Search Results (14)

Gastrointestinal malignancies remain among the leading causes of cancer-related morbidity and mortality worldwide, largely due to late diagnosis, aggressive tumor progression, and resistance to conventional therapies. Tumor angiogenesis and the tumor microenvironment (TME) play crucial roles in the initiation, growth, and metastatic dissemination of gastrointestinal cancers. Hypoxia-driven signaling pathways, including hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and inflammatory mediators such as NF-κB and MAPK, are key regulators of these processes. Increasing evidence suggests that natural products derived from medicinal plants and other biological sources may modulate these pathways and exhibit anti-angiogenic, anti-inflammatory, and anti-fibrotic properties. This review summarizes recent findings on natural compounds that influence angiogenesis and tumor microenvironment dynamics through the regulation of molecular pathways involved in hypoxia signaling, extracellular matrix remodeling, fibroblast activation, and inflammatory responses. Compounds such as neotuberostemonine, aloperine, silymarin derivatives, tanshinone IIA, berberine, asiatic acid, and phloretin demonstrate promising biological activities in experimental models by targeting pathways including HIF-1α, PI3K/AKT/mTOR, TGF-β/Smad, and NF-κB signaling. However, further studies focusing on gastrointestinal cancer models and clinical validation are required to translate these preclinical observations into effective therapeutic strategies. Full article

Peripheral nerve injuries affect 13–23 out of 100,000 people annually, with Wallerian degeneration and subsequent inflammatory/oxidative responses critically impacting recovery. Aloperine, a natural alkaloid from Sophora alopecuroides L., exhibits potent anti-inflammatory and antioxidant properties but has never been studied for nerve repair. In this study, we aimed to investigate whether aloperine could enhance peripheral nerve regeneration by modulating inflammation and oxidative stress in a rat sciatic nerve injury model. Thirty male Wistar rats underwent sciatic nerve neurotmesis with epineural repair. Animals were divided into surgical controls (Group A), aloperine-treated rats (Group B; single 100 mg/kg intraperitoneal dose), and intact controls (Group C). After 8 weeks, outcomes were assessed via functional tests (pinprick, hot plate, extensor postural thrust), biochemical analyses (TNF-α, IL-6, IL-10, TOS/TAS), and histomorphometric evaluations (axon counts, diameter indices, immunohistochemistry). Aloperine treatment significantly improved functional recovery, with near-normal hot plate latency and motor performance. Biochemically, it reduced pro-inflammatory markers (TNF-α) while elevating IL-10. Oxidative stress was attenuated. Histologically, treated nerves showed better-preserved axonal architecture (reduced inflammation). This first investigation of aloperine for nerve repair demonstrates its therapeutic potential through dual anti-inflammatory and antioxidant mechanisms, significantly improving functional and structural outcomes. These findings support its development as a novel treatment for peripheral nerve injuries. Full article

Background: Oral squamous cell carcinoma (OSCC) is a major epithelial malignancy of the head and neck with high morbidity and mortality. The conventional antineoplastic medications used in clinical practice have become less effective due to the heterogeneity of tumors, accompanied by severe side effects. Therefore, the development of novel chemotherapeutic agents has become an important goal of anti-OSCC therapy. Methods: Our group has previously developed a novel wogonin–aloperine co-amorphous (Wog–Alop). In this study, the anti-OSCC efficacy of Wog–Alop was evaluated by a patient-derived tumor xenograft (PDX) model. Subsequently, network pharmacology was employed to predict the key targets of Wog–Alop on OSCC, and the predicted key targets were further confirmed by Western blot and immunochemistry. Results: The results revealed that Wog–Alop manifests the higher efficacy in inhibition of OSCC proliferation by regulating the expression of the key targets, Bcl-2, Bax, P53, and Caspase3, implying that the apoptotic mechanism is implicated in Wog–Alop-induced inhibition of proliferation in OSCC. Conclusions: Collectively, the present work demonstrated anti-OSCC bioactivity of Wog–Alop, suggesting that Wog–Alop could be developed as an innovative therapeutic agent for OSCC therapy. Full article

