2026, 19(9), 1365; https://doi.org/10.3390/ph19091365 - 28 Aug 2026

Abstract

Background/Objectives: Berberis species are recognized for their ethnomedicinal importance and phytochemical richness associated with antidiabetic activity. Although B. crataegina is widely distributed in the Turkish flora and has a history of traditional use, its phytochemical properties and biological activities remain less extensively [...] Read more.

Background/Objectives: Berberis species are recognized for their ethnomedicinal importance and phytochemical richness associated with antidiabetic activity. Although B. crataegina is widely distributed in the Turkish flora and has a history of traditional use, its phytochemical properties and biological activities remain less extensively investigated than those of other Berberis species. This study aimed to comparatively evaluate the phytochemical profiles, in vitro antidiabetic potential, and cytoprotective effects of extracts prepared from different parts of B. crataegina in a high-glucose-induced SH-SY5Y cell-based model of diabetic neuropathy. Methods: Crude hydroethanolic extracts (70% ethanol) were prepared from the leaves, flowers, shoots, roots, and fresh fruits of B. crataegina collected from Kızılcahamam, Ankara, Türkiye. The total phenolic and flavonoid contents, antioxidant capacities and α-glucosidase inhibitory activities of leaf, flower, shoot, root, and fruit extracts were determined. The cytoprotective effects of the crude extracts were evaluated in a high-glucose-induced SH-SY5Y cell model. The metabolomic profiles of the extracts were comparatively analyzed using liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). The most active fruit extract was fractionated by reversed-phase vacuum liquid chromatography (RP-VLC), and the phytochemical contents and α-glucosidase inhibitory activities of the fractions were evaluated. The major phenolic compounds in the most active fruit extract were quantitatively determined using high-performance liquid chromatography–diode array detection (HPLC-DAD). The relationships between metabolites and biological activities were investigated through correlation analysis. Results: The fruit extract was distinguished by its α-glucosidase inhibitory activity, total phenolic content, antioxidant capacity, and cytoprotective effect in the high-glucose-induced SH-SY5Y cell model. It showed no marked cytotoxicity at concentrations ranging from 25 to 400 µg/mL and, at 25 µg/mL, attenuated the high-glucose-induced reduction in cell viability, restoring viability to a level close to that of the normal control. Untargeted metabolomic analysis identified 191 metabolites detected in at least two crude extracts, while the metabolites detected exclusively in the fruit extract were predominantly flavonoids and flavonoid glycosides. Fractionation showed that α-glucosidase inhibitory activity was mainly concentrated in the medium-polarity fractions; however, none of the fractions reached the activity level of the crude extract. Chlorogenic acid, rutin, caffeic acid, protocatechuic acid, quercetin, and quercetin-3-O-glucoside were detected and quantified in the fruit extract by HPLC-DAD. Correlation analysis indicated that the observed biological activities may be associated with phenolic acids, flavonoids, and other polyphenolic metabolites. Conclusions: The fruit extract of B. crataegina showed promising α-glucosidase inhibitory activity and cytoprotective effects in the high-glucose-induced SH-SY5Y cell model. The findings suggest that these effects may arise from the combined contribution of multiple constituents within a polyphenolic matrix rather than from a single compound; however, synergistic interactions were not experimentally demonstrated. These results support further evaluation of the fruit extract through mechanistic, in vivo, and standardization studies. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods: From Traditional Medicine to Modern Applications in Nutrition and Health)

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22 pages, 7386 KB

Open AccessArticle

Synthesis, Spectroscopic Characterization, Molecular Docking Studies Toward the GABA_A Receptor, ADMET Prediction, GABA Aminotransferase Inhibition, and Anxiolytic Evaluation of Novel Thiazine Derivatives

by Sonu, Kamal Y. Thajudeen, Saad Ali Alshehri, Mohammed Muqtader Ahmed, Mayur Porwal and Sagar Verma

Pharmaceuticals 2026, 19(9), 1364; https://doi.org/10.3390/ph19091364 - 28 Aug 2026

Abstract

Background: The current study uses a computational technique to investigate synthesized thiazine compounds that exhibit potential interactions with the GABA_A receptor. A series of novel thiazine derivatives was synthesized via the cyclization reaction of chalcone with thiourea. Methods: For the synthesized compounds, [...] Read more.

Background: The current study uses a computational technique to investigate synthesized thiazine compounds that exhibit potential interactions with the GABA_A receptor. A series of novel thiazine derivatives was synthesized via the cyclization reaction of chalcone with thiourea. Methods: For the synthesized compounds, spectroscopic characterization, namely FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry, was carried out. In addition, the AutoDock Vina 4.2 software was applied to carry out an in silico docking study. Results: The synthesized compounds C3 and C6 exhibited comparable predicted docking scores (−9.0 and −9.1 kcal/mol, respectively), with favorable predicted interactions at the GABAA receptor binding site. Furthermore, in silico ADMET analysis provided insights into the drug-likeness and pharmacokinetic profiles of the synthesized compounds; however, potential safety liabilities, including Ames positivity, hERG II liability, and hepatotoxicity, were predicted for some derivatives. Conclusions: It was determined that the synthesized compounds’ various physiologically significant and physiologically relevant parameters fell within the range of Lipinski’s rule of five. The synthesized compounds (C1–C10) were tested for anxiolytic activity by the elevated plus maze test, and compound C6 was found to be the most potent. Additionally, the in vitro GABA-AT enzyme activity assay showed that compound C6 had the highest inhibitory potential, with an IC50 of 13.29 ± 1.622 µM. Full article

(This article belongs to the Special Issue Advances in the Medicinal Synthesis of Bioactive Compounds)

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30 pages, 3659 KB

Open AccessArticle

Artificial Intelligence-Guided Prioritization and Experimental Evaluation of Synergistic Target Combinations for Breast Cancer Therapy

by Chunlai Feng, Qiuqi Feng, Shengnan She, Ruojing Yang, Mengru Li, Lu Gong and Mengjie Rui

Pharmaceuticals 2026, 19(9), 1363; https://doi.org/10.3390/ph19091363 - 28 Aug 2026

Abstract

Background/Objectives: Breast cancer exhibits substantial molecular heterogeneity, resulting in diverse therapeutic vulnerabilities and limiting the efficacy of single-agent therapies. Although multi-target strategies may offer improved therapeutic benefit, the systematic identification of synergistic higher-order target combinations remains challenging. This study aimed to identify and [...] Read more.

