Flavonoids

Flavonoids are a large group of plant secondary metabolites, with a common phenyl benzopyrone structure. They are one of the largest groups of secondary metabolites, with over 2,000 naturally occurring compounds. They are classified into two main groups based on the saturation level of the central heterocyclic ring [27]. Unsaturated flavonoids include anthocyanidins, flavones, flavonols, and isoflavones, while saturated flavonoids include flavanones, dihydroflavonols, and flavan-3-ols [28]. Flavonoids are generally found to be conjugated with sugars as glycosides or in ester or polymer forms [29]. The antioxidant capacity of flavonoids is determined by the positioning of the catechol B-ring on the pyran C-ring, as well as the quantity and arrangement of hydroxy groups on the B-ring [30]. Flavonoids originate from two distinct biosynthetic pathways viz; the phenyl propanoid pathway, which is responsible for the phenyl propanoid skeleton, and the polyketide pathway, which generates polymeric building blocks [31]. These compounds offer various therapeutic benefits, such as antioxidant activity, cardiovascular protection, anti-inflammatory effects, neuroprotection, and anti-platelet aggregation [32]. Additionally, flavonoids play a crucial role in cancer prevention by influencing processes such as apoptosis, necrosis, cell cycle arrest, and autophagy [33]. Some selected compounds from this category are discussed below.

Flavonoids are classified into seven subclasses, based on their structural differences. This includes flavanols, flavones, isoflavones, anthocyanidins, flavanones, flavonols, and chalcones [34, 35]. Flavones are characterized by a double bond between C2 and C3 and a ketone group at C4 position. They are commonly found in parsley and celery, with examples like apigenin and luteolin which are known for their anti-inflammatory and anticancer properties [36]. Flavanols have an additional hydroxyl group at C3 and are present in onions, kale, and berries, exhibiting strong antioxidant activities. Examples of this include quercetin and kaempferol [37]. Flavan-3-ols, like catechin and epicatechin, have a hydroxyl group at C3 and are found in green tea and cocoa, noted for their cardiovascular benefits [37]. Anthocyanidins are flavonoids without a ketone group at C4 position. They are responsible for red, blue, and purple pigmentation in plants such as berries and grapes, and include cyanidin and delphinidin, which are well-known for their antioxidant properties [38]. Isoflavanoids, with the B ring attached to C3, are found in soybeans and include genistein and daidzein, beneficial for menopausal symptoms and osteoporosis [39]. Chalcones, with an open-chain structure, are present in apples and strawberries, with examples like phloretin, and are known for their anti-inflammatory and antimicrobial activities [40].

Some selected compounds from this category are discussed below.

Non-flavonoid

Non-flavonoid molecules represent a diverse group of phytochemicals that include phenolic acids, lignans, tannins, and stilbenes, each with unique structural and functional properties. Among these, phenolic acids stand out as the most prevalent category of phytochemicals, characterized by aromatic rings linked to organic acids such as cinnamic and benzoic compounds [81].

Uttroside B

Uttroside B (Utt-B), a saponin abundantly found in the roots, stem, and leaves of Solanum nigrum, has captured attention due to its potent cytotoxic properties against liver cancer cells. In vitro and in vivo studies from our laboratory have demonstrated the anti-HCC potential and pharmacological safety of Utt-B [156]. In a comparative analysis assessing the therapeutic efficacy of Utt-B against sorafenib, an established FDA-approved drug for HCC, Utt-B emerged as a superior anti-cancer agent in in vitro and in vivo experimental settings. Utt-B induced better cleavage of caspase-7 and down-regulation of the cell proliferation markers PCNA and Ki67, compared to sorafenib, resulting in a remarkable reduction in tumor size in mice harboring human HCC [157].

Furthermore, our investigations have revealed that Utt-B possesses the ability to induce pro-survival autophagy in liver cancer cells. This effect is mediated through the inhibition of mTOR signaling and activation of AMPK signaling, both pivotal in regulating autophagy in cancer cells. Interestingly, the inhibition of autophagy by chloroquine, a renowned anti-malarial drug and autophagy inhibitor, not only enhanced the anti-tumor efficacy of Utt-B but also improved the pharmacological safety, in vivo [158]. These findings strongly suggest the potential benefits of repurposing chloroquine in combination with Utt-B for the treatment of HCC, opening a promising avenue for future therapeutic interventions.

