Comprehensive review of Bcl-2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules.

Cancer has a considerably higher fatality rate than other diseases globally and is one of the most lethal and profoundly disruptive ailments. The increasing incidence of cancer among humans is one of the greatest challenges in the field of healthcare. A significant factor in the initiation and progression of tumorigenesis is the dysregulation of physiological processes governing cell death, which results in the survival of cancerous cells. B-cell lymphoma 2 (Bcl-2) family members play important roles in several cancer-related processes. Drug research and development have identified various promising natural compounds that demonstrate potent anticancer effects by specifically targeting Bcl-2 family proteins and their associated signaling pathways. This comprehensive review highlights the substantial roles of Bcl-2 family proteins in regulating apoptosis, including the intricate signaling pathways governing the activity of these proteins, the impact of reactive oxygen species, and the crucial involvement of proteasome degradation and the stress response. Furthermore, this review discusses advances in the exploration and potential therapeutic applications of natural compounds and small molecules targeting Bcl-2 family proteins and thus provides substantial scientific information and therapeutic strategies for cancer management.

Piper retrofractum ameliorates imiquimod-induced skin inflammation via modulation of TLR4 axis and suppression of NF-κB activity.

Chronic inflammation is a significant concern due to its association with various pathological conditions. As a result, extensive research has been conducted to identify new natural products that can effectively treat acute inflammation, which has the potential to inhibit the chronic inflammation. In our study, we aimed to identify Indonesian medicinal plants with the ability to inhibit proinflammatory agents, specifically targeting NF-κB, a crucial regulator of gene transcription involved in the production of proinflammatory proteins/cytokines. Through a series of identification processes, we found that Piper retrofractum (Javanese chili) extract demonstrated promising inhibitory effects on NF-κB and proinflammatory molecules. Further investigation was conducted using a variety of assays, including reporter assay, viability test, ELISA, and Western blotting. The results revealed that the extract significantly reduced LPS, NO, COX-2, IL-6, IL-1, and NF-κB through the TLR4 axis. Notably, Piper retrofractum extract was found to enhance the survival of human keratinocytes by protecting them from cell death induced by TRAIL, a member of the TNF superfamily. Moreover, immunohistochemistry analysis in an Imiquimod-induced skin inflammation mice model showed downregulation of COX-2 and IL-1ß expression upon treatment with the extract. In conclusion, our findings suggest that Piper retrofractum extract possesses anti-inflammatory properties by reducing proinflammatory cytokine production through inhibition of NF-κB signaling pathway. These promising results highlight the potential of Piper retrofractum extract as a candidate for future drug development in the clinical treatment of inflammation-related conditions, offering hope for the advancement of therapeutic interventions.

Ethyl P-Methoxycinnamate: An Active Anti-Metastasis Agent and Chemosensitizer Targeting NFκB from Kaempferia galanga for Melanoma Cells.

The most common type of skin cancer is melanoma. While significant advances in chemotherapy have occurred in a few instances, only marginal progress has been made in treating metastatic melanoma. Natural medicine has traditionally been used to treat various illnesses, including cancer. The purpose of this study was to identify the active compound in Kaempferia galanga, which could be used to treat melanoma as an anti-metastasis and chemosensitizer agent. The active compound in K. galanga was isolated and identified using chromatography and spectroscopy techniques, and given six compounds. Inhibitory activity on NFκB activation and cell viability was determined using reporter assay methods. Among the isolated compounds, ethyl p-methoxycinnamate (EPMC) demonstrated potent NFκB inhibitory activity against melanoma cell B16F10- NFκB Luc2 with an IC50 of 88.7 µM. Further investigation was conducted by evaluating the anti-metastasis effect of EPMC in vitro by using wound-healing assays, invasion tests, and molecular mechanism assays using Western blotting. NFκB has been implicated in tumorigenesis through the PI3K/Akt/NFκB pathway. The results of this study indicated that EPMCs act as inhibitors of p38 and thereby Akt phosphorylation inhibitors at serine 473, inhibiting NFκB-dependent transcription. Further analysis with paclitaxel demonstrated that the combinations could sensitize to apoptosis in response to well-known chemotherapy agents. Additional studies were conducted using the human melanoma cancer cell line SK-Mel 28. Along with the induction of apoptosis, we observed an increase in p-γH2AX expression (a molecular marker for double strand breaks in DNA damage) in response to treatment with paclitaxel and EPMC. The result showed EPMC to be a potential, viable adjuvant for improving the clinical efficacy of anti-metastatic and cancer chemotherapy.

Anti-inflammatory effects of Morus alba Linne bark on the activation of toll-like receptors and imiquimod-induced ear edema in mice.