Background/Objectives: Breast cancer exhibits substantial molecular heterogeneity, resulting in diverse therapeutic vulnerabilities and limiting the efficacy of single-agent therapies. Although multi-target strategies may offer improved therapeutic benefit, the systematic identification of synergistic higher-order target combinations remains challenging. This study aimed to identify and validate effective higher-order target combinations for heterogeneous breast cancer. Methods: DeepMDS, a previously developed deep learning-based multi-compound synergy prediction model, was used to prioritize candidate target combinations for breast cancer. Exhaustive two-target and three-target combinations were ranked in the gene-expression contexts of ER-positive luminal-like MCF-7 and triple-negative MDA-MB-231 breast cancer cells. The top-ranked target combinations were evaluated using single, pairwise, and triple small interfering RNA (siRNA) perturbations. Representative inhibitors were subsequently assessed in fixed-ratio combinations in MCF-7, MDA-MB-231, and 4T1 cells and in a 4T1 syngeneic mouse experiment. Results: BIRC5-NAMPT-TOP1 ranked first in both cell lines. Triple siRNA co-transfection targeting BIRC5, NAMPT, and TOP1 produced the strongest antiproliferative effects, with inhibition rates of 62.94% in MCF-7 cells and 55.62% in MDA-MB-231 cells. The corresponding inhibitors, LQZ-7I, FK866, and topotecan, exhibited synergistic antiproliferative activity at multiple molar ratios, with combination index values below 1. The optimized 2.5:10:1 molar ratio showed strong synergy in MCF-7, MDA-MB-231, and 4T1 cells, with combination index values of 0.26, 0.19, and 0.15, respectively. In tumor-bearing mice model, the triple-inhibitor regimen achieved a tumor inhibition rate of 62.05%. Topotecan-containing groups showed hematological alterations, whereas no statistically detectable elevations were observed in the measured terminal serum hepatic or renal biomarkers. Conclusions: The BIRC5-NAMPT-TOP1 combination showed reproducible phenotypic activity in the tested genetic and pharmacological models. These findings support the use of DeepMDS as a hypothesis-generation tool for higher-order target prioritization. Full article

(This article belongs to the Section AI in Drug Development)

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22 pages, 11900 KB

Open AccessArticle

Shenling Baizhu Powder Modulates Gut Microbiota and Bile Acid Signaling to Alleviate Diet-Induced Diarrhea

by Qin Liu, Huiyi Peng, Min Su, Zhoujin Tan and Maijiao Peng

Pharmaceuticals 2026, 19(9), 1362; https://doi.org/10.3390/ph19091362 - 28 Aug 2026

Abstract

Background: Shenling Baizhu Powder (SLBZP) is a traditional Chinese medicine formula used to treat diarrhea. This study investigated its therapeutic effects and potential mechanisms in mice with fatigue- and high-fat diet-induced diarrhea, focusing on gut microbiota, bile acid metabolism, and farnesoid X [...] Read more.

Background: Shenling Baizhu Powder (SLBZP) is a traditional Chinese medicine formula used to treat diarrhea. This study investigated its therapeutic effects and potential mechanisms in mice with fatigue- and high-fat diet-induced diarrhea, focusing on gut microbiota, bile acid metabolism, and farnesoid X receptor (FXR)-related signaling. Methods: Male Kunming mice were used to establish a model of diarrhea, followed by treatment with SLBZP. Fecal moisture content, serum levels of diamine oxidase and liver enzymes, and intestinal and hepatic histopathological changes were assessed. Small-intestinal microbiota composition, bile acid profiles in colonic contents, and FXR-related signaling in the ileum and liver were further analyzed. Results: SLBZP significantly reduced fecal moisture content. It also modulated the small-intestinal microbiota, with a significant increase in Faecalibaculum. In colonic contents, SLBZP reduced total bile acid levels, increased the secondary-to-primary bile acid ratio, and altered multiple bile acid species. These changes were accompanied by increased ileal FXR expression and changes in downstream regulators involved in hepatic bile acid synthesis. Correlation analysis further showed associations of selected bacterial taxa and FXR protein expression with colonic bile acid profiles. Conclusions: SLBZP alleviates diarrhea induced by fatigue combined with a high-fat diet in mice. Its effects may involve coordinated modulation of the gut microbiota, bile acid homeostasis, and FXR-related signaling, providing experimental support for the pharmacological basis of this traditional formula in diet-related diarrhea. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics, 2nd Edition)

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23 pages, 1496 KB

Open AccessReview

Precision Pharmacotherapy for Obstructive Sleep Apnea: Matching Targeted Drugs to Patient Endophenotypes

by Jayoung Oh and Ji Ho Choi

Pharmaceuticals 2026, 19(9), 1361; https://doi.org/10.3390/ph19091361 - 28 Aug 2026

Abstract

Background: Obstructive sleep apnea (OSA) remains under-treated because continuous positive airway pressure, though efficacious, is frequently limited by poor tolerance and adherence. Long considered a purely anatomical disease refractory to drugs, OSA is now understood as the shared endpoint of four measurable [...] Read more.