Timosaponin A-III

Timosaponin A-III (TSAIII) is a bioactive compound derived from the medicinal plant, Anemarrhena asphodeloides Bunge [159]. TSAIII is a white to off-white solid, soluble in methanol, butanol, 80% ethanol, and aqueous pentanol, but insoluble in water. The pharmacological effects of TSAIII are notably influenced by the sugar chain at the C-3 position. Specifically, the disaccharide form of TSAIII demonstrates greater activity compared to the monosaccharide TSAI, while the trisaccharide TSAV exhibits lower activity [160]. TSAIII exhibits efficacy against cancer development through various modes such as anti-inflammatory and antioxidant effects and inhibition of cell proliferation, induction of cell cycle arrest and apoptosis, initiation of autophagy, suppression of tumor cell migration, invasion, and angiogenesis [159].

TSAIII has been shown to inhibit the expression of various inflammatory mediators, including COX-2 and matrix metalloproteinase-9 (MMP-9) [144], and exert anti-inflammatory effects by inhibiting NF-κB, a key player in the inflammatory response [161]. The compound exhibits remarkable efficacy across various cancer types through the intricate modulation of specific signaling pathways. In pancreatic cancer cells, TSAIII inhibits the PI3K/AKT pathway, leading to G1 phase arrest and apoptosis [162]. TSAIII activates ATM/Chk2- and p38 MAPK-regulated pathways to induce apoptosis in breast cancer cells and triggers mitochondria-mediated apoptosis in HepG2 cells [163]. In glioblastoma multiforme, TSAIII inhibits cell growth by down-regulating the Wnt/β-catenin pathways [164]. Moreover, TSAIII has been reported to modulate autophagy by inhibiting the mTOR/Unc-51-like kinase 1 (ULK1) pathway, promoting autophagosome formation, and compromising tumor cell growth [165]. Furthermore, in NSCLC A549 cells, TSAIII inhibits the ERK1/2, proto oncogene tyrosine protein kinase (Src)/FAK, and β-catenin signaling pathways [166]. These findings underscore the diverse and promising therapeutic potential of TSAIII in targeting specific pathways critical for cancer progression and metastasis [167].

Ginsenoside Rg3

Ginsenoside Rg3, a dammarane-type ginsenoside, abundant in Panax ginseng and Panax japonicus, possesses hydroxy substitutions at the 3β, 12β, and 20 pro-S positions. This compound undergoes transformations, such as the conversion of the 3-position hydroxy group into β-D-glucopyranosyl-β-D-glucopyranoside and the introduction of a double bond at the 24-25 position. It represents one among the more than 100 ginsenosides derived from Panax ginseng, historically revered in East Asia for its natural tonic properties [168]. These ginsenosides, including Rg3, manifest diverse pharmacological activities encompassing hepatoprotection, neuroprotection, cardiovascular protection, immune system enhancement, anti-fatigue properties, and antioxidant properties [169].

By inhibiting nucleotide-binding domain, leucine-rich-domain containing family, pyrin domain containing-3 (NLRP3) inflammasome activation and modulating gut microbiota homeostasis, Rg3 demonstrates efficacy in alleviating ulcerative colitis [170]. Moreover, Rg3 exhibits robust antioxidant and anti-inflammatory activities, validated in inflammation and oxidative stress models [171]. Rg3 extends its protective effects to diverse organs and systems. Rg3 has been reported to attenuate lung inflammation, prevent liver and kidney function damage, mitigate neuroinflammation, and offer protection against cerebral and myocardial ischemia/reperfusion (I/R) injury. Additionally, Rg3 shows promise in improving symptoms associated with hypertension and diabetes [171]. Studies also show that Rg3 directly inhibits LPS-mediated inflammation by targeting TLR4 signaling in macrophages [172]. These collective findings underscore ginsenoside Rg3 as a promising candidate for treating conditions characterized by inflammatory and oxidative stress.