Drug resistance is still one of the main challenges for the treatment of colorectal cancer (CRC). Whilst some resistance mechanisms are well known, from the static therapy success rate, clearly, still much is undiscovered. Intracellular transport mechanisms have attracted attention as having a possible role in drug resistance, and here, the Endosomal Sorting Complex Required for Transport (ESCRT) protein family is studied as a source of drug resistance modulation using human CRC cell lines and clinical material. From an initial screening of ESCRT proteins in a panel of 10 CRC wild-type cell lines using immunoblotting, Vacuolar Protein Sorting-Associated Protein A4 (VPS4A) was identified as being consistently highly expressed, and it was selected for further investigation. Immunohistopathological evaluation in a small panel of CRC patient samples demonstrated high expression in the tumor epithelium compared to normal intestinal epithelium. The knockdown of VPS4A resulted in enhanced sensitivity of cells to oxaliplatin, and it was subsequently seen that oxaliplatin-resistant sublines had significantly higher VPS4A expression than their wild-type variants. In addition, it was demonstrated that a small molecule inhibitor of VPS4A, aloperine, could interact synergistically with oxaliplatin to enhance its sensitivity in an oxaliplatin-resistant cell line. We hypothesize from initial RNA sequencing analysis that the mechanism of action of VPS4A modulation is through depleting levels of the drug efflux transporter MRP2 in the cell, preventing oxaliplatin egress and increasing cell exposure to the drug. The evidence presented here thus indicates that ESCRT machinery, specifically VPS4A, may act as a modulator of oxaliplatin resistance in CRC. Full article

Background: Pulmonary hypertension (PH) remains a life-threatening rare disease characterized by inflammation and oxidative stress in pulmonary artery smooth muscle cells (PASMCs). Wogonin (Wog), a plant-derived polyphenolic compound extracted from Scutellaria baicalensis Georgi, exhibits notable antioxidant activity and anti-PH efficacy, whereas its clinical applications are greatly limited by poor aqueous solubility. Methods: Herein, an innovative wogonin-aloperine co-amorphous (Wog-Alop) was developed to improve the aqueous solubility and, thus, anti-PH efficacy of Wog. Results: As expected, the aqueous solubility of Wog-Alop is about 40-fold that of Wog; meanwhile, the Wog-Alop demonstrates better oral bioavailability and anti-PH efficacy than Wog; moreover, the Wog-Alop exhibits significantly enhanced capacity to attenuate oxidative stress in human PASMCs compared to Wog. Conclusions: The results suggested that Wog-Alop could not only improve the solubility of Wog, thereby enhancing its oral bioavailability but also alleviate Wog’s oxidative stress effects. These synergistic effects ultimately culminate in the enhanced anti-PH efficacy of Wog. In summary, the present study developed an innovative co-amorphous strategy for the delivery of Wog and improved its anti-PH efficacy. Full article

Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH. Full article

African swine fever (ASF) has become a global pandemic due to inadequate prevention and control measures, posing a significant threat to the swine industry. Despite the approval of a single vaccine in Vietnam, no antiviral drugs against the ASF virus (ASFV) are currently available. Aloperine (ALO), a quinolizidine alkaloid extracted from the seeds and leaves of bitter beans, exhibits various biological functions, including anti-inflammatory, anti-cancer, and antiviral activities. In this study, we found that ALO could inhibit ASFV replication in MA-104, PK-15, 3D4/21, and WSL cells in a dose-dependent manner without cytotoxicity at 100 μM. Furthermore, it was verified that ALO acted on the co- and post-infection stages of ASFV by time-of-addition assay, and inhibited viral internalization rather than directly inactivating the virus. Notably, RT-qPCR analysis indicated that ALO did not exert anti-inflammatory activity during ASFV infection. Additionally, gene ontology (GO) and KEGG pathway enrichment analyses of transcriptomic data revealed that ALO could inhibit ASFV replication via the PRLR/JAK2 signaling pathway. Together, these findings suggest that ALO effectively inhibits ASFV replication in vitro and provides a potential new target for developing anti-ASFV drugs. Full article

Malignant tumors pose a serious threat to human health, reducing quality of life. Natural antitumor drugs play a vital role in the treatment of cancer. Sophora alopecuroides, a traditional Chinese medicine not a part of the Chinese Pharmacopoeia, grows in the arid desert and edge zone of grassland. Previous studies have extensively investigated the antitumor effects of S. alopecuroides and its major alkaloids. Of these, aloperine, matrine, oxymatrine, sophoridine, and sophocarpine have received the most attention. In recent years, a variety of extraction and separation methods have been applied to the study of the alkaloids of Sophora alopecuroides, which has greatly promoted the study of the chemical constituents and pharmacological activities of the plant. S. alopecuroides has been shown to impede cancer cell growth, induce cell cycle arrest, enhance apoptosis and cellular differentiation, and impede cancer metastasis and invasion. Several mechanisms have been proposed for modulating cancer signaling and molecular pathways or targets based on multitudinous studies in various types of cancerous cells. This review provides an in-depth overview of the antitumor effects of S. alopecuroides and the potential targets of 12 alkaloids in S. alopecuroides via a pharmacophore mapping approach and offers a scientific basis for the further exploration of the mechanism related to the antitumor effects of this plant. Full article