Background: Obstructive sleep apnea (OSA) remains under-treated because continuous positive airway pressure, though efficacious, is frequently limited by poor tolerance and adherence. Long considered a purely anatomical disease refractory to drugs, OSA is now understood as the shared endpoint of four measurable endotypes—a collapsible upper airway, poor pharyngeal dilator-muscle responsiveness, high loop gain, and a low arousal threshold—each a distinct pharmacological target. This review synthesizes the mechanistic rationale and clinical evidence for targeting them. Methods: In this narrative review, we searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (January 2000 to February 2026) for randomized trials, meta-analyses, and mechanistic endotyping studies, appraising the evidence narratively. Results: Tirzepatide became the first drug approved for OSA, acting through weight loss to reduce obesity-related mechanical loading, and the noradrenergic–antimuscarinic combination AD109 met its primary endpoint in a pivotal phase 3 trial by targeting dilator-muscle activity independently of weight. Both, however, used AHI-based endpoints in clinically defined rather than endotype-selected populations; AD109’s placebo-corrected effect was modest (−4.0 events/h), and 21.2% versus 3.1% of participants discontinued for adverse events. They are therefore best described as mechanism-informed rather than endotype-validated. Carbonic anhydrase inhibition with acetazolamide or sultiame and selected sedating agents address ventilatory instability and a low arousal threshold, while solriamfetol and pitolisant relieve residual sleepiness. Conclusions: Mechanism-informed pharmacotherapy for OSA is now clinically credible, but scalable bedside endotyping, attention to tolerability, and trait-stratified trials are needed before treatment can be called endotype-guided. Full article

(This article belongs to the Special Issue Pharmacology of Respiratory Diseases)

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31 pages, 9832 KB

Open AccessArticle

Cycloastragenol Attenuates Angiotensin II-Induced Cardiac Remodeling in Association with Enhanced EGFR Lysosomal Turnover and Changes in MAPK Signaling and Autophagy

by Dongsheng Wei, Han Li, Mei Zhao, Mai Liu, Yongyue Liu, Menglan Zhao, Huiming Cao and Xiaoqing Zhang

Pharmaceuticals 2026, 19(9), 1360; https://doi.org/10.3390/ph19091360 - 27 Aug 2026

Abstract

Background: Pathological cardiac remodeling is a major driver of heart failure progression and is closely associated with fibroblast activation, myocardial inflammation, oxidative injury, and impaired autophagic homeostasis. Epidermal growth factor receptor (EGFR) signaling participates in adverse remodeling through activation of MAPK pathways, but [...] Read more.

Background: Pathological cardiac remodeling is a major driver of heart failure progression and is closely associated with fibroblast activation, myocardial inflammation, oxidative injury, and impaired autophagic homeostasis. Epidermal growth factor receptor (EGFR) signaling participates in adverse remodeling through activation of MAPK pathways, but the relationship between pharmacologically modulated EGFR turnover and cardiac remodeling remains insufficiently defined. Methods: This study investigated the protective effects of cycloastragenol (CAG), a triterpenoid sapogenin derived from Astragalus membranaceus, in Angiotensin II (Ang II)-induced cardiac remodeling and examined changes in EGFR turnover and associated MAPK signaling and autophagy-related processes. Circulating soluble EGFR was associated with heart failure severity after adjustment for age and sex. Separately, an independent exploratory transcriptomic analysis of left ventricular samples from GSE161472 showed that myocardial EGFR expression distinguished HFrEF from non-failing samples with an AUC of 0.870. Male C57BL/6 mice subjected to continuous Ang II infusion at 500 ng/kg/min for 28 days were used to establish the in vivo cardiac remodeling model and evaluate the effects of CAG on cardiac function, myocardial injury, fibrosis, inflammation, oxidative stress, apoptosis, and autophagy-related changes, with enalapril used as a positive control. Primary cardiac fibroblasts were further used to assess proliferation, migration, collagen production, EGFR membrane accumulation, lysosomal trafficking, MAPK signaling, and autophagic flux. Circulating soluble EGFR increased with heart failure severity and was associated with BNP elevation, ventricular dilation, and reduced ejection fraction. Results: CAG improved cardiac performance, reduced myocardial injury markers, alleviated fibrosis and hypertrophy, and suppressed inflammatory and oxidative responses in Ang II-treated mice. In cardiac fibroblasts, CAG reduced sustained EGFR membrane accumulation, increased EGFR recovery in pan-ubiquitin immunoprecipitates and lysosomal localization, and accelerated EGFR protein turnover, consistent with a predominantly lysosome-associated pathway. The K716R mutation attenuated CAG-associated changes in EGFR turnover, MAPK phosphorylation, and autophagic flux. Conclusions: These findings suggest that CAG attenuates Ang II-induced cardiac remodeling and is associated with enhanced EGFR lysosomal turnover, accompanied by changes in MAPK signaling and autophagy-related processes. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 6674 KB

Open AccessArticle

Ketone Supplementation Decreased Lipopolysaccharide-Generated Anxiety-like Behavior in Female WAG/Rij Rats

by Enikő Rauch, Csilla Ari, Dominic P. D’Agostino and Zsolt Kovács

Pharmaceuticals 2026, 19(9), 1359; https://doi.org/10.3390/ph19091359 - 27 Aug 2026

Abstract

Background/Objectives: Inflammatory processes, including elevated pro-inflammatory cytokines such as interleukin 1β (IL-1β), have been implicated in the pathophysiology of anxiety disorders. The ketone body β-hydroxybutyrate (βHB) was shown to mitigate inflammatory processes induced by lipopolysaccharide (LPS) administration. It was also suggested that exogenous [...] Read more.