Ginsenoside Rg3 showcases potent anti-cancer effects by targeting multiple signaling pathways across various types of cancer. In nasopharyngeal carcinoma (NPC), Rg3 has been found to sensitize cells to radiation therapy, curb radiation-induced EMT, and promote apoptosis [173]. In lung cancer, Rg3 impedes cell migration, invasion, and angiogenesis by suppressing the expression of COX-2 and VEGF [174]. Similarly, in renal cell carcinoma (RCC), Rg3 restricts cell migration, invasion, colony formation, and tube formation while enhancing apoptosis. These effects are achieved by promoting the demethylation of key genes such as p53, p21, and p16, along with histone acetylation [175]. Similarly, in prostate carcinoma, Rg3 was found to inhibit cell growth via modulation of the MAPK pathway [176].

Paclitaxel

Paclitaxel, a tetracyclic diterpenoid originally derived from the bark of the Pacific yew tree, Taxus brevifolia, emerged as a potent anti-cancer agent following a screening program by the National Cancer Institute in 1960 [190]. This compound, often obtained in needle form using aqueous methanol extraction or as a fine white powder, acts as a mitotic inhibitor in chemotherapy, specifically classified as a microtubule-stabilizing agent, a metabolite, a human metabolite, and an antineoplastic agent [191]. Originally known by the generic name “Taxol”, its usage is now restricted due to its registration as a trademark. Isolated in 1971, it was discovered that endophytic fungi within Taxus species were responsible for its synthesis [192]. Administered intravenously for cancer treatment, paclitaxel is available in various formulations, such as abraxane, which features albumin-bound paclitaxel [193]. With a melting point in the range of 415°F to 421°F, paclitaxel gained approval by the US FDA 21 years after its discovery, initially for ovarian cancer and subsequently for breast cancer, solidifying its status as a highly effective anti-cancer agent [194].

Paclitaxel is renowned for its anti-inflammatory properties. In vitro studies reveal its ability to inhibit the activities of key enzymes involved in inflammation, namely COX-1, COX-2, and 5-LOX [195]. Paclitaxel has been reported to suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and promote the synthesis of anti-inflammatory cytokines like IL-10 [196]. In vivo studies show that paclitaxel treatment reduces the levels of inflammatory mediators such as inducible NO synthase (iNOS) and COX-2 [197]. These findings suggest that paclitaxel has the potential to suppress inflammation and may be beneficial in the treatment of inflammatory conditions.

Paclitaxel exerts significant anti-cancer effects through multiple mechanisms, including the induction of apoptosis, inhibition of cell proliferation, and suppression of angiogenesis. This compound interacts with diverse molecular targets implicated in cancer progression, encompassing regulators of the cell cycle, signaling pathways, and DNA repair mechanisms [198].

Studies conducted by our group have revealed interesting findings regarding the enhancement of the therapeutic efficacy of paclitaxel when combined with curcumin [135]. Pre-treatment with curcumin synergistically decreased tumor incidence and tumor volume in animals, exceeding the effects observed with either paclitaxel or curcumin alone. Interestingly, curcumin alone did not exhibit significant effects at the same concentration [135]. Another study from our lab reported that AKT functions upstream of NF-κB in the signaling cascade triggered by paclitaxel and that complete inhibition of NF-κB abolishes the synergistic effect between paclitaxel and curcumin [199].

Paclitaxel modulates critical pathways involved in breast cancer, including PI3K/AKT signaling, the Hippo pathway, microtubule stabilization, and DNA methylation, thereby influencing cell proliferation, apoptosis, and drug resistance. Paclitaxel has been reported to inhibit the PI3K/AKT/mTOR pathway in liver cancer, leading to reduced cell proliferation and migration alongside enhanced apoptosis [200]. Similar studies in colon cancer cells revealed that paclitaxel induces apoptosis by suppressing signaling pathways such as Janus kinases (JAKs)/STAT3 and PI3K/AKT/mTOR [201].