BACKGROUND: Morus alba L. bark has been widely used in traditional medicine for treating several inflammatory diseases, such as hypertension, diabetes mellitus and coughing; however, the molecular mechanisms underlying its anti-inflammatory effects are not well understood. METHODS: We examined the effects of an extract of Morus alba L. bark (MabE) on Toll-like receptor (TLR) ligand-induced activation of RAW264.7 macrophages using a luciferase reporter assay and immunoassays. For the in vivo experiment, we used an imiquimod-induced ear edema model to examine the anti-inflammatory effects of MabE. RESULTS: MabE inhibited the TLR ligand-induced activation of NF-κB in RAW264.7 cells without affecting their viability. Consistent with the inhibition of NF-κB activation, MabE also inhibited the production of IL-6 and IL-1ß from TLR ligand-treated RAW264.7 cells. In vivo MabE treatment inhibited the ear swelling of IMQ-treated mice, in addition to the mRNA expression of IL-17A, IL-1ß and COX-2. The increases in splenic γδT cells in IMQ-treated mice and the production of IL-17A from splenocytes were significantly inhibited by MabE treatment. CONCLUSION: Our study suggests that the anti-inflammatory effects of MabE on the activation of the macrophage cell line RAW246.7 by TLRs and IMQ-induced ear edema are through the inhibition of NF-κB activation and IL-17A-producing γδT cells, respectively.

Anti­inflammatory compounds moracin O and P from Morus alba Linn. (Sohakuhi) target the NF­κB pathway.

Accumulating evidence suggests that inflammation is linked to multiple pathological processes and induces cellular and molecular damage through the activation of inflammatory signaling pathways, including the NF­κB pathway. The aim of the present study was to identify natural anti­inflammatory products that can target NF­κB activity, in order to establish a novel therapeutic approach for inflammatory diseases. Using a 4T1 breast cancer cell line that expresses the firefly luciferase gene under the control of an NF­κB response element, 112 natural products were tested for their anti­inflammatory properties. Sohakuhi (Morus alba Linn. bark) extract was observed to strongly suppress NF­κB activity without affecting cell viability. To further examine the anti­inflammatory effect of Sohakuhi, tumor necrosis factor­related apoptosis­inducing ligand (TRAIL)­induced cellular damage of human HaCaT keratinocytes was evaluated. While TRAIL triggered the phosphorylation of the p65 subunit of NF­κB, leading to cellular damage in HaCaT cells, treatment with Sohakuhi extract protected HaCaT cells against TRAIL­induced cellular damage. Moreover, Sohakuhi treatment also upregulated the anti­apoptotic proteins Bcl­xL and Bcl­2. Importantly, through chemical fractionation of Sohakuhi extract, moracin O and P were confirmed to mediate its anti­inflammatory effects. Collectively, the present results indicated that Sohakuhi and moracin may represent potential candidates for the development of novel anti­inflammatory drugs.

Anti-inflammatory activities of isopimara-8(9),15-diene diterpenoids and mode of action of kaempulchraols B-D from Kaempferia pulchra rhizomes.

Kaempulchraols B-D (2-4), isopimara-8(9),15-diene diterpenoids isolated from Kaempferia pulchra rhizomes collected in Myanmar, were identified as potent NF-κB inhibitors. These compounds were also effective as NO inhibitory agents, with IC50 values of 47.69, 44.97, and 38.17 µM, respectively, without showing any cytotoxicity against LPS-induced RAW264.7 cells. Investigations of the mechanisms of action of 2-4 revealed that they inhibit the NF-κB-mediated transactivation of a luciferase reporter gene, IL-6 production, and COX-2 expression, with an effective dose of 25 µM. Thus, isopimarane diterpenoids are suggested to be potent inhibitors of NF-κB pathways and could be further explored as potential anti-inflammatory lead compounds.

Anti-inflammatory activities of isopimara-8(14),-15-diene diterpenoids and mode of action of kaempulchraols P and Q from Kaempferia pulchra rhizomes.

Inflammation is an extensively recognized link to many pathological diseases. It is a host response for protection from infections and tissue damage. Infections trigger acute inflammation; however, persistent infection will contribute to chronic inflammation and higher disease susceptibility. Deregulated inflammatory responses can cause excessive or long-lasting tissue damage, manifested as cancer, immune disorders, diabetes, etc. NF-κB is a central mediator of pro-inflammatory gene induction and functions in both innate and adaptive immune cells; therefore, the anti-inflammatory regulation of NF-κB is needed. Natural products reportedly play an important role in controlling the inflammatory response pathways. However, the anti-inflammatory activities of isopimara-8-(14),15-diene diterpenoids have not yet been fully elucidated. To elucidate the anti-inflammatory activities of the isopimara-8(14),15-diene diterpenoids, we investigated 21 isopimara-8(14),15-diene diterpenoids previously isolated from Kaempferia pulchra rhizomes. Eleven compounds exhibited NO inhibitory activity against lipopolysaccharide (LPS)-induced RAW264.7 cells, with IC50 values ranging from 30 to 100 µM. Furthermore, the most potent kaempulchraols P and Q, with IC50 values of 39.88 and 36.05 µM, respectively, inhibited the NF-κB-mediated transactivation of a luciferase reporter gene, IL-6 production, and COX-2 expression, with an effective dose of 25 µM. These findings provide new insights into the anti-inflammatory activities of the isopimara-8(14),15-diene diterpenoids.