Background/Objectives: Inflammatory processes, including elevated pro-inflammatory cytokines such as interleukin 1β (IL-1β), have been implicated in the pathophysiology of anxiety disorders. The ketone body β-hydroxybutyrate (βHB) was shown to mitigate inflammatory processes induced by lipopolysaccharide (LPS) administration. It was also suggested that exogenous ketone supplements, such as ketone esters (KEs) and ketone salts (KSs), can decrease anxiogenic effects through increased blood ketone levels in the body (ketosis) in preclinical animal models. Methods: Thus, we investigated whether standard rodent food supplemented with KEKS (KEKS food: mix of a KE R/S-1,3-butanediol-acetoacetate diester and a KS Na⁺- and Ca²⁺- R/S-βHB salt in 1:1 ratio) for 7 days can alleviate the intraperitoneal (i.p.) 1 mg/kg LPS-generated anxiogenic effect in female Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. For the evaluation of anxiogenic effects, the light–dark box (LDB) test was used. Results: KEKS food significantly increased the blood R-β-hydroxybutyrate (R-βHB) level and decreased the blood glucose level compared to the baseline. Moreover, the LPS significantly (i) decreased the time spent in the light compartment, the number of chamber transitions, the number of re-entries to the light compartment and the number of rearing in the light compartment, and also (ii) increased the time of latency to the first re-entry to the light compartment compared to control. Nevertheless, KEKS food treatment abolished LPS-generated anxiety-like behavior. Conclusions: The current study demonstrated that a 7-day KEKS-supplemented diet can increase blood R-βHB levels and abolish acute LPS administration-evoked increases in anxiety levels in female WAG/Rij rats. Moreover, our results support the important role of neuroinflammation in pathological processes resulting in anxiety. Thus, these results suggest that exogenous ketone supplement-generated ketosis may be a promising therapeutic tool in the treatment of inflammatory process-mediated diseases, such as anxiety disorders. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 1706 KB

Open AccessReview

Targeting HMGB1 for Renal Ischemia and Reperfusion Injury: Mechanisms and Therapeutic Strategies

by Xiao-Hui Chi, Ming-Feng Liao and Ya-Qun Zhou

Pharmaceuticals 2026, 19(9), 1358; https://doi.org/10.3390/ph19091358 - 27 Aug 2026

Abstract

Although the underlying mechanisms of renal IRI have been extensively studied, the corresponding effective treatments are still lacking. HMGB1, an important nuclear factor that is secreted outside cells when experiencing stress conditions, acts as a DAMP and exerts crucial effects on renal IRI. [...] Read more.

Although the underlying mechanisms of renal IRI have been extensively studied, the corresponding effective treatments are still lacking. HMGB1, an important nuclear factor that is secreted outside cells when experiencing stress conditions, acts as a DAMP and exerts crucial effects on renal IRI. Many studies have suggested that the effect of HMGB1 on kidney damage is mediated mainly through the interaction of HMGB1 with pattern recognition receptors such as TLR4 and RAGE, which then results in the aggravation of local inflammatory response, increased infiltration of leukocytes, and finally renal tubular damage. Preclinical studies using animal models have demonstrated that inhibition of HMGB1 and downstream signal pathways can attenuate renal injury. This review critically evaluates HMGB1 in renal IRI across redox state, subcellular localization, temporal and cell-specific release, receptor usage, integrated stress pathways, autophagy, and regulated cell death. It also compares direct neutralization, inhibition of release or translocation, epigenetic/RNA-based regulation, and receptor-directed strategies. The evidence is predominantly derived from short-term rodent studies, with one large-animal antibody study and no therapeutic human trials. Accordingly, HMGB1 is best regarded as a biologically compelling but clinically unvalidated target whose therapeutic value will depend on redox- and phase-selective inhibition, kidney-directed delivery, and rigorous pharmacokinetic and safety evaluation. Full article

(This article belongs to the Section Pharmacology)

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35 pages, 2342 KB

Open AccessArticle

Pharmaceutical Market Analysis of Topical Semi-Solid Dosage Forms for Skin Disorders in Kazakhstan

by Artyom Savelyev, Dmitriy Khrustalev, Irina Losseva, Azamat Yedrissov, Anastassiya Khrustaleva, Vladimir Kazantsev, Sofiya Shapovalenko, Marlen Kiikbayev, Polina Rusyaeva and Kristina Perepelitsyna

Pharmaceuticals 2026, 19(9), 1357; https://doi.org/10.3390/ph19091357 - 27 Aug 2026

Abstract

Background: Topical semi-solid dosage forms are crucial for treating inflammatory skin disorders, wounds, burns, and superficial infections. Despite their widespread clinical use, comprehensive pharmaceutical market analyses of registered topical medicines remain limited in Central Asia. The aim of this study was to characterize [...] Read more.

Background: Topical semi-solid dosage forms are crucial for treating inflammatory skin disorders, wounds, burns, and superficial infections. Despite their widespread clinical use, comprehensive pharmaceutical market analyses of registered topical medicines remain limited in Central Asia. The aim of this study was to characterize the pharmaceutical market of topical semi-solid dosage forms registered in the Republic of Kazakhstan, including their dosage-form distribution, pharmacotherapeutic composition, manufacturer structure, and structural diversity of active pharmaceutical ingredients (APIs), with particular attention to heterocyclic compounds. Methods: A cross-sectional descriptive analysis was conducted using the State Register of Medicinal Products of the Republic of Kazakhstan. Registration records of topical semi-solid dosage forms were identified according to predefined inclusion criteria and classified by dosage form, pharmacotherapeutic category, manufacturer, country of origin, and API chemical structure. Descriptive statistical analysis, market concentration indices, and structural classification of heterocyclic compounds were applied. Therapeutic recommendations for dermatitis management from selected CIS countries were reviewed to provide a contextual interpretation of the observed market structure. Results: A total of 1046 registered topical semi-solid dosage forms met the inclusion criteria. Ointments (39.5%), gels (28.9%), and creams (25.4%) accounted for 93.8% of all registered products, indicating a highly concentrated dosage-form structure. Anti-inflammatory agents represented the largest pharmacotherapeutic group, whereas wound-healing and combination products accounted for smaller proportions of the market. Structural classification demonstrated broad representation of established heterocyclic chemical classes, while no registered medicinal products containing dihydropyrimidine-2(1H)-thione (DHPM-thione) derivatives were identified in the registry. Comparison with regional clinical recommendations indicated differences between recommended therapeutic approaches and the distribution of registered pharmacotherapeutic categories. Conclusions: This study provides the first comprehensive descriptive assessment of the registered market of topical semi-solid dosage forms in Kazakhstan. The results establish a reference dataset describing the current pharmaceutical landscape, including dosage forms, therapeutic categories, manufacturers, and API chemical classes. The absence of registered DHPM-thione-containing medicinal products indicates that this chemical class is currently not represented in the national medicines registry. Together with previously published preclinical evidence, this observation supports consideration of DHPM-thione derivatives as a subject for future pharmaceutical research, although the present study does not permit conclusions regarding their clinical effectiveness, market demand, or future commercialization. Full article