Ursolic acid

Ursolic acid (UA), a pentacyclic triterpenoid derived from various medicinal plants, exhibits notable pharmacological properties encompassing anti-inflammatory, antioxidant, antiapoptotic, and anticarcinogenic effects [202]. This compound is widely distributed across a range of botanical sources, including orchard apple, pomegranate, marjoram leaves, oregano leaves, rosemary, sage, thyme, lavender, eucalyptus leaves, black elder, hawthorn, coffee leaves, and the wax layer of various edible fruits [203].

UA has been shown to exhibit promising anti-inflammatory properties, particularly in treating skin conditions like eczema, psoriasis, and dermatitis [204]. Studies indicate that UA and its derivatives possess robust anti-inflammatory effects, capable of suppressing the production of inflammatory mediators [205]. Moreover, UA interferes with multiple inflammation-related signaling pathways, positioning it as a potential therapeutic option for inflammatory diseases [206].

Furthermore, UA has been reported to inhibit NF-κB-mediated inflammatory pathways and enhance ROS-scavenging, elucidating the key mechanisms underlying its anti-inflammatory effects [207]. These findings highlight UA as a promising candidate for combating inflammation and suggest its potential in therapeutic interventions targeting inflammatory disorders.

UA has garnered considerable attention in research owing to its capacity to suppress the production of proinflammatory cytokines and its remarkable efficacy in combating various types of cancer. Studies show that UA not only inhibits cell viability and migration but also influences autophagy, apoptosis, and cell cycle progression. It is able to induce apoptotic effects, premature senescence, and even reverse paclitaxel resistance [208].

UA has been found to initiate pro-apoptotic signaling and disrupt mitochondrial function, leading to the activation of caspases 3, 8, and 9 in liver and gastric cancer. Moreover, in gastric cancer, UA targets the Hippo pathway, exhibiting inhibitory effects on tumor growth and promoting apoptosis [209]. In CRC, UA was found to inhibit cellular proliferation and induce apoptosis through modulation of signaling pathways crucial for cell cycle regulation and apoptosis [210]. UA also exhibits apoptotic activity against NSCLC by down-regulating the JAK2/STAT3 pathway and suppressing the expression of VEGF and PD-L1, thereby inhibiting tumor angiogenesis, migration, invasion, and metastasis [57]. Similarly, studies in skin cancer indicate that UA activates peroxisome proliferator-activated receptor α (PPARα) and AMPK and induces apoptosis in mouse squamous cell carcinoma and skin papilloma [211].

Cucurbitacin B

Cucurbitacin B (CuB) is a tetracyclic triterpenoid commonly found in glycosidic forms [212]. It possesses a distinctive structural framework identified as 19-(10→9β)-abeo-10α-lanost-5-ene, characterized by high unsaturation and multiple ketone groups [213]. The cytotoxicity of CuB is believed to be linked to the presence of a 25-acetoxy group, although studies indicate that saturating the conjugated 23(24) double bond may mitigate this effect [214]. Cus B, I, and E, among others, demonstrate promise in inhibiting selected types of cancer including breast, hepatocellular, laryngeal, lung, melanoma, pancreatic, and prostate cancers [215].

Remarkable anti-inflammatory properties of CuB are reflected in its ability to modulate various pivotal regulators of signaling pathways, including JAK/STAT3, Nrf2/antioxidant response element (ARE), NF-κB, AMPK, MAPK, PI3K/AKT, cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A), Wnt, FAK, Notch, and Hippo-YAP [216]. Additionally, CuB holds promise for attenuating cerebral I/R injury by inhibiting inflammation mediated by the NLRP3 inflammasome and reducing oxidative stress [217]. Moreover, Cus B, E, and I demonstrate anti-platelet and anti-thrombotic effects by disrupting cytoskeletal dynamics and integrin function [218]. CuB has been reported to down-regulate TNF receptor 1 (TNF-R1), leading to inhibition of expression of the intracellular adhesion molecule-1 (ICAM-1) and suppression of the NF-κB signaling pathway, thereby attenuating inflammatory processes [219]. These multifaceted actions highlight CuB as a promising candidate for therapeutic interventions by targeting inflammation-related disorders and ischemic injuries.