COVID-19, caused by the highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly spread and become a pandemic since its outbreak in 2019. We have previously discovered that aloperine is a new privileged scaffold that can be modified to become a specific antiviral compound with markedly improved potency against different viruses, such as the influenza virus. In this study, we have identified a collection of aloperine derivatives that can inhibit the entry of SARS-CoV-2 into host cells. Compound 5 is the most potent tested aloperine derivative that inhibited the entry of SARS-CoV-2 (D614G variant) spike protein-pseudotyped virus with an IC₅₀ of 0.5 µM. The compound was also active against several other SARS-CoV-2 variants including Delta and Omicron. Results of a confocal microscopy study suggest that compound 5 inhibited the viral entry before fusion to the cell or endosomal membrane. The results are consistent with the notion that aloperine is a privileged scaffold that can be used to develop potent anti-SARS-CoV-2 entry inhibitors. Full article

Aloperine is an alkaloid found in the seeds and leaves of the medicinal plant Sophora alopecuroides L. It has been used as herbal medicine in China for centuries due to its potent anti-inflammatory, antioxidant, antibacterial, and antiviral properties. Recently, aloperine has been widely investigated for its therapeutic activities. Aloperine is proven to be an effective therapeutic agent against many human pathological conditions, including cancer, viral diseases, and cardiovascular and inflammatory disorders. Aloperine is reported to exert therapeutic effects through triggering various biological processes, including cell cycle arrest, apoptosis, autophagy, suppressing cell migration, and invasion. It has also been found to be associated with the modulation of various signaling pathways in different diseases. In this review, we summarize the most recent knowledge on the modulatory effects of aloperine on various critical biological processes and signaling mechanisms, including the PI3K, Akt, NF-κB, Ras, and Nrf2 pathways. These data demonstrate that aloperine is a promising therapeutic candidate. Being a potent modulator of signaling mechanisms, aloperine can be employed in clinical settings to treat various human disorders in the future. Full article

Sophora alopecuroides is known to produce relatively large amounts of alkaloids; however, their ecological consequences remain unclear. In this study, we evaluated the allelopathic potential of the main alkaloids, including aloperine, matrine, oxymatrine, oxysophocarpine, sophocarpine, sophoridine, as well as their mixture both in distilled H₂O and in the soil matrix. Our results revealed that all the alkaloids possessed inhibitory activity on four receiver species, i.e., Amaranthus retroflexus, Medicago sativa, Lolium perenne and Setaria viridis. The strength of the phytotoxicity of the alkaloids was in the following order: sophocarpine > aloperine > mixture > sophoridine > matrine > oxysophocarpine > oxymatrine (in Petri dish assays), and matrine > mixture > sophocarpine > oxymatrine > oxysophocarpine > sophoridine > aloperine (in pot experiments). In addition, the mixture of the alkaloids was found to significantly increase the IAA content, MDA content and POD activity of M. sativa seedlings, whereas CTK content, ABA content, SOD activity and CAT activity of M. sativa seedlings decreased markedly. Our results suggest S. alopecuroides might produce allelopathic alkaloids to improve its competitiveness and thus facilitate the establishment of its dominance; the potential value of these alkaloids as environmentally friendly herbicides is also discussed. Full article

Twenty-seven novel 12N-substituted aloperine derivatives were synthesized and investigated for their inhibitory effects on collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells, taking aloperine (1) as the hit. A structure-activity relationship (SAR) study disclosed that the introduction of suitable substituents on the 12N atom might enhance the activity. Compound 4p exhibited a good promise on down-regulating COL1A1 expression with the IC₅₀ value of 16.5 μM. Its inhibitory activity against COL1A1 was further confirmed on both mRNA and protein levels. Meanwhile, it effectively inhibited the expression of other fibrogenic proteins, such as transforming growth factor β1 (TGF-β1) and smooth muscle actin (α-SMA). It also exhibited good in vivo safety profile with the oral LD₅₀ value of 400 mg kg⁻¹ in mice. The results initiated the anti-liver fibrogenic study of aloperine derivatives, and the key compound 4p was selected as a novel lead for further investigation against liver fibrogenesis. Full article

Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine; we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells. Full article

The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with aloperine treatment. This study suggests the potential therapeutic use of aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Full article