(This article belongs to the Section Pharmacology)

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25 pages, 4746 KB

Open AccessArticle

Comparative Neuropharmacological Effects of Antiseizure Drugs on Cultured Myenteric and Dorsal Root Ganglion Neurons

by Aleksandr Subbotin, Holger A. Volk, Sebastian Meller, Gemma Mazzuoli-Weber and Kristin Elfers

Pharmaceuticals 2026, 19(9), 1356; https://doi.org/10.3390/ph19091356 - 27 Aug 2026

Abstract

Background/Objectives: Antiseizure drugs (ASDs) are the primary therapeutic approach for epilepsy in small animals. Although ASDs are primarily used to modulate central neuronal excitability, they are commonly administered systemically, most often by the oral route, and may therefore influence neuronal populations outside the [...] Read more.

Background/Objectives: Antiseizure drugs (ASDs) are the primary therapeutic approach for epilepsy in small animals. Although ASDs are primarily used to modulate central neuronal excitability, they are commonly administered systemically, most often by the oral route, and may therefore influence neuronal populations outside the central nervous system. Nevertheless, their functional effects on peripheral neuronal populations, including enteric and dorsal root ganglion (DRG) neurons, remain incompletely characterized at a comparative pharmacological level. This study aimed to perform a comparative functional neuropharmacological profiling of commonly used ASDs in primary cultured myenteric and DRG neurons. Methods: Changes in neuronal activity were assessed in primary cultured guinea pig myenteric and DRG neurons using voltage-sensitive dye imaging with Di-8-ANEPPS following direct ASD application under standardized in vitro conditions. Results: ASDs exerted distinct drug- and neuron-type-specific effects on peripheral neuronal excitability. Topiramate induced the most pronounced reduction in neuronal excitability in myenteric neurons, whereas phenobarbital and levetiracetam produced only minor changes compared with buffer control. Potassium bromide induced mainly excitatory effects in both enteric and DRG neurons. Overall, most ASDs predominantly increased neuronal excitability in DRG neurons. Conclusions: These findings demonstrate distinct functional response profiles of ASDs in enteric and sensory neuronal populations. This comparative in vitro approach may provide a basis for future studies investigating peripheral neuronal drug effects and may help relate experimental pharmacological profiling to clinically relevant challenges associated with ASD treatment across different disorders. Full article

(This article belongs to the Section Pharmacology)

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21 pages, 16080 KB

Open AccessArticle

Physiological Hypoxia and Pharmacological HIF Stabilization Induce Distinct but Overlapping Responses in Retinal Pigment Epithelial Cells

by Tamás Gáll, Dávid Pethő, Szilárd Póliska, József Balla and György Balla

Pharmaceuticals 2026, 19(9), 1355; https://doi.org/10.3390/ph19091355 - 27 Aug 2026

Abstract

Background/Objectives: Hypoxia is a major contributor to the development of retinal diseases by promoting metabolic adaptation and pathological angiogenesis through hypoxia-inducible factor (HIF) signaling. HIF-prolyl hydroxylase inhibitors (HIF-PHIs), which stabilize HIF under normoxic conditions, are widely used to treat anemia associated with chronic [...] Read more.

Background/Objectives: Hypoxia is a major contributor to the development of retinal diseases by promoting metabolic adaptation and pathological angiogenesis through hypoxia-inducible factor (HIF) signaling. HIF-prolyl hydroxylase inhibitors (HIF-PHIs), which stabilize HIF under normoxic conditions, are widely used to treat anemia associated with chronic kidney disease. However, it remains unclear whether pharmacological HIF stabilization fully reproduces the cellular responses induced by physiological hypoxia. Methods: In this study, ARPE-19 cells were exposed to either physiological hypoxia or HIF-PHI treatment and analyzed using RNA sequencing, pathway enrichment, and pharmacological inhibition of PI3K/Akt, mTOR, and HIF-related signaling pathways. Results: Both treatments elicited a common transcriptional response marked by the induction of glycolytic and hypoxia-responsive genes together with increased vascular endothelial growth factor a VEGFA expression. Despite these similarities, only a small number of genes differed between the two conditions, suggesting that physiological hypoxia activates additional regulatory mechanisms beyond HIF stabilization alone. Rapamycin inhibited VEGFA production only under physiological hypoxia, further supporting mechanistic differences between the two models. Functionally, conditioned media from hypoxic ARPE-19 cells promoted endothelial tube formation, which was significantly reduced by pathway inhibition. Conclusions: Collectively, these findings show that HIF-PHIs reproduce many, but not all, aspects of the physiological hypoxic response in RPE cells. Full article

(This article belongs to the Section Pharmacology)

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27 pages, 10247 KB

Open AccessArticle

Predicting the Toxicity In Silico of the Aqueous Extract of Chiranthodendron pentadactylon Flowers. Experimental Evaluation In Vivo

by Oscar Salvador Barrera-Vázquez, Gil Alfonso Magos-Guerrero, Juan Luis Escobar-Ramírez, Rubén San Miguel-Chávez and Maira Huerta-Reyes

Pharmaceuticals 2026, 19(9), 1354; https://doi.org/10.3390/ph19091354 - 26 Aug 2026

Abstract

Chiranthodendron pentadactylon Larreat (“flor de manita”) is traditionally used for gastrointestinal, cardiovascular, and neurological disorders. Objective: This study comprehensively integrated phytochemical characterization, in silico toxicological profiling, an exposure-informed Integrative Toxicity Prediction Model (ITPM), uncertainty analysis, and acute testing of a fresh flower aqueous [...] Read more.