CuB exhibits potential as an anti-cancer agent across various types of cancer. In pancreatic cancer, CuB induces apoptosis both in vitro and in vivo, highlighting its role in cancer immunotherapy through inhibition of the JAK/STAT3 pathway [220]. Furthermore, the diverse anticancer effects of CuB include the reduction of tumor invasiveness, suppression of metastasis-promoting genes, and inhibition of proliferation, invasion, and migration of tumor cells. Many of these effects reflect the ability of CuB to target the EGFR/STAT3/AKT signaling pathway and inhibit the EMT, ultimately inducing apoptosis and obstruction of the critical STAT3-regulated signaling pathways [221].

CuB exhibits promising antitumor effects across various cancer types through distinct mechanisms. In liver CSCs, CuB has been reported to inhibit the JAK2/STAT3 signaling pathway, targeting a crucial pathway involved in cancer stemness [222]. Moreover, CuB demonstrates significant therapeutic potential in NSCLC by inhibiting DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), highlighting its role in epigenetic regulation and cancer cell modulation [223].

Interestingly, in vivo studies conducted in our laboratory demonstrated the effectiveness of CuB in attenuating tumor growth in a NOD-SCID murine model of human melanoma through the inhibition of MEK1/2 and ERK1/2 signaling pathways. Our study also confirmed the pharmacological safety of the compound in Swiss albino mice [224].

Tryptanthrin

Tryptanthrin (indolo[2,1-b]quinazolin-6,12-dione) is an alkaloid possessing an indolo[2,1-b]quinazoline core with various pharmacological properties, including anti-tumor, anti-inflammatory, and anti-bacterial activities. The name tryptanthrin originated from the fact that it was initially isolated from Candida lipolytica, a type of bacteria that grows primarily on L-tryptophan [237]. In addition to Candida lipolytica, other sources of tryptanthrin include fungi like Schizophyllum commune and Leucopaxillus cerealis, as well as plants like Couroupita guianensis, Wrightia tinctoria, Strobilanthes cusia, Polygonum tinctorium, and Isatis tinctoria [238–243].

Tryptanthrin exhibits remarkable anti-inflammatory properties across a spectrum of conditions. In LPS-treated BV-2 microglia cells, tryptanthrin has been found to reduce pro-inflammatory cytokine levels through modulating NF-κB and Nrf2/heme oxygenase-1 (HO-1) pathways, effectively mitigating inflammation in a mouse model of edema [244, 245]. Studies indicate that tryptanthrin alleviates rheumatoid arthritis by reducing proinflammatory cytokine expression and collagen-induced arthritis by down-regulating MMP-3 and IL-6 [246]. The wound healing efficacy of tryptanthrin has been demonstrated in a mouse excisional wound model, where tryptanthrin accelerated the wound healing response by lowering VEGF and MMP-9 levels [247].

Tryptanthrin ameliorates psoriasis by modulating the levels and activity of inflammatory mediators that target T helper 17 (Th17). These include IL-6, IL-8, S100A9 peptide, C-C motif chemokine ligand 20 (CCL20) chemokine, TNF-α, and IL-1β [248]. Furthermore, tryptanthrin displays promising results against neuroinflammation by reducing the levels of pro-inflammatory cytokines, iNOS, and COX-2 levels in LPS-induced neuroinflammation through inhibition of the TLR4-myeloid differentiation primary response gene 88 (MyD88)- and NF-κB-dependent pathways [249]. It is suggested that tryptanthrin guards the liver tissue by down-regulating apoptotic processes, lowering inflammatory cell infiltration, and stimulating the AMPK and p38 pathways [250].

Tryptanthrin has been found to boost anti-inflammatory factors and reduce pro-inflammatory markers in HMC-1 cells triggered by atopic dermatitis [251]. It also diminishes leukotriene production, modulates the subcellular localization of 5-LOX, and decreases the levels of its products, thereby alleviating inflammation in pleurisy [252]. Moreover, tryptanthrin significantly mitigates inflammation in dextran sodium sulfate-induced colitis, ensuring 100% survival in treated animals [242].

Tryptanthrin demonstrates potent anti-tumor actions by altering the levels of key proteins involved in cell growth and survival while inducing cell cycle arrest, apoptosis, and autophagy in cancer cells. Additionally, it has been shown to modulate the inflammatory tumor microenvironment, further contributing to its anti-tumor effects [253].

In vitro studies using MCF-7 cells have revealed that tryptanthrin inhibits cell proliferation, migration, and invasion while up-regulating E-cadherin and down-regulating MMP-2 and SNAIL [254]. Another derivative of tryptanthrin, termed benzo[b]tryptanthrin, exhibits potent inhibitory activity against multidrug resistance protein 1 (MDR1) in adriamycin-resistant breast cancer cells [255]. By activating p53 and controlling the TRAIL/death receptors (DRs) pathway, tryptanthrin induces apoptosis in lung cancer cells [256]. Tryptanthrin has been shown to have potent anti-tumor effects against HCC cells, causing S-phase arrest by down-regulating cyclin A1, B1, CDK2, and p-Cdc2, and inducing caspase-dependent apoptosis. It also regulates signaling targets and protects liver cells from oxidative injury [253]. Studies using the human chronic myeloid leukemia cell line K562 suggest that tryptanthrin inhibits the proliferation of leukemia cells and induces apoptosis in these cells through the up-regulation of cytosolic cytochrome-c, BAX, and activated caspase-3 while down-regulating Bcl-2, mitochondrial cytochrome-c, and pro-caspase-3 [257].

Studies from our laboratory have revealed that tryptanthrin from Wrightia tinctoria exhibits potent anti-tumor activity against malignant melanoma (A375) cells by targeting key molecules including BRAF, Wnt/β-catenin, AKT, and NF-κB pathways that converge on MITF-M. Furthermore, through preclinical investigations, we have demonstrated that tryptanthrin significantly reduces malignant melanoma growth in mice insert [258]. Additionally, our research has extended to explore the anti-tumor effects of tryptanthrin on non-melanoma skin cancer (NMSC) in mouse models. Here, we observed that tryptanthrin inhibits NMSC by inactivating ERK1/2 and p38 regulated pathways, resulting in the suppression of c-Myc and cyclin-D1 expression while promoting β-catenin activity [259].

Cepharanthine

Cepharanthine, derived from Stephania tubers, exhibits a variety of pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, antitumoral, and antiviral activities [260]. Its interaction with the voltage-dependent anion channel (VDAC) results in voltage-independent channel narrowing, leading to dose-dependent cytotoxicity by altering transport between mitochondria and cytoplasm [261]. Cepharanthine boosts apoptosis in glioma and neuronal cells via ROS and alters mitochondria-to-cytoplasm transport, showcasing diverse medicinal properties, including pathway inhibition, immunomodulation, and antiviral activity against SARS-CoV-2, with over 70 years of clinical use [262]. Additionally, cepharanthine shows promise in treating HCC and alleviating ulcerative colitis by modulating the levels of pro-inflammatory cytokines as well as the gut microbiota [263, 264]. Additionally, cepharanthine has been reported to hinder the release of pro-inflammatory cytokines and the expression of aconitate decarboxylase 1 (ACOD1) in macrophages, reducing macrophage infiltration and ACOD1 levels in colon tissue [265]. Furthermore, cepharanthine diminishes the viability and promotes apoptosis of myofibroblasts while suppressing the expression of myofibroblast markers. These findings suggest that cepharanthine holds promise as an anti-inflammatory agent for a range of diseases [34].