Chiranthodendron pentadactylon Larreat (“flor de manita”) is traditionally used for gastrointestinal, cardiovascular, and neurological disorders. Objective: This study comprehensively integrated phytochemical characterization, in silico toxicological profiling, an exposure-informed Integrative Toxicity Prediction Model (ITPM), uncertainty analysis, and acute testing of a fresh flower aqueous extract (FFAE). Methods: Thirty-six phytochemicals were screened for hepatotoxicity, nephrotoxicity, Ames mutagenicity, carcinogenicity, hERG inhibition, reproductive-effects alerts, and acute oral toxicity. Five organ- or effect-specific endpoints were integrated into an exploratory Toxicological Alert Score (TAS), whereas reproductive alerts and predicted LD₅₀ were reported separately. Seventeen compounds quantified in the FFAE were compared with a 20-compound literature-informed profile through 50,000 Monte Carlo iterations. Male CD-1 mice received a single FFAE dose of 300–5000 mg/kg and were observed for 14 days. Results: Positive predictions occurred for hERG inhibition in 33 compounds (91.7%), hepatotoxicity in 29 (80.6%), nephrotoxicity and carcinogenicity in 28 each (77.8%), and mutagenicity in 21 (58.3%). Six compounds had predicted LD₅₀ values ≤ 1000 mg/kg. The proportional ITPM toxicity-evidence index was 6.91% for the experimental profile and 19.34% for the literature-informed profile. Monte Carlo means were 6.98% (95% uncertainty interval, 5.65–8.44%) and 19.32% (16.76–22.37%), respectively. No mortality, overt clinical signs, or treatment-related body weight differences occurred up to 5000 mg/kg. Conclusions: Compound-level predictions identified priorities for confirmatory testing, while the extract-specific model yielded a lower comparative toxicity-evidence proportion, and the animal study showed low overall acute toxicity under the evaluated conditions. These findings do not establish general or long-term safety, calibrated risk probabilities, or biological neutralization of toxicological liabilities. Full article

(This article belongs to the Special Issue Advances in Natural Products: Basic, Therapeutic, and Computational Approaches in Chronic and Infectious Diseases)

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39 pages, 2600 KB

Open AccessArticle

Consensus In Silico Pharmacodynamic Screening of Twelve Fabaceae Isoflavones Targeting Glycation, Oxidative Stress, Antidiabetic Activity, and NF-κB-Related Inflammation

by Saied A. Aboushanab, Denis A. Oberiukhtin, Irina G. Danilova, Pavel M. Vassiliev, Ksenia V. Sokolova, Kewei Chen, Elena G. Kovaleva, Alicia C. Mondragon, Ekaterina I. Demicheva and Jose M. Miranda

Pharmaceuticals 2026, 19(9), 1353; https://doi.org/10.3390/ph19091353 - 26 Aug 2026

Abstract

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by chronic hyperglycemia, oxidative stress, protein glycation, low-grade inflammation, and dysregulation of signaling pathways, including those involving nuclear factor kappa B (NF-κB). Isoflavones from Fabaceae species exhibit diverse biological activities and [...] Read more.

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by chronic hyperglycemia, oxidative stress, protein glycation, low-grade inflammation, and dysregulation of signaling pathways, including those involving nuclear factor kappa B (NF-κB). Isoflavones from Fabaceae species exhibit diverse biological activities and may represent multifunctional candidates for addressing the interconnected mechanisms underlying T2DM. This study performed a consensus in silico pharmacodynamic screening of twelve representative Fabaceae isoflavones to prioritize compounds with predicted antiglycating, deglycating, antidiabetic, antioxidant, and NF-κB-related anti-inflammatory activities. Methods: Twelve representative Fabaceae isoflavones were evaluated using a multimethod computational workflow. Antiglycating and deglycating activities were predicted using IT Microcosm, antidiabetic and hypoglycemic activities were assessed using Prediction of Activity Spectra for Substances (PASS), antioxidant potential was evaluated using similarity-based prediction and quantum-chemical calculations, and NF-κB-related anti-inflammatory activity was investigated using similarity-based prediction combined with molecular docking. Molecular docking was applied specifically to the NF-κB-related anti-inflammatory analysis and did not contribute to the hypoglycemic/antidiabetic prediction. The individual predictions were integrated using a consensus scoring strategy to prioritize compounds across multiple pharmacodynamic domains. Results: The investigated isoflavones demonstrated moderate but broad predicted multifunctional activities. Malonylgenistin, biochanin A, and formononetin showed the most favorable predicted antiglycating profiles. Genistin, acetyldaidzin, acetylglycitin, and puerarin ranked highest in terms of predicted antidiabetic activity, whereas genistein exhibited the strongest predicted antioxidant profile. Daidzin and genistin received the highest integrated NF-κB-related computational rankings, although these predictions apply to intact glycosides rather than their expected in vivo hydrolysis products. Conclusions: This study presents a consensus computational framework for the comparative prioritization of Fabaceae isoflavones based on their predicted multifunctional pharmacodynamic profiles. The results provide a rational basis for selecting candidate compounds for future biochemical, cell-based, pharmacokinetic, and in vivo investigations, although it is emphasized that the present findings are based exclusively on computational predictions and require experimental validation. Full article

(This article belongs to the Special Issue Emerging Therapies for Diabetes and Obesity)

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22 pages, 5259 KB

Open AccessReview

PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

by Pasquale Degennaro, Imane Ghafir El Idrissi, Rosa Purgatorio, Annalisa Fanizzi, Mariagrazia Rullo, Leonardo Pisani, Eleonora Macchia, Luisa Torsi, Angela Stefanachi and Francesco Leonetti

Pharmaceuticals 2026, 19(9), 1352; https://doi.org/10.3390/ph19091352 - 26 Aug 2026