Cepharanthine also exhibits potent anti-cancer effects against a range of cancers, including HCC, CRC, leukemia, ovarian cancer, and gastric cancer [266]. Its mechanism of action involves the induction of apoptosis, reduction of cell viability, and modulation of critical signaling pathways implicated in cancer progression. Some of its targets within cells include the Bcl-2 family proteins, PARP cleavage, ERK, STAT3, and AKT. The efficacy of cepharanthine extends to both p53 wild-type and mutant cancer cells, suggesting potential utility in treating CRC harboring mutant p53, often resistant to conventional chemotherapy [260]. In liver cancer, cepharanthine was found to inhibit cellular proliferation and invasion, promote apoptosis, and suppress the hedgehog/glioma associated oncogene homolog 1 (Gli1) and Wnt/β-catenin signaling pathways [267]. Additionally, it is cytotoxic to NSCLC cells through the induction of apoptosis, generation of ROS, and modulation of STAT3, PI3K/AKT, and MAPK/ERK signaling pathways [266].

Oxysophocarpine

Oxysophocarpine (OSP) serves as a prominent quinolizidine natural alkaloid present in leguminous plants such as Sophora viciifolia Hance [268], Sophora alopecuroides [269], Sophora flavescens Ait [270], and other species within the Robinia genus [271]. It is a constituent of traditional Chinese medicine, notably found in compound Kushen injection (CKI), utilized for various ailments, including several types of cancer [272]. OSP demonstrates diverse pharmacological properties, including analgesic effects, anti-inflammatory activity, antitumor properties, neuroprotective effects, and antiviral activity [268, 273–275].

OSP demonstrates remarkable anti-inflammatory effects across various disease models. It effectively attenuates inflammation by inhibiting neutrophil recruitment to lesions and reducing levels of key pro-inflammatory cytokines and chemokines, including TNF-α, IL-1β, IL-6, macrophage inflammatory protein 2 (MIP-2), granulocyte colony stimulating factor (G-CSF), and KC, in tuberculosis-associated inflammation [272]. Moreover, it mitigates inflammation in ulcerative colitis by targeting oxidative stress-related factors such as PGE2, myeloperoxidase (MPO), and superoxide dismutase (SOD), along with inflammation-associated factors like IL-6, TNF-α, and IL-1β. These effects are mediated through TNF-R-associated factor 6 (TRAF6) down-regulation and NF-κB phosphorylation [268]. In neuronal inflammation, OSP was found to modulate the expression of inflammatory markers including TNF-α, IL-1β, pERK1/2, p-JNK1/2, and p-p38 MAPK [273]. It also reduces carrageenan-induced inflammation in mice by targeting the ERK1/2-COX-2-PGE2 signaling pathway, leading to neutrophil removal and reduced pain perception, further highlighting its broad anti-inflammatory actions. Sophocarpine has been found to alleviate inflammation induced by various agents (e.g., hot plate and xylene) in mice by down-regulating proinflammatory cytokines such as IL-1β, IL-6, and PGE2, and by lowering serum NO levels [276]. Moreover, OSP significantly reduces inflammation in BV-2 microglia under conditions of oxygen-glucose deprivation/reperfusion (OGD/R) by decreasing the expression levels of COX-2, NO synthase, and various inflammatory mediators, while also preventing microglial cell apoptosis [277].

Studies in HCC cell lines, including HepG2 and Hepa1-6, suggest that OSP inhibits cell proliferation and migration while promoting apoptosis. Additionally, it enhances the responsiveness of HCC cells to CD8+ T-cell immunotherapy by modulating IL-6-mediated JAK2/STAT3 signaling [278]. It also acts as an anti-tumor agent against oral squamous cell carcinoma by suppressing cell proliferation and metastasis, mediated by the down-regulation of Nrf2 and the HO gene [279].

Berberine

Berberine is an isoquinoline quaternary alkaloid (or a 5,6-dihydrodibenzo[a,g]quinolizinium derivative) extracted from various medicinal plants such as Hydrastis canadensis, Berberis aristata, Coptis chinensis, Coptis rhizome, Coptis japonica, Phellodendron amurense, and Phellodendron chinense Schneid [280]. Traditionally, it has been utilized as an antidiarrheal, antibacterial, antifungal, and antiprotozoal agent [281]. However, recent studies have highlighted its potential benefits in treating neurodegenerative diseases, primarily due to its strong antioxidant properties. Berberine, an isoquinoline alkaloid, is found in multiple plants, including species from the Coptis and Berberis genera [282].