Abstract

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce the selective degradation of a protein of interest by recruiting an E3 ubiquitin ligase, thereby triggering ubiquitination and proteasomal clearance. As part of the broader targeted protein degradation (TPD) paradigm, PROTACs offer a powerful strategy [...] Read more.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce the selective degradation of a protein of interest by recruiting an E3 ubiquitin ligase, thereby triggering ubiquitination and proteasomal clearance. As part of the broader targeted protein degradation (TPD) paradigm, PROTACs offer a powerful strategy to eliminate pathogenic proteins that are difficult to modulate with traditional occupancy-based inhibitors. However, their clinical translation is often limited by poor aqueous solubility, suboptimal cellular permeability, and off-target effects. Notably, some PROTACs retain potent biological activity despite limited membrane permeability, owing to their catalytic mechanism of action, which allows even a small number of molecules reaching the target site to drive substantial protein degradation and produce important pharmacological effects. Growing evidence supports the application of PROTAC-based approaches in neurodegenerative diseases, where the selective removal of toxic or misfolded proteins is particularly attractive. This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development. Full article

(This article belongs to the Topic Imatinib (Glivec or Gleevec): Commemorative Topic in Honor of Dr. Jürg Zimmermann on the Occasion of His 70th Anniversary)

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14 pages, 1847 KB

Open AccessArticle

Representative Conformational Sampling for Chiroptical Analysis of the Flexible Dopamine Agonist Rotigotine

by Yi-Xuan Li, Xiao-Li Zhou, Jing-Wen Xu, Chen Zhao, You-Yang Li, Hai-You Zhao, Liang-Peng Li, Xin-Xin Tan, Yu-Xiang Zhang, Bei-Bei Yang, Li Li and Li-Hui Yin

Pharmaceuticals 2026, 19(9), 1351; https://doi.org/10.3390/ph19091351 - 26 Aug 2026

Abstract

Background/Objectives: Rotigotine is a conformationally flexible chiral dopamine agonist, but its solution-phase chiroptical behavior and conformational heterogeneity have not been systematically assessed. This study characterized its electronic circular dichroism (ECD), optical rotatory dispersion (ORD), and vibrational circular dichroism (VCD) responses and evaluated [...] Read more.

Background/Objectives: Rotigotine is a conformationally flexible chiral dopamine agonist, but its solution-phase chiroptical behavior and conformational heterogeneity have not been systematically assessed. This study characterized its electronic circular dichroism (ECD), optical rotatory dispersion (ORD), and vibrational circular dichroism (VCD) responses and evaluated their consistency with its absolute configuration. Methods: ECD and ORD data were acquired for rotigotine ((S)-1) and its simplified analog (S)-2 in acetonitrile and methanol, and VCD spectra were recorded in appropriate deuterated solvents. Conformational searches, Boltzmann weighting, and density functional theory/time-dependent density functional theory calculations were performed. A principal-component-analysis/torsion (PCA-Tor) workflow selected a compact but structurally representative conformer ensemble for (S)-1. Results: In acetonitrile, (S)-1 exhibited a positive Cotton effect (CE) at 208.5 nm and a negative CE at 194.0 nm. The Boltzmann-weighted ECD spectrum reproduced the intense negative band below 200 nm and the positive band near 210 nm. The calculated VCD spectrum agreed with the signs and positions of the main experimental bands in the 1500–1100 cm⁻¹ region. Experimental ORD curves of both compounds were negative in acetonitrile and methanol. The calculations reproduced the sign and overall trend, although their magnitudes were protocol- and population-sensitive. Ring puckering strongly affected the calculated ECD and ORD data, whereas side-chain flexibility expanded the accessible conformational space. Conclusions: The combined results support the known S configuration of rotigotine and demonstrate the value of representative conformational sampling for flexible chiral pharmaceuticals. This study also defines the practical utility and limitations of simplified molecular models in chiroptical analysis. Full article

(This article belongs to the Section Medicinal Chemistry)

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22 pages, 3359 KB

Open AccessReview

Natural Products and Traditional Chinese Medicine in Hepatocellular Carcinoma: From Pharmacological Mechanisms to Clinical Translation

by Jingyi Shen, Xiaoya Liu, Xuanyan Yan, Tao Zhang, Xianfang Zhang, Huiquan Gu, Weimin Chen, Zhengwen Wang and Qiang Liu

Pharmaceuticals 2026, 19(9), 1350; https://doi.org/10.3390/ph19091350 - 26 Aug 2026

Abstract

Hepatocellular carcinoma (HCC) remains difficult to control because recurrence, impaired hepatic reserve, and treatment resistance limit durable benefit. Natural products and traditional Chinese medicine (TCM) provide resources that range from drug-lead discovery to adjunctive multicomponent therapy. This review integrates pharmacological and clinical evidence [...] Read more.

Hepatocellular carcinoma (HCC) remains difficult to control because recurrence, impaired hepatic reserve, and treatment resistance limit durable benefit. Natural products and traditional Chinese medicine (TCM) provide resources that range from drug-lead discovery to adjunctive multicomponent therapy. This review integrates pharmacological and clinical evidence for purified compounds, semisynthetic derivatives, extracts, formulas, and delivery systems. It focuses on metabolic reprogramming and redox homeostasis, stress responses and regulated cell death, tumor cell plasticity and vascular remodeling, and the immune microenvironment and host response. Recent studies have strengthened selected mechanistic claims through chemical probes, functional perturbation, and resistance models. Clinical research has concentrated on recurrence control after surgery or minimally invasive treatment and on combinations with transarterial chemoembolization, targeted agents, and immunotherapy. Randomized trials and prospective cohorts suggest potential benefit in specific settings, although product standardization, external validation, and long-term follow-up remain limited. Major translational barriers include uncertain active constituents, inadequate batch comparability, missing tumor-exposure data, and sparse herb–drug interaction studies. Future development should match target validation, pharmacokinetics, safety assessment, and clinical endpoints to each product class and clarify whether a candidate is best positioned as a drug lead, adjunctive therapy, or supportive intervention. Full article

(This article belongs to the Section Natural Products)

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21 pages, 19075 KB

Open AccessArticle

Identification of Hypolipidemic Constituents from Microctis folium Using an Integrated Strategy of Chemical Profiling, Pharmacokinetics, Network Pharmacology and Experimental Validation

by Zhihao Zeng, Yanchang Liu, Xiaoli Bi, Wanchun Chen, Yunhui Ouyang, Jingnian Zhang, Weitao Chen and Guanlin Xiao

Pharmaceuticals 2026, 19(9), 1349; https://doi.org/10.3390/ph19091349 - 26 Aug 2026

Abstract

Background/Objective: Traditionally derived from the dried leaves of Microcos paniculata L., Microctis folium (M. folium) has been employed to manage various inflammatory and metabolic conditions. Despite its reported hypolipidemic potential, the active constituents contributing to this effect and their molecular [...] Read more.