Berberine induces apoptosis in cancer cells by activating various pathways, such as caspase-mediated pathways, mitochondrial pathways, and PI3K/AKT signaling inhibition. It can inhibit the proliferation of cancer cells by affecting cell cycle progression, particularly by arresting cells in the G1 or G2/M phases. Berberine has been reported to inhibit angiogenesis, the process by which new blood vessels are formed to supply nutrients to tumors, thereby suppressing tumor growth [283].

Berberine also exhibits potent anti-inflammatory effects, which are crucial in cancer therapy and other inflammatory conditions. Berberine can suppress the production and release of pro-inflammatory cytokines and mediators, such as TNF-α, IL-6, and COX-2. It inhibits the activation of NF-κB, a key transcription factor involved in the regulation of inflammatory responses, and can modulate immune responses, activating anti-inflammatory pathways and regulating inflammatory cascades [283].

Evodiamine

Evodiamine is a quinolone alkaloid with a tetracyclic structure containing both indole and quinazoline ring systems. Its molecular structure includes hydroxyl, methoxy, and carbonyl groups, contributing to its pharmacological activities [284]. It is the primary component extracted from the fruit of Evodia rutaecarpa. It has been demonstrated to have multiple biological effects, such as stimulating testosterone and catecholamine secretion while exhibiting antinociceptive, anti-inflammatory, anti-obesity, vasodilatory, thermoregulatory, and uterotonic properties [285]. Nanocarriers can potentially increase the therapeutic efficacy of evodiamine in cancer therapy while minimizing adverse effects. Numerous studies have focused on developing smart nanocarriers to overcome evodiamine’s limitations [286].

Evodiamine has been demonstrated to have significant anti-tumor properties by inhibiting the proliferation of various cancer cell lines, including cervical, colon, lung, melanoma, leukemic T-lymphocyte, prostate, and breast cancer cells. One key mechanism involves arresting cell cycle progression at the G2/M phase through the activation of Cdc2/cyclin B. Additionally, evodiamine induces apoptosis in tumor cells through multiple pathways. The PI3K/AKT and ERK signaling pathways play crucial roles in the apoptotic response of tumor cells to evodiamine [287].

Evodiamine induces apoptosis by modulating NF-κB activation, which inhibits NF-κB-regulated gene products such as cyclin D1, X linked inhibitor of apoptosis protein (XIAP), Bcl-2, and Bcl-Xl. Other studies have shown that evodiamine increases the expression of the apoptosis inducer, BAX, and decreases the expression of the apoptosis suppressor, Bcl-2, thereby inducing apoptosis via the caspase pathway. ROS and NO generation also regulate p53, p21, protein tyrosine kinases (PTK), and other signaling proteins involved in evodiamine-induced apoptosis [288].

Limitations of phytochemicals

Phytochemicals, despite their significant anticancer potential and therapeutic benefits, face several limitations that hinder their widespread clinical application. Some of the limitations include poor bioavailability, solubility, hydrophobicity, and restricted therapeutic potential, leading to reduced efficacy [302]. Apart from these, obstacles such as toxicity, high production cost, inadequate availability of raw materials, and ineffective regulatory system impede further barriers to the commercial utilization of plant-based bioactive compounds [303].

Even modern drug delivery systems, including nano drug delivery systems, encounter several limitations despite their promising advantages. A few of the challenges include limited solubility, stability of the natural products when administrated orally, short durations of effectiveness, non-specific targeting that hinders the potential of the system, and poor bioavailability. Apart from these, issues like poor patient compliance, dermal discomfort, and pain associated with parenteral routes further restrict the efficacy of protein based drug delivery systems [304].

Even though nanotechnology offers solutions to improve the pharmacological and therapeutic qualities of conventional medicines, strict regulatory standards are necessary to address drawbacks and ensure the safe and effective delivery of drugs at the cellular levels. Despite these limitations, ongoing advancements in phytochemical and nano drug delivery systems continue to demonstrate promising strategies to overcome challenges and transform the field of medicine [305].