Background/Objective: Traditionally derived from the dried leaves of Microcos paniculata L., Microctis folium (M. folium) has been employed to manage various inflammatory and metabolic conditions. Despite its reported hypolipidemic potential, the active constituents contributing to this effect and their molecular mechanisms of action remain to be determined. Therefore, this study aimed to systematically identify the active hypolipidemic constituents of M. folium and elucidate their mechanisms of action through an integrated strategy combining chemical profiling, pharmacokinetic screening, network pharmacology, and experimental validation. Methods: UPLC fingerprint and UPLC-QQQ-MS/MS were employed to characterize and quantify the chemical constituents of M. folium. Pharmacokinetic analysis was conducted to identify systemically absorbed compounds. Network pharmacology was applied to predict potential targets and signaling pathways. The lipid-lowering effects were subsequently validated in vitro using an oleic acid/palmitic acid (OA/PA)-induced lipid accumulation model in HepG2 cells and in vivo in a Triton WR-1339-induced hyperlipidemia mouse model. Results: UPLC fingerprint analysis identified 15 common peaks among 21 batches of M. folium, with similarity values ranging from 0.885 to 0.990, indicating good chemical consistency. Eighteen representative compounds were quantified, among which flavone C-glycosides and phenolic acids were predominant. Pharmacokinetic results demonstrated that multiple M. folium’s constituents were absorbed into systemic circulation. Network pharmacology analysis identified 73 potential targets related to hyperlipidemia and highlighted the PI3K-Akt signaling pathway as a key regulatory pathway. In vitro experiments showed that M. folium’s compounds significantly reduced intracellular lipid accumulation and oxidative stress in OA/PA-induced HepG2 cells. Furthermore, in vivo studies demonstrated that vitexin, ferulic acid, isoferulic acid, and N-trans-feruloyltyramine significantly reduced serum and hepatic lipid levels, including TC, TG, and LDL-c, alleviated hepatic steatosis, and improved liver injury and oxidative stress markers in Triton WR-1339-induced hyperlipidemic mice. Conclusions: M. folium exerts significant lipid-lowering effects through multi-component and multi-target mechanisms involving regulation of lipid metabolism and oxidative stress, partly mediated by activation of the PI3K-Akt signaling pathway. These findings provide a scientific basis for the development of M. folium’s natural agents for the treatment of hyperlipidemia. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 4739 KB

Open AccessSystematic Review

Efficacy and Safety of Cadonilimab in Digestive System Neoplasms: A Systematic Review and Single-Arm Meta-Analysis

by Qiuqi Zhuang, Zhitao Yang and Yan Liu

Pharmaceuticals 2026, 19(9), 1348; https://doi.org/10.3390/ph19091348 - 26 Aug 2026

Abstract

Objective: This study aimed to systematically evaluate the efficacy and safety of cadonilimab in the treatment of digestive system neoplasms. Methods: PubMed, Embase, Cochrane Library, Web of Science, Wiley Online Library, CNKI, Wanfang Data, CBM, and VIP databases were systematically searched to collect [...] Read more.

Objective: This study aimed to systematically evaluate the efficacy and safety of cadonilimab in the treatment of digestive system neoplasms. Methods: PubMed, Embase, Cochrane Library, Web of Science, Wiley Online Library, CNKI, Wanfang Data, CBM, and VIP databases were systematically searched to collect randomized controlled trials, non-randomized studies, and real-world studies investigating cadonilimab for the treatment of digestive system neoplasms. The initial search spanned from the inception of the databases to 4 February 2026, with an update search conducted in June 2026. Meta-analysis was performed using Stata 16.0 to systematically assess efficacy and safety outcomes. Results: A total of 10 studies, predominantly single-arm or retrospective, were included in this meta-analysis. Regarding the primary outcomes, because of the clinical heterogeneity across tumor types, pooled estimates should be interpreted as a summary across diverse diseases rather than as a single-tumor estimate. The overall pooled disease control rate (DCR) was 84% (95% CI = 76–91%), with tumor-specific DCRs of 87% in ESCC, 79% in HCC, 88% in G/GEJ adenocarcinoma, and 86% in PDAC. The pooled incidence of any-grade treatment-related adverse events (TRAEs) was 98% (95% CI = 95–100%), and the pooled incidence of any-grade immune-related adverse events (irAEs) was 32% (95% CI = 18–47%). For secondary outcomes: The partial response (PR) rate was 33% (95% CI = 21–46%), and the progressive disease (PD) rate was 11% (95% CI = 5–18%). The pooled incidence of grade ≥ 3 TRAEs was 52% (95% CI = 38–66%), and the pooled incidence of grade ≥ 3 irAEs was 11% (95% CI = 8–16%). However, incomplete reporting of low-frequency AEs across studies likely underestimates the pooled irAE rate. Conclusions: This study suggests that cadonilimab has the potential for antitumor activity in digestive system neoplasms. The observed safety profile was consistent with the known toxicities of immunotherapy, with notably high rates of TRAEs warranting vigilant monitoring. These findings should be considered hypothesis-generating and are insufficient to establish clinical benefit. Full article

(This article belongs to the Section Pharmacology